TWI378795B - Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis - Google Patents
Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis Download PDFInfo
- Publication number
- TWI378795B TWI378795B TW093111920A TW93111920A TWI378795B TW I378795 B TWI378795 B TW I378795B TW 093111920 A TW093111920 A TW 093111920A TW 93111920 A TW93111920 A TW 93111920A TW I378795 B TWI378795 B TW I378795B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- receptor
- synthetic
- treatment
- amino
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims description 94
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 46
- 201000010099 disease Diseases 0.000 title claims description 45
- 230000004663 cell proliferation Effects 0.000 title claims description 21
- 230000033115 angiogenesis Effects 0.000 title claims description 18
- 206010035226 Plasma cell myeloma Diseases 0.000 title claims description 15
- 230000006907 apoptotic process Effects 0.000 title description 6
- 238000013508 migration Methods 0.000 title description 2
- 230000012292 cell migration Effects 0.000 title 1
- 201000000050 myeloid neoplasm Diseases 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 137
- 206010028980 Neoplasm Diseases 0.000 claims description 97
- 239000003814 drug Substances 0.000 claims description 63
- 239000002464 receptor antagonist Substances 0.000 claims description 59
- 229940044551 receptor antagonist Drugs 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 54
- 201000011510 cancer Diseases 0.000 claims description 52
- 239000002246 antineoplastic agent Substances 0.000 claims description 50
- 229940127089 cytotoxic agent Drugs 0.000 claims description 44
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 claims description 39
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 claims description 39
- 229940124597 therapeutic agent Drugs 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 21
- 201000006491 bone marrow cancer Diseases 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 15
- 208000034578 Multiple myelomas Diseases 0.000 claims description 14
- 230000033001 locomotion Effects 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 102000001253 Protein Kinase Human genes 0.000 claims description 8
- 230000001613 neoplastic effect Effects 0.000 claims description 8
- 108060006633 protein kinase Proteins 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 150000003246 quinazolines Chemical class 0.000 claims description 7
- 206010005949 Bone cancer Diseases 0.000 claims description 6
- 208000018084 Bone neoplasm Diseases 0.000 claims description 6
- HUBFZPNTUUCCMJ-UHFFFAOYSA-N CCOS(=O)=O Chemical compound CCOS(=O)=O HUBFZPNTUUCCMJ-UHFFFAOYSA-N 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 5
- 208000025113 myeloid leukemia Diseases 0.000 claims description 5
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 4
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 230000009087 cell motility Effects 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 206010006007 bone sarcoma Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 208000006178 malignant mesothelioma Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 239000007943 implant Substances 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 206010062717 Increased upper airway secretion Diseases 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 206010038923 Retinopathy Diseases 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 claims 1
- 208000026435 phlegm Diseases 0.000 claims 1
- 150000003385 sodium Chemical class 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 108010002164 tyrosine receptor Proteins 0.000 claims 1
- 239000005557 antagonist Substances 0.000 description 92
- 239000003112 inhibitor Substances 0.000 description 67
- -1 2 and 3 Chemical compound 0.000 description 59
- 210000004027 cell Anatomy 0.000 description 52
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 49
- 101800003838 Epidermal growth factor Proteins 0.000 description 48
- 102400001368 Epidermal growth factor Human genes 0.000 description 48
- 229940116977 epidermal growth factor Drugs 0.000 description 47
- 108020003175 receptors Proteins 0.000 description 41
- 102000005962 receptors Human genes 0.000 description 40
- 238000001959 radiotherapy Methods 0.000 description 36
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 34
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 34
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 28
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 28
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 27
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 27
- 239000002207 metabolite Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- 150000003431 steroids Chemical class 0.000 description 26
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 25
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 25
- 108091008605 VEGF receptors Proteins 0.000 description 25
- 230000005764 inhibitory process Effects 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 23
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 23
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 23
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 23
- 101150038994 PDGFRA gene Proteins 0.000 description 22
- 238000002648 combination therapy Methods 0.000 description 22
- 238000011363 radioimmunotherapy Methods 0.000 description 22
- 150000003384 small molecules Chemical class 0.000 description 22
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 20
- 102000009076 src-Family Kinases Human genes 0.000 description 20
- 108010087686 src-Family Kinases Proteins 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 19
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 18
- 230000005855 radiation Effects 0.000 description 17
- 108060006698 EGF receptor Proteins 0.000 description 16
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 16
- 239000003102 growth factor Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 15
- 230000004913 activation Effects 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 102000001301 EGF receptor Human genes 0.000 description 14
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 14
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 14
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 12
- 108090000695 Cytokines Proteins 0.000 description 12
- 102000004889 Interleukin-6 Human genes 0.000 description 12
- 108090001005 Interleukin-6 Proteins 0.000 description 12
- 206010061535 Ovarian neoplasm Diseases 0.000 description 12
- 206010060862 Prostate cancer Diseases 0.000 description 12
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 12
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 12
- 230000003054 hormonal effect Effects 0.000 description 12
- 229940100601 interleukin-6 Drugs 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 230000004614 tumor growth Effects 0.000 description 12
- 206010033128 Ovarian cancer Diseases 0.000 description 11
- 229960003957 dexamethasone Drugs 0.000 description 11
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 10
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 10
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 108020004707 nucleic acids Proteins 0.000 description 10
- 102000039446 nucleic acids Human genes 0.000 description 10
- 150000007523 nucleic acids Chemical class 0.000 description 10
- 230000028327 secretion Effects 0.000 description 10
- 241000894007 species Species 0.000 description 10
- 102000016736 Cyclin Human genes 0.000 description 9
- 108050006400 Cyclin Proteins 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 9
- 210000000988 bone and bone Anatomy 0.000 description 9
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 102000006495 integrins Human genes 0.000 description 9
- 108010044426 integrins Proteins 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 9
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 8
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 229960002584 gefitinib Drugs 0.000 description 8
- 229960004961 mechlorethamine Drugs 0.000 description 8
- 230000009401 metastasis Effects 0.000 description 8
- 229960004857 mitomycin Drugs 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 108091054455 MAP kinase family Proteins 0.000 description 7
- 102000043136 MAP kinase family Human genes 0.000 description 7
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 7
- 108091034117 Oligonucleotide Proteins 0.000 description 7
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 206010036790 Productive cough Diseases 0.000 description 7
- 206010041067 Small cell lung cancer Diseases 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000011262 co‐therapy Methods 0.000 description 7
- 229960004679 doxorubicin Drugs 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- 208000000587 small cell lung carcinoma Diseases 0.000 description 7
- 208000024794 sputum Diseases 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 7
- 108010006654 Bleomycin Proteins 0.000 description 6
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 6
- 229930192392 Mitomycin Natural products 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 108700020796 Oncogene Proteins 0.000 description 6
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 6
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 229960001220 amsacrine Drugs 0.000 description 6
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 6
- 229940045799 anthracyclines and related substance Drugs 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 230000000340 anti-metabolite Effects 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 229940100197 antimetabolite Drugs 0.000 description 6
- 239000002256 antimetabolite Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 229960001561 bleomycin Drugs 0.000 description 6
- 229960004562 carboplatin Drugs 0.000 description 6
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 6
- 230000009977 dual effect Effects 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 229940088597 hormone Drugs 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 6
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 6
- IDBIFFKSXLYUOT-UHFFFAOYSA-N netropsin Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)CN=C(N)N)=CN1C IDBIFFKSXLYUOT-UHFFFAOYSA-N 0.000 description 6
- 150000003058 platinum compounds Chemical class 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 210000003802 sputum Anatomy 0.000 description 6
- 229960001052 streptozocin Drugs 0.000 description 6
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 229960000303 topotecan Drugs 0.000 description 6
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical class C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 5
- 102000003915 DNA Topoisomerases Human genes 0.000 description 5
- 108090000323 DNA Topoisomerases Proteins 0.000 description 5
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 5
- 108010092160 Dactinomycin Proteins 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 108010000817 Leuprolide Proteins 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 241000699660 Mus musculus Species 0.000 description 5
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 230000001772 anti-angiogenic effect Effects 0.000 description 5
- 238000004166 bioassay Methods 0.000 description 5
- TZSMWSKOPZEMAJ-UHFFFAOYSA-N bis[(2-methoxyphenyl)methyl] carbonate Chemical compound COC1=CC=CC=C1COC(=O)OCC1=CC=CC=C1OC TZSMWSKOPZEMAJ-UHFFFAOYSA-N 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 229960001433 erlotinib Drugs 0.000 description 5
- GBTRMNJQEKCYRN-UHFFFAOYSA-N fluoren-2-one Chemical compound C1=CC=CC2=CC3=CC(=O)C=CC3=C21 GBTRMNJQEKCYRN-UHFFFAOYSA-N 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 5
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 5
- 229960004338 leuprorelin Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 230000003076 paracrine Effects 0.000 description 5
- 230000002215 photochemotherapeutic effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 5
- 229950003647 semaxanib Drugs 0.000 description 5
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 5
- 230000002195 synergetic effect Effects 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- 238000013519 translation Methods 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 5
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- OEWYWFJWBZNJJG-UHFFFAOYSA-N 1-(aziridin-1-yl)-3-(2-nitroimidazol-1-yl)propan-2-ol Chemical compound C1=CN=C([N+]([O-])=O)N1CC(O)CN1CC1 OEWYWFJWBZNJJG-UHFFFAOYSA-N 0.000 description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 4
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 4
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N 3-[2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 4
- SYYMNUFXRFAELA-BTQNPOSSSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol;hydrobromide Chemical compound Br.N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 SYYMNUFXRFAELA-BTQNPOSSSA-N 0.000 description 4
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 4
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 4
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 4
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- 108010077544 Chromatin Proteins 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 4
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 4
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 4
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 4
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- 230000000970 DNA cross-linking effect Effects 0.000 description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 4
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 4
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 4
- 102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000002927 anti-mitotic effect Effects 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 4
- 229960001467 bortezomib Drugs 0.000 description 4
- 229940127093 camptothecin Drugs 0.000 description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
- 229960004117 capecitabine Drugs 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 210000003483 chromatin Anatomy 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 238000003501 co-culture Methods 0.000 description 4
- 239000003431 cross linking reagent Substances 0.000 description 4
- 229960000684 cytarabine Drugs 0.000 description 4
- 231100000599 cytotoxic agent Toxicity 0.000 description 4
- 239000002619 cytotoxin Substances 0.000 description 4
- 230000002354 daily effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 4
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 4
- 229940126864 fibroblast growth factor Drugs 0.000 description 4
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 4
- 229940022353 herceptin Drugs 0.000 description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
- 229960002411 imatinib Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229940084651 iressa Drugs 0.000 description 4
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 4
- 229960001929 meloxicam Drugs 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- 229960001924 melphalan Drugs 0.000 description 4
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- OYKBQNOPCSXWBL-SNAWJCMRSA-N n-hydroxy-3-[(e)-3-(hydroxyamino)-3-oxoprop-1-enyl]benzamide Chemical compound ONC(=O)\C=C\C1=CC=CC(C(=O)NO)=C1 OYKBQNOPCSXWBL-SNAWJCMRSA-N 0.000 description 4
- 229950008835 neratinib Drugs 0.000 description 4
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 4
- 229960003171 plicamycin Drugs 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- 229910052761 rare earth metal Inorganic materials 0.000 description 4
- 150000002910 rare earth metals Chemical class 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- OSQUFVVXNRMSHL-LTHRDKTGSA-M sodium;3-[(2z)-2-[(e)-4-(1,3-dibutyl-4,6-dioxo-2-sulfanylidene-1,3-diazinan-5-ylidene)but-2-enylidene]-1,3-benzoxazol-3-yl]propane-1-sulfonate Chemical compound [Na+].O=C1N(CCCC)C(=S)N(CCCC)C(=O)C1=C\C=C\C=C/1N(CCCS([O-])(=O)=O)C2=CC=CC=C2O\1 OSQUFVVXNRMSHL-LTHRDKTGSA-M 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229940120982 tarceva Drugs 0.000 description 4
- 229940063683 taxotere Drugs 0.000 description 4
- 229960003433 thalidomide Drugs 0.000 description 4
- 230000005747 tumor angiogenesis Effects 0.000 description 4
- 229950000578 vatalanib Drugs 0.000 description 4
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 4
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 4
- 229960003048 vinblastine Drugs 0.000 description 4
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 4
- 229960000237 vorinostat Drugs 0.000 description 4
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 3
- BWDQBBCUWLSASG-MDZDMXLPSA-N (e)-n-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1h-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 description 3
- ZZVDXRCAGGQFAK-UHFFFAOYSA-N 2h-oxazaphosphinine Chemical compound N1OC=CC=P1 ZZVDXRCAGGQFAK-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 3
- MMURVNDSFNJHAM-OWOJBTEDSA-N 4-[(e)-2-(4-carbamimidoylphenyl)ethenyl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1\C=C\C1=CC=C(C(N)=N)C=C1 MMURVNDSFNJHAM-OWOJBTEDSA-N 0.000 description 3
- CTNPALGJUAXMMC-PMFHANACSA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-n-[(2s)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound C([C@@H](O)CNC(=O)C=1C(C)=C(\C=C/2C3=CC(F)=CC=C3NC\2=O)NC=1C)N1CCOCC1 CTNPALGJUAXMMC-PMFHANACSA-N 0.000 description 3
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 229960005532 CC-1065 Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 3
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 3
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 3
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 3
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 3
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 3
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 3
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 3
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 3
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 3
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 3
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229940122558 EGFR antagonist Drugs 0.000 description 3
- 206010014733 Endometrial cancer Diseases 0.000 description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 102000009465 Growth Factor Receptors Human genes 0.000 description 3
- 108010009202 Growth Factor Receptors Proteins 0.000 description 3
- 101710113864 Heat shock protein 90 Proteins 0.000 description 3
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 3
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 3
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 3
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 3
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 3
- 101001019117 Homo sapiens Mediator of RNA polymerase II transcription subunit 23 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 3
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- 102100034771 Mediator of RNA polymerase II transcription subunit 23 Human genes 0.000 description 3
- 244000294411 Mirabilis expansa Species 0.000 description 3
- 235000015429 Mirabilis expansa Nutrition 0.000 description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- 108010042309 Netropsin Proteins 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 229930187135 Olivomycin Natural products 0.000 description 3
- 102000043276 Oncogene Human genes 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- 108091005682 Receptor kinases Proteins 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 229930189077 Rifamycin Natural products 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 229960004420 aceclofenac Drugs 0.000 description 3
- GYUDLEOKVQWEHB-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21.C1=CC=CC2=CC3=CC=CC=C3N=C21 GYUDLEOKVQWEHB-UHFFFAOYSA-N 0.000 description 3
- 229930183665 actinomycin Natural products 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229960002932 anastrozole Drugs 0.000 description 3
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 3
- 239000003080 antimitotic agent Substances 0.000 description 3
- 239000003972 antineoplastic antibiotic Substances 0.000 description 3
- 229950003145 apolizumab Drugs 0.000 description 3
- 229950010993 atrasentan Drugs 0.000 description 3
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 229960000997 bicalutamide Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 229950002826 canertinib Drugs 0.000 description 3
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 229960003184 carprofen Drugs 0.000 description 3
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 3
- 229960000590 celecoxib Drugs 0.000 description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 description 3
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960002436 cladribine Drugs 0.000 description 3
- 238000011278 co-treatment Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960000978 cyproterone acetate Drugs 0.000 description 3
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229940115080 doxil Drugs 0.000 description 3
- 229960005501 duocarmycin Drugs 0.000 description 3
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 3
- 229930184221 duocarmycin Natural products 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 229960001904 epirubicin Drugs 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 229960001842 estramustine Drugs 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960004039 finasteride Drugs 0.000 description 3
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 229960004369 flufenamic acid Drugs 0.000 description 3
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 3
- 229960003973 fluocortolone Drugs 0.000 description 3
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 229960002074 flutamide Drugs 0.000 description 3
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 201000005787 hematologic cancer Diseases 0.000 description 3
- 239000003667 hormone antagonist Substances 0.000 description 3
- 239000003652 hormone inhibitor Substances 0.000 description 3
- 229940116978 human epidermal growth factor Drugs 0.000 description 3
- 229960001330 hydroxycarbamide Drugs 0.000 description 3
- 229960000908 idarubicin Drugs 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 239000000411 inducer Substances 0.000 description 3
- 229950010897 iproplatin Drugs 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- UHEBDUAFKQHUBV-UHFFFAOYSA-N jspy-st000261 Chemical compound C1=CC=C2C3=C(C(=O)NC4)C4=C(C=4C(=CC=C(C=4)COC(C)C)N4CCCOC(=O)CN(C)C)C4=C3CC2=C1 UHEBDUAFKQHUBV-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 231100000682 maximum tolerated dose Toxicity 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229950011129 minodronic acid Drugs 0.000 description 3
- 235000013536 miso Nutrition 0.000 description 3
- 230000000394 mitotic effect Effects 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 3
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 3
- 230000022632 negative regulation of interleukin-6 secretion Effects 0.000 description 3
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 3
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 3
- 229950005848 olivomycin Drugs 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229960000639 pazopanib Drugs 0.000 description 3
- 108010001564 pegaspargase Proteins 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 235000017807 phytochemicals Nutrition 0.000 description 3
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 3
- 229930000223 plant secondary metabolite Natural products 0.000 description 3
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 3
- 239000003600 podophyllotoxin derivative Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- WTFXJFJYEJZMFO-UHFFFAOYSA-N propamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCOC1=CC=C(C(N)=N)C=C1 WTFXJFJYEJZMFO-UHFFFAOYSA-N 0.000 description 3
- 229960003761 propamidine Drugs 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 3
- 229960003292 rifamycin Drugs 0.000 description 3
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 229960000371 rofecoxib Drugs 0.000 description 3
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 3
- 229960005399 satraplatin Drugs 0.000 description 3
- 190014017285 satraplatin Chemical compound 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 108010042747 stallimycin Proteins 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 101150036453 sur-2 gene Proteins 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 3
- 229950007866 tanespimycin Drugs 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 3
- 229960001196 thiotepa Drugs 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229960005294 triamcinolone Drugs 0.000 description 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 3
- 229960001055 uracil mustard Drugs 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 3
- 229960000604 valproic acid Drugs 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- FUXFIVRTGHOMSO-UHFFFAOYSA-N (1-hydroxy-2-imidazol-1-yl-1-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 FUXFIVRTGHOMSO-UHFFFAOYSA-N 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 2
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 2
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 2
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 2
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 2
- VESKBLGTHHPZJF-QNWVGRARSA-N (2s)-2-amino-5-[[(2r)-2-amino-3-[2-[bis[bis(2-chloroethyl)amino]phosphoryloxy]ethylsulfonyl]propanoyl]-[(r)-carboxy(phenyl)methyl]amino]-5-oxopentanoic acid Chemical compound ClCCN(CCCl)P(=O)(N(CCCl)CCCl)OCCS(=O)(=O)C[C@H](N)C(=O)N(C(=O)CC[C@H](N)C(O)=O)[C@@H](C(O)=O)C1=CC=CC=C1 VESKBLGTHHPZJF-QNWVGRARSA-N 0.000 description 2
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 2
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- DEEULBIVHZVMHX-UHFFFAOYSA-N 1-nitroacridine Chemical compound C1=CC=C2C=C3C([N+](=O)[O-])=CC=CC3=NC2=C1 DEEULBIVHZVMHX-UHFFFAOYSA-N 0.000 description 2
- OMPIYDSYGYKWSG-UHFFFAOYSA-N 2-(2-ethoxy-2-oxoethyl)-2-hydroxybutanedioic acid Chemical compound CCOC(=O)CC(O)(C(O)=O)CC(O)=O OMPIYDSYGYKWSG-UHFFFAOYSA-N 0.000 description 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 2
- QRBLKGHRWFGINE-UGWAGOLRSA-N 2-[2-[2-[[2-[[4-[[2-[[6-amino-2-[3-amino-1-[(2,3-diamino-3-oxopropyl)amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2s,3r,4r,5s)-4-carbamoyl-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)- Chemical compound N=1C(C=2SC=C(N=2)C(N)=O)CSC=1CCNC(=O)C(C(C)=O)NC(=O)C(C)C(O)C(C)NC(=O)C(C(O[C@H]1[C@@]([C@@H](O)[C@H](O)[C@H](CO)O1)(C)O[C@H]1[C@@H]([C@](O)([C@@H](O)C(CO)O1)C(N)=O)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C QRBLKGHRWFGINE-UGWAGOLRSA-N 0.000 description 2
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 2
- WGDADRBTCPGSDG-UHFFFAOYSA-N 2-[[4,5-bis(4-chlorophenyl)-1,3-oxazol-2-yl]sulfanyl]propanoic acid Chemical compound O1C(SC(C)C(O)=O)=NC(C=2C=CC(Cl)=CC=2)=C1C1=CC=C(Cl)C=C1 WGDADRBTCPGSDG-UHFFFAOYSA-N 0.000 description 2
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 2
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 2
- MHIITNFQDPFSES-UHFFFAOYSA-N 25,26,27,28-tetrazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1(25),2,4,6,8(27),9,11,13,15,17,19,21,23-tridecaene Chemical class N1C(C=C2C3=CC=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 MHIITNFQDPFSES-UHFFFAOYSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 2
- GYVSOOVXJXMCIJ-UHFFFAOYSA-M 5-[3-(2-nitroimidazol-1-yl)propyl]phenanthridin-5-ium;bromide Chemical compound [Br-].[O-][N+](=O)C1=NC=CN1CCC[N+]1=CC2=CC=CC=C2C2=CC=CC=C12 GYVSOOVXJXMCIJ-UHFFFAOYSA-M 0.000 description 2
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 108020004491 Antisense DNA Proteins 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 2
- CULUWZNBISUWAS-UHFFFAOYSA-N Benznidazole Chemical compound [O-][N+](=O)C1=NC=CN1CC(=O)NCC1=CC=CC=C1 CULUWZNBISUWAS-UHFFFAOYSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 241000219198 Brassica Species 0.000 description 2
- 235000003351 Brassica cretica Nutrition 0.000 description 2
- 235000003343 Brassica rupestris Nutrition 0.000 description 2
- 229940124638 COX inhibitor Drugs 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 2
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- 230000004544 DNA amplification Effects 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- 101710088194 Dehydrogenase Proteins 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 2
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 102000009127 Glutaminase Human genes 0.000 description 2
- 108010073324 Glutaminase Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 206010024291 Leukaemias acute myeloid Diseases 0.000 description 2
- 108010074338 Lymphokines Proteins 0.000 description 2
- 102000008072 Lymphokines Human genes 0.000 description 2
- 229930126263 Maytansine Natural products 0.000 description 2
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 2
- 102100026262 Metalloproteinase inhibitor 2 Human genes 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 2
- 102100037821 Nucleoporin NUP42 Human genes 0.000 description 2
- 101710160546 Nucleoporin NUP42 Proteins 0.000 description 2
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- LTQCLFMNABRKSH-UHFFFAOYSA-N Phleomycin Natural products N=1C(C=2SC=C(N=2)C(N)=O)CSC=1CCNC(=O)C(C(O)C)NC(=O)C(C)C(O)C(C)NC(=O)C(C(OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C LTQCLFMNABRKSH-UHFFFAOYSA-N 0.000 description 2
- 108010035235 Phleomycins Proteins 0.000 description 2
- FAFRRYBYQKPKSY-AJSRVUJESA-N Phomopsin A Chemical compound OC(=O)/C=C(C(O)=O)/NC(=O)C(=C(C)/CC)\NC(=O)[C@@H]1C=CCN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC)[C@H]1O)C(C)=C)[C@](CC)(C)OC2=CC1=CC(Cl)=C2O FAFRRYBYQKPKSY-AJSRVUJESA-N 0.000 description 2
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 2
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 2
- XJTXBUKLGQCZHC-UHFFFAOYSA-N Steganacin Natural products C1=C2C=3C(OC)=C(OC)C(OC)=CC=3CC3C(=O)OCC3C(OC(C)=O)C2=CC2=C1OCO2 XJTXBUKLGQCZHC-UHFFFAOYSA-N 0.000 description 2
- 108700011582 TER 286 Proteins 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 108010031372 Tissue Inhibitor of Metalloproteinase-2 Proteins 0.000 description 2
- 206010062129 Tongue neoplasm Diseases 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 2
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 2
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 2
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 2
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- KSZGVNZSUJHOJA-UHFFFAOYSA-N Zindoxifene Chemical compound CC=1C2=CC(OC(C)=O)=CC=C2N(CC)C=1C1=CC=C(OC(C)=O)C=C1 KSZGVNZSUJHOJA-UHFFFAOYSA-N 0.000 description 2
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 2
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 2
- 229960002184 abarelix Drugs 0.000 description 2
- 108010023617 abarelix Proteins 0.000 description 2
- 229960004892 acemetacin Drugs 0.000 description 2
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 229960005142 alclofenac Drugs 0.000 description 2
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 230000002491 angiogenic effect Effects 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 2
- 239000003816 antisense DNA Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- 229960003272 asparaginase Drugs 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 2
- 230000035578 autophosphorylation Effects 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- 229960003005 axitinib Drugs 0.000 description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 2
- 229960004001 benznidazole Drugs 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical class ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229960003655 bromfenac Drugs 0.000 description 2
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 description 2
- 229950004398 broxuridine Drugs 0.000 description 2
- 229940088954 camptosar Drugs 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229950010886 clidanac Drugs 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229960002923 denileukin diftitox Drugs 0.000 description 2
- 108010017271 denileukin diftitox Proteins 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 229960000616 diflunisal Drugs 0.000 description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 2
- 229930188854 dolastatin Natural products 0.000 description 2
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 229940082789 erbitux Drugs 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 229960005293 etodolac Drugs 0.000 description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229950011548 fadrozole Drugs 0.000 description 2
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 2
- 229960001395 fenbufen Drugs 0.000 description 2
- 229960001419 fenoprofen Drugs 0.000 description 2
- 229960002679 fentiazac Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229950007979 flufenisal Drugs 0.000 description 2
- 229940091249 fluoride supplement Drugs 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 229960004421 formestane Drugs 0.000 description 2
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 101150108262 gnrh1 gene Proteins 0.000 description 2
- 239000002474 gonadorelin antagonist Substances 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 229950009183 ibufenac Drugs 0.000 description 2
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960004716 idoxuridine Drugs 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 229960004187 indoprofen Drugs 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960004125 ketoconazole Drugs 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- KYYQSAMPTLGNIQ-CIGKBZFWSA-N liblomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN(C)CCCN(CC=1C=C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)=CC=1)CC=1C=C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C KYYQSAMPTLGNIQ-CIGKBZFWSA-N 0.000 description 2
- 108700020781 liblomycin Proteins 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 229950008959 marimastat Drugs 0.000 description 2
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229950008001 matuzumab Drugs 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229960003803 meclofenamic acid Drugs 0.000 description 2
- 229960003464 mefenamic acid Drugs 0.000 description 2
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- OJGQFYYLKNCIJD-UHFFFAOYSA-N miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 description 2
- 229950006616 miroprofen Drugs 0.000 description 2
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 2
- 229950010514 misonidazole Drugs 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 229950003063 mitumomab Drugs 0.000 description 2
- 235000010460 mustard Nutrition 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- BYQPDMUOXXCZOV-UHFFFAOYSA-N n-[3-(2-nitroimidazol-1-yl)propyl]acridin-9-amine;hydrochloride Chemical compound Cl.[O-][N+](=O)C1=NC=CN1CCCNC1=C(C=CC=C2)C2=NC2=CC=CC=C12 BYQPDMUOXXCZOV-UHFFFAOYSA-N 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 2
- 229940086322 navelbine Drugs 0.000 description 2
- 230000024717 negative regulation of secretion Effects 0.000 description 2
- 229960000965 nimesulide Drugs 0.000 description 2
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 2
- MDJFHRLTPRPZLY-UHFFFAOYSA-N nimorazole Chemical compound [O-][N+](=O)C1=CN=CN1CCN1CCOCC1 MDJFHRLTPRPZLY-UHFFFAOYSA-N 0.000 description 2
- 229960004918 nimorazole Drugs 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229960000435 oblimersen Drugs 0.000 description 2
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 229930193498 phomopsin Natural products 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229940109328 photofrin Drugs 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229960000851 pirprofen Drugs 0.000 description 2
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960003101 pranoprofen Drugs 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- VBDRTGFACFYFCT-UHFFFAOYSA-M sodium;hydroxy-[(1r)-1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate;hydrate Chemical compound O.[Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O VBDRTGFACFYFCT-UHFFFAOYSA-M 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229950001248 squalamine Drugs 0.000 description 2
- XJTXBUKLGQCZHC-GCKMJXCFSA-N steganacin Chemical compound C1=C2C=3C(OC)=C(OC)C(OC)=CC=3C[C@@H]3C(=O)OC[C@H]3[C@H](OC(C)=O)C2=CC2=C1OCO2 XJTXBUKLGQCZHC-GCKMJXCFSA-N 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960004492 suprofen Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 229960002871 tenoxicam Drugs 0.000 description 2
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 2
- 229960005353 testolactone Drugs 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CXVCSRUYMINUSF-UHFFFAOYSA-N tetrathiomolybdate(2-) Chemical compound [S-][Mo]([S-])(=S)=S CXVCSRUYMINUSF-UHFFFAOYSA-N 0.000 description 2
- 229960001312 tiaprofenic acid Drugs 0.000 description 2
- 229950006150 tioxaprofen Drugs 0.000 description 2
- 229950002376 tirapazamine Drugs 0.000 description 2
- 229960002905 tolfenamic acid Drugs 0.000 description 2
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 2
- 229960001017 tolmetin Drugs 0.000 description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 2
- 201000006134 tongue cancer Diseases 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 2
- 229950000212 trioxifene Drugs 0.000 description 2
- 229960004824 triptorelin Drugs 0.000 description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 2
- MDYOLVRUBBJPFM-UHFFFAOYSA-N tropolone Chemical compound OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-L tyrosinate(2-) Chemical compound [O-]C(=O)C(N)CC1=CC=C([O-])C=C1 OUYCCCASQSFEME-UHFFFAOYSA-L 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 208000037964 urogenital cancer Diseases 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 229950006514 zindoxifene Drugs 0.000 description 2
- 229950011303 zoledronic acid monohydrate Drugs 0.000 description 2
- 229960003414 zomepirac Drugs 0.000 description 2
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JQJBQVRTSMGDJX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxy]decane Chemical compound CCCCCCCCCCOC(C)(C)C JQJBQVRTSMGDJX-UHFFFAOYSA-N 0.000 description 1
- CGTNCTXIQDWSOL-UHFFFAOYSA-N 1-butoxydecane Chemical compound CCCCCCCCCCOCCCC CGTNCTXIQDWSOL-UHFFFAOYSA-N 0.000 description 1
- ZCJAYDKWZAWMPR-UHFFFAOYSA-N 1-chloro-2-fluorobenzene Chemical compound FC1=CC=CC=C1Cl ZCJAYDKWZAWMPR-UHFFFAOYSA-N 0.000 description 1
- IDCPFAYURAQKDZ-UHFFFAOYSA-N 1-nitroguanidine Chemical compound NC(=N)N[N+]([O-])=O IDCPFAYURAQKDZ-UHFFFAOYSA-N 0.000 description 1
- QMDJUFMEHKQQAV-UHFFFAOYSA-N 1-nitropyrazolidine Chemical compound [O-][N+](=O)N1CCCN1 QMDJUFMEHKQQAV-UHFFFAOYSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- RXACEEPNTRHYBQ-UHFFFAOYSA-N 2-[[2-[[2-[(2-sulfanylacetyl)amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)CNC(=O)CNC(=O)CS RXACEEPNTRHYBQ-UHFFFAOYSA-N 0.000 description 1
- UPGATMBHQQONPH-UHFFFAOYSA-N 2-aminooxycarbonylbenzoic acid Chemical class NOC(=O)C1=CC=CC=C1C(O)=O UPGATMBHQQONPH-UHFFFAOYSA-N 0.000 description 1
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical compound FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 description 1
- UDAIGHZFMLGNDQ-UHFFFAOYSA-N 2-nitroquinoline Chemical compound C1=CC=CC2=NC([N+](=O)[O-])=CC=C21 UDAIGHZFMLGNDQ-UHFFFAOYSA-N 0.000 description 1
- TVSPPYGAFOVROT-UHFFFAOYSA-N 2-phenoxybutanoic acid Chemical compound CCC(C(O)=O)OC1=CC=CC=C1 TVSPPYGAFOVROT-UHFFFAOYSA-N 0.000 description 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 1
- XUSNPFGLKGCWGN-UHFFFAOYSA-N 3-[4-(3-aminopropyl)piperazin-1-yl]propan-1-amine Chemical compound NCCCN1CCN(CCCN)CC1 XUSNPFGLKGCWGN-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- QRDZSRWEULKVNW-UHFFFAOYSA-N 6-hydroxy-2-oxo-1h-quinoline-4-carboxylic acid Chemical compound C1=C(O)C=C2C(C(=O)O)=CC(=O)NC2=C1 QRDZSRWEULKVNW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- 102000035101 Aspartic proteases Human genes 0.000 description 1
- 108091005502 Aspartic proteases Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 229940124204 C-kit inhibitor Drugs 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 102000002554 Cyclin A Human genes 0.000 description 1
- 108010068192 Cyclin A Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000079420 Fluda Species 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000005133 Glutamate 5-kinase Human genes 0.000 description 1
- 108700023479 Glutamate 5-kinases Proteins 0.000 description 1
- 229940123011 Growth factor receptor antagonist Drugs 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101500024558 Homo sapiens Pancreatic icosapeptide Proteins 0.000 description 1
- 101000686915 Homo sapiens Reticulophagy regulator 2 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 101150026109 INSR gene Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101000851005 Mus musculus Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 208000008558 Osteophyte Diseases 0.000 description 1
- 240000007019 Oxalis corniculata Species 0.000 description 1
- 235000016499 Oxalis corniculata Nutrition 0.000 description 1
- 102100036201 Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial Human genes 0.000 description 1
- 241000920340 Pion Species 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000743048 Puya Species 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 102100024733 Reticulophagy regulator 2 Human genes 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041235 Snoring Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000133426 Streptomyces zelensis Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 108091061763 Triple-stranded DNA Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SVEDUIXBYIUURL-UHFFFAOYSA-L [Na+].[Na+].[O-][PH2]=O.[O-][PH2]=O Chemical compound [Na+].[Na+].[O-][PH2]=O.[O-][PH2]=O SVEDUIXBYIUURL-UHFFFAOYSA-L 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- ZVDDJPSHRNMSKV-UHFFFAOYSA-N acetaldehyde;hydrochloride Chemical compound Cl.CC=O ZVDDJPSHRNMSKV-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229960004663 alminoprofen Drugs 0.000 description 1
- FPHLBGOJWPEVME-UHFFFAOYSA-N alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 description 1
- 150000008425 anthrones Chemical class 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940127079 antineoplastic immunimodulatory agent Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001607 bioavailable molecules Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229960005286 carbaryl Drugs 0.000 description 1
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960000579 clodronate disodium Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000037011 constitutive activity Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 239000000430 cytokine receptor antagonist Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000011334 debulking surgery Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- CSMFSDCPJHNZRY-UHFFFAOYSA-N decyl hydrogen sulfate Chemical compound CCCCCCCCCCOS(O)(=O)=O CSMFSDCPJHNZRY-UHFFFAOYSA-N 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000002786 epipodophyllotoxin derivative Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 229950001284 fluprofen Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229940125798 integrin inhibitor Drugs 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 210000004692 intercellular junction Anatomy 0.000 description 1
- 230000017306 interleukin-6 production Effects 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 201000011061 large intestine cancer Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- MGIUUAHJVPPFEV-ABXDCCGRSA-N magainin ii Chemical compound C([C@H](NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O)C1=CC=CC=C1 MGIUUAHJVPPFEV-ABXDCCGRSA-N 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- SILBTMNCGYLTOK-UHFFFAOYSA-N methyl 2-oxo-1h-pyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1O SILBTMNCGYLTOK-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- OXKUGIFNIUUKAW-UHFFFAOYSA-N n,n-dimethylformamide;hydrazine Chemical compound NN.CN(C)C=O OXKUGIFNIUUKAW-UHFFFAOYSA-N 0.000 description 1
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 125000004999 nitroaryl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960005419 nitrogen Drugs 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 108091008685 nuclear receptors type I Proteins 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229950007283 oregovomab Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 239000002770 polo like kinase inhibitor Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- CHUPNGGCNPHUEN-UHFFFAOYSA-M potassium;ethanesulfonate Chemical compound [K+].CCS([O-])(=O)=O CHUPNGGCNPHUEN-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- IVNFTPCOZIGNAE-UHFFFAOYSA-N propan-2-yl hydrogen sulfate Chemical compound CC(C)OS(O)(=O)=O IVNFTPCOZIGNAE-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 239000000718 radiation-protective agent Substances 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000034932 regulation of DNA biosynthetic process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- QXTCFDCJXWLNAP-UHFFFAOYSA-N sulfidonitrogen(.) Chemical compound S=[N] QXTCFDCJXWLNAP-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- HPQYKCJIWQFJMS-UHFFFAOYSA-L tetrathionate(2-) Chemical compound [O-]S(=O)(=O)SSS([O-])(=O)=O HPQYKCJIWQFJMS-UHFFFAOYSA-L 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Radiation-Therapy Devices (AREA)
Description
1378795 九、發明說明: 【發明所屬之技術領域】 =發明係、關於-種治療涉及細胞增生、骨趟癌細胞之移 動或/周零或血管生叙疾狀方法,財 種治療及/或需要該種共同治療的人共同投予有效=要該 (1) 一選擇性的蛋白質酪胺酸激酶受體拮抗劑,·及 ⑼至少I種化學治療劑或天然、半合成或合成 劑;及/或 μ (ill)放射線治療或放射免疫治療。 本發明亦關於適合的醫藥組合物,其包括有效量之: ⑴一選擇性的蛋白質酪胺酸激酶受體拮抗劑;及 ⑼至少另*"種化學治療劑或天'然、半合成或合成治療 劑; ’、 及視需要適合與放射治療或放射免疫治療共同治療作為一 組合製備物,可同時、分開或連續用於治療涉及細胞增生、 骨髓癌細胞之移動或〉周零或血管生成之疾病,特別是抑制 腫瘤生長、存活及轉移。 本發明亦關於組合使用有效量之: (i) 一選擇性的蛋白質酪胺酸激酶受體拮抗劑:及 (11)至少另一種化學治療劑或天然、半合成或合成治療 作為製造醫藥組合製備物,可供同時、分開或連續用於治 療涉及細胞增生、骨髓癌細胞之移動或凋零或血管生成之 疾病,特別是抑制腫瘤生長、存活及轉移,視需要可與放 92580.doc 1378795 射治療或放射免疫治療組合作為共同治療。 本發明亦關於有效量之蛋白質激酶受體拮抗劑用於製造 醫藥組合物之用途,且該醫藥組合物適合同時、分開或連 續與放射治療或放射免疫治療共同治療涉及細胞增生、骨 髓癌細胞之移動或凋零或血管生成之疾病,特別是抑制腫 瘤生長、存活及轉移。 【先前技術】 在過去十年中,有幾種蛋白質酪胺酸激酶受體家族之型 式及亞型之生物活性已被定性出,例如表皮生長因子受體 EGFR及其亞型 ErbB-2 及 ErbB-4(Brignola等人,Journal of Biological Chemistry, Vol. 277, No. 2, pp. 1576-1585, 2002),或血管内皮生長因子受體VEGFR 1-3與其配體VEGF 及其目前已知之四種亞型(Jung等人,European Journal of Cancer,Vol. 38, pp 1 133-1140, 2002)。在之前類似的研究報 告中顯示,某些該等受體之過度表現與腫瘤的多種形式有 關聯。例如研究中提出之證據為表皮生長因子EGF在腫瘤 中係為一生長因子,及血管内皮生長因子VEGF為最常見的 腫瘤血管生成介質之一,其為實體腫瘤生長及轉移所必 須。受體抑制劑因此仍被評定為腫瘤治療(參見例如 Cerrington 等人之文獻,In Advances in Cancer Research, Academic Press 2000, pp.1-38)。 最近的研究亦建議結合幾種受體拮抗劑,或進一步與化 學治療劑或放射線結合。例如WO 02/070008建議將特定針 對VEGF受體之拮抗劑與特定針對EGF受體之拮抗劑結 92580.doc 1378795 合’視需要可與放射線或化學治療劑結合,用於抑制腫瘤 生長。適合的特定拮抗劑之實例,在W0 02/070008中揭示 了 VEGF受體單株抗體及EGF受體單株抗體。 因此,許多蛋白質酪胺酸激酶目前在臨床發展上已作為 冶療癌症之用(見例如Expert Opinion Review of Laid & Cherrington in Expert Opin. Invest. Drugs, Vol. 12, NO. 1, PP· 51-64,2003)。然而’因為缺乏優於標準療法之利益或 因為發現了無法接受之副作用,這些物質(單獨使用或與其 他癌症療法組合)用於治療腫瘤性(onc〇l〇gical)疾病之功 效’到目前為止尚無法證明。 例如’最近公開一種已於臨床試驗之血管生成抑制劑, 亦與化學治療結合’即由法瑪西亞公司(Pharmacia)所開發 代號名稱為SU5416之治療癌症抑制劑,其與妨礙副作用, 即增加血栓有關(Ken Garber 及 Ann Arbor, Nature Biotechnology, Vol. 20, pp. 1067-1068, Nov. 2002) 〇 對於治療腫瘤性質(oncological nature)疾病,已建議了許 多的化學治療劑,其可作為單方治療(以一種藥劑治療)之用 或作為組合治療(以一種以上藥劑同時、分開或連續治療) 之用,及/或可與放射治療或放射免疫治療併用。在此方 面’化學治療劑係指一種天然、半合成或合成化合物,單 獨或經由進一步活化,例如在放射免疫治療中以放射線抑 制或殺死生長中的細胞’並且可用於(或已用於)治療通稱為 癌症之腫瘤性質疾病。在文獻中,這些藥劑一般係根據其 作用機制來分類。例如美國化學學會(American Chemical 92580.doc 1378795
Society),1995年,W. 0. Foye所編輯之「癌症化學治療劑 (Cancer Chemotherapeutic Agents)」中所作之分類可作為本 項之參照。 因此,在本發明之定義中,下列各類之化學治療劑為特 別有利,而其並非代表一種限制: •合成之小分子VEGF受體拮抗劑 •小分子生長因子(GF)受體拮抗劑 •不屬於合成小分子之EGF受體及/或VEGF受體及/或整 合素(inte grin)受體或任何其他蛋白質路胺酸激酶受體 之抑制劑。 •融合蛋白之EGF受體及/或VEGF受體及/或整合素受體 或任何其他蛋白質酪胺酸激酶受體抑制劑。 •與核酸相互作用之化合物,及分類為烷化劑之化合物 或翻化合物 •與核酸相互作用之化合物,及分類為蒽環類 (anthracycline)之化合物、作為DNA驗基結合劑 (intercalator)或作為DNA交鏈劑之化合物 •抗代謝物 •天然、半合成或合成博萊黴素(bleomycin)類抗生素 (BLM-群之抗生素) • DNA轉錄酵素抑制劑,特別是拓撲異構酶 I(topoisomerase I)或拓撲異構酶II(topoisomerase II)抑 制劑。 •染色質(chromatin)修飾劑 92580.doc 1378795 •細胞分裂抑制劑、抗有絲分裂劑或細胞週期抑制劑 •蛋白質降解體(proteasome)抑制劑 •酵素 •荷爾蒙、荷爾蒙拮抗劑或荷爾蒙抑制劑、或類固醇生 物合成抑制劑 •類固醇 •細胞激素、缺氧選擇性細胞毒素、細胞激素抑制劑、 淋巴激素、細胞激素抗體或口服及非經腸耐受誘導系 統 •載劑 •化學放射敏化劑及保護劑 •光化學活化藥物 •合成^^核酸或寡核普酸 •其他化學治療劑或天然、半合成或合成治療劑,例如 細胞毒性抗生素、癌細胞表面分子抗體、金屬蛋白酶 抑制劑、癌基因(onc〇gene)抑制劑、基因轉錄或rna 轉譯或蛋白質表現抑制劑、或稀土元素複合物 到目前為止不是分類為化學治療劑之其他.種類化合物, 其為天然、半合成或合成治療劑,例如非類固醇抗發炎藥, 特別是S氧化酶(COX)抑制劑及更特別的$ c〇x_2抑制 劑,亦可有利的作為組合治療。 縱使組合幾種治療劑或治療 組合治療正在研究及臨床試驗 效的治療劑作為治療細胞增生 之觀念已提出,及已有各種 中,但仍需要一種新賴及有 、骨髓癌細胞之移動或凋零 92580.doc -10· 1378795 或血管生成之也,卜 _ '、病’及仍需要發展其他可增進功效及降低 副作用之組合。 ,這些疾病亦可為腫瘤性質之疾病,其包括所有形式之惡 性腫瘤或癌症’或非腫瘤性質例如糖尿病視網膜病變、類 風濕關節炎或牛皮癬。 【發明内容】 目别已發現共同投予需要此種治療的人或共同治療需要 此種治療的人有效量之 (0 一選擇性的蛋白質酪胺酸激酶受體拮抗劑;及 (11)至V另一種化學治療劑或天然、半合成或合成治療 劑;及/或 (iii)放射治療或放射免疫治療, 相較於只單獨投予任何該等物質及/或單獨以放射治療或 放射免疫治療者,其對需要此種治療的人以高功效在治療 涉及細胞增生 '骨髓癌細胞之移動或凋零或血管生成之疾 病上提供了意想不到的優點。 另外發現’若選擇的蛋白質酪胺酸激酶受體拮抗劑為至 少一種選自 VEGFR1 至 3、PDGFRa及 /3、FGFR1、2 及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之结抗劑時,該 共同投藥或共同治療特別有效。 另外發現’若選擇性蛋白質酪胺酸激酶受體拮抗劑為至 少一種選自 VEGFR1 至 3、PDGFRo;及 /3、FGFR1、2 及 3、 EGFR、HER2、IGF1R、HGFR或c-Kh受體之拮抗劑,及另 一種src酪胺酸激酶家族成員之拮抗劑,特別是src、lck、lyn 92580.doc 1378795 及fyn,及/或另一種由週期素依賴性激酶與其特定的週期 素或與病毒週期素(例如CDK1、CDK2、CDK3、CDK4、 CDK5、CDK6、CDK7、CDK8及CDK9與特定的週期素 A、 Bl、B2、C、Dl、D2、D3、E、F、Gl、G2、Η、I及 K)所 形成之至少一種複合物之拮抗劑,及/或另一種旁泌素 (paracrine)IL-6分泌作用抑制劑時,該共同投藥或共同治療 特別有效。 另外發現,可用根據本發明組合來治療之疾病為所有涉 及細胞增生、骨髓癌細胞之移動或凋零或血管生成之疾 病,其可為腫瘤性質,例如所有種類的惡性腫瘤或癌症, 或非腫瘤性質,例如糖尿病視網膜病變、類風濕關節炎或 牛皮癬。 另外發現,根據本發明之組合治療對於抑制腫瘤生長、 存活及轉移特別有效。 另外發現,根據本發明之組合治療對於選擇性活性物 質、選擇性劑量及選擇性劑型特別有效。 因此,本發明提供了一種治療涉及細胞增生、骨髓癌細 胞之移動或凋零或血管生成之疾病之方法,該方法包括同 時、分開或連續將有效量之: (i)至少一種選自 VEGFR 1 至 3、PDGFRo:及 /3、FGFR1、 2及 3、EGFR、HER2、IGF1R、HGFR 或 c-Kit 受體之 拮抗劑,其為另一種src酪胺酸激酶家族成員之拮抗 劑,或其同質異形物、代謝物或醫藥上可接受之鹽 類;及 92580.doc -12- 1378795 (ii)至少另一種其他的化學治療劑或天然、半合成或合 成治療劑; 以組合調製備物的形式對需要此種治療的人共同投藥,視 需要可與放射治療或放射免疫治療共治療。 本發明亦提供一種治療涉及細胞增生、骨髓癌細胞之移 動或凋零或血管生成之疾病之方法,該方法包括同時、分 開或連續將有效量之至少一種選自VEGFR 1至3、PDGFRa 及、FGFR1、2及 3、EGFR、HER2、IGF1R、HGFR或 c-Kit 受體之拮抗劑,其為另一種src酪胺酸激酶家族成員之拮抗 劑,或其同質異形物、代謝物或醫藥上可接受之鹽類,與 放射線治療或放射免疫治療共同治療。 用於根據本發明方法中之蛋白質酪胺酸激酶受體拮抗 劑,較佳的為至少一種選自VEGFR1至3、PDGFRa及/3、 FGFR1、2及 3、EGFR、HER2、IGF1R、HGFR或 c-Kit受體 之拮抗劑,及另一種src酪胺酸激酶家族成員之拮抗劑,特 別是 src、lck、lyn或 fyn。 在另一較佳的實施例中,蛋白質酪胺酸激酶受體拮抗劑 可另外為週期素依賴性激酶與其特定的週期素或與病毒週 期素(例如 CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、 CDK7、CDK8 及 CDK9 與特定的週期素A、B、B1、B2、C、 Dl、D2、D3、E、F、Gl、G2、Η、I及 K)所形成之至少一 種複合物之拮抗劑,及/或另一種旁泌素(Paracrine)IL_6分泌 作用抑制劑。 在一較佳的實施例中,蛋白質酪胺酸激酶受體拮抗劑係 92580.doc -13- 1378795 選自特定之化合物。 用於根據本發明中之化學治療劑或天^、半合成或合成 治療劑可為任何可取得之化學治療劑或天然、半合成或合 成治療劑,特別是一般用於治療癌症之化學治療劑。較佳 的化學治療劑係選自下列各物··合成之小分子vegf受體结 抗劑;小分子生長因子(GF)受體拮抗劑;不屬於合成小分 子之EGF受體及/或VEGF受體及/或整合素(integrin)受體或 任何其他蛋白質酪胺酸激酶受體之抑制劑;融合蛋白之 EGF受體及/或VEGF受體及/或整合素受體或任何其他蛋白 質赂fe酸激酶梵體抑制劑;與核酸相互作用之化合物及分 類為烧化劑之化合物或鉑化合物;與核酸相互作用之化合 物及分類為蒽環類(anthracycline)之化合物 '作為DNA驗基 結合劑(包括DNA副溝槽面(minor-groove)結合化合物)或作 為DNA交鏈劑之化合物;抗代謝物;天然、半合成或合成 博萊黴素(bleomycin)抗生素(BLM-群之抗生素);DNA轉錄 酵素抑制劑,特別是拓撲異構酶I或拓撲異構酶Π抑制劑; 染色質修飾劑;有絲分裂抑制劑;抗有絲分裂劑;細胞週 期抑制劑;蛋白質降解體抑制劑;酵素;荷爾蒙、荷爾蒙 拮抗劑或荷爾蒙抑制劑、或類固醇生物合成抑制劑;類固 醇;細胞激素、缺氧選擇性細胞毒素、細胞激素抑制劑、 淋巴激素、細胞激素抗體或口服及非經腸耐受誘導系統; 載劑;化學放射敏化劑及保護劑;光化學活化藥物;合成 聚核苷酸或寡核苷酸;視需要經修飾或改變,非類固醇抗 發炎藥;纟〒胞毒性抗生素;癌細胞表面分子抗體,金屬蛋 92580.doc -14- 1378795 白酶抑制劑;金屬;癌基因(_。洲)抑制劑:基因轉錄或 職轉譯或蛋白質表現抑制劑;稀土元素複合物或光化學 治療劑。 在-較佳的實施例令’化學治療劑或天然、半合成或合 成治療劑甲特定之化合物為較佳。 在-實施例中’以根據本發明方法治療之疾病較佳的為 腫瘤性疾病。在一較佳的實施例中,該疾病係選自實體腫 瘤’例如泌尿生殖器癌症(例如前列腺癌、腎細胞癌、膀胱 癌)、婦科癌症(例如印巢癌、子宮頸癌、子宮内膜癌)、肺 癌、腸胃道癌症(例如大腸直腸癌、胰臟癌、胃癌、食道癌' 肝癌、膽管細胞癌)、頭及職、惡性間皮瘤、乳癌、亞性 黑色素瘤或骨頭及軟組織肉冑、及血液腫瘤,例例如多發 性骨髓癌、急性非淋巴性白血病、慢性非淋巴性白血病、 骨髓發育不良徵候群及急性淋巴性白企病。在一較佳的實 施例中’該疾病為荷爾蒙敏感性或荷爾蒙抗性之前列腺 癌、卵巢癌、或小細胞肺癌。 ,在另-實施例中,以根據本發明方法治療之疾病較佳的 為選自糖尿病視網膜病變、類風濕關節炎或牛皮癖之非腫 瘤性疾病。 因此,根據本發明方法之有利的功效主要係以組合治療 之添加及協力效果為基礎,或增進病人對治療的耐受性、 例如投予較低劑量的相關治療劑。 上述意想不到的益處亦可能因為,當藉由腫瘤傳導之蛋 白質酿胺_酶受體之構成活性存活訊號被選擇的蛋白質 92580.doc -15- 1378795 酪胺酸激酶受體拮抗劑抑制時,由化學治療劑引發更有效 的細胞凋亡所產生。 在使用蛋白質酪胺酸激酶受體拮抗劑或其他與血管生成 有關之介質拮抗劑時,例如血管内表生長因子(VEGF)、血 管滲透因子、纖維母細胞生長因子(bFGF)、白細胞介素 -6(IL-6)或白細胞介素-8(IL_8)、表皮生長因子(EgF)或血小 板何生生長因子(PDGF),根據本發明之方法及組合的優點 之一係在於將治療目標放在與腫瘤有關之企管系統,而不 疋(或共同以)腫瘤本身,以切斷癌細胞之能量供應。 另一項優點為,可在以化學治療劑作組合治療之病人身 上引發或重建對化學治療劑之敏感度,因為該敏感度在治 療過程中或VEGFR拮抗劑中會喪失掉。特別是在罹患難治 的多發性骨髓癌及以類固醇作為化學治療劑之病人的情況 中。以類固醇及VEGFR拮抗劑作組合治療可使罹患難治的 多發性骨髓癌的病人恢復對類固醇之敏感度。 根據本發明,協力組合製備物係指包含一定量之選擇的 蛋白質酪胺酸激酶受體拮抗劑,或該活性物質之同質異形 物、代謝物或醫藥上可接受之鹽類,及一定量之化學治療 劑或天然、半合成或合成治療劑,及/或放射治療或放射免 疫治療,其中單獨的個別治療劑之量並不足以達到投予該 治療劑之組合所達到之效果,且其中一定量之治療劑的組 合效果比個別治療劑之量所能達到的總治療效果更好。 從不同方面來看,本發明亦關於用於治療涉及細胞增 生、骨髓殤細胞之移動或凋零或血管生成之疾病之醫藥組 9258〇.d〇c -16- 1378795 σ,其包括一選擇的特定蛋白 另-種化學治療劑或天铁、半 激酶受體拮抗劑及 射治療或放射免疫治療:作::成種或::治、療劑-或放 治痒兮黧左户+ ,人 π %、为開或連續用於 〜屠該#疾病之組合製備物, 可桩兵夕雄您才丨^要了與一或多種醫藥上 了接又之稀释劑及/或載劑一起。 從不同方面來看,.發 亦關用於治療涉及細胞增 生月髓癌細胞之移動或凋零或血管咕出 人制供此太 令及血&生成之疾病之醫藥組 &袅備物套組,其包括一户疼 麋上有效量之選擇的蛋白質酪 胺酸激受體拮抗劑或盆同質显來你 JC,、丨J貝異形物、代謝物或醫藥上可 接受之鹽類,及治療上右钕吾夕£ ^ 縻上有效里之另一種化學治療劑或天 然、半合成或合成治療劑,其特徵為該蛋白質路胺酸激酶 受體拮抗劑係包含在第一隔間及另一化學治療劑或天然、 半合成或合成治療劑係包含在第二隔間,由此可同時、分 開或連續投藥於需要該組合治療之病人,該組合製備物套 組視需要另外適合與放射治療或放射免疫治療共同治療。 根據本發明一實施例,在每個醫藥組合製備物套組的隔 間中,每一種活性物質係調配作為口服投藥。 從另一方面來看’本發明因此亦提供了選擇的蛋白質路 胺酸激酶受體拮抗劑與另一種化學治療劑或天然、半合成 或合成治療劑組合’及/或適合與放射治療或放射免疫治療 共同治療之用途,其係用於製造供治療前文中所述之疾病 或徵狀之醫藥組合製備物。 在本發明的定義中,有效量之治療劑及/或以放射治療或 放射免疫療法之治療係指藥劑之量及/或以放射治療或玫 92580.doc -17- 1378795 以組合使用時可有&達到治療 射免疫治療法之治療量 效果。 【實施方式】 •疾病 如前文料,π根據本發明組合來治療 涉及細胞增生、骨髓痣έ ^ 、届為所有 月髓癌細胞之移動或凋零或血管 病,其可為腫瘤性皙,也丨l & 一 疾 廇性質例如所有種類的惡性腫 或非腫瘤性質,例如牆尽产·Β ^ & 糖尿隸賴錢、類職關節炎或 :’。在癌症中’選擇的特定目標徵狀為實體腫瘤 如泌尿生殖器癌症(例如前列腺癌、腎細胞癌、膀胱癌)、婦 科癌症(例如印巢癌、子宮頸癌、子宮内膜癌)、肺癌、勝田 道癌症(例如大腸直腸癌、騰臟癌、胃癌、食道癌、肝癌月、 膽管細胞癌)、頭及頸癌、惡性間皮瘤、乳癌、惡性愛色素 瘤或骨頭及軟組織肉瘤、及血液腫瘤,例例如多發性骨腾 癌、急性非淋巴性白血病、慢性非淋巴性白血病' 骨髓發 育不良徵候群及急性淋巴性白血病。 根據本發明組合治療對抑制腫瘤生長、存活及轉移特別 有效。 特別有利的組n療為荷爾蒙敏感性或荷爾蒙抗性之前 列腺癌、«癌、小細胞肺癌、非小細胞肺癌或多發性骨 髓癌之治療。 •選擇的蛋白質路胺酸激酶受體拮抗劑 如刖文所述,可用於本發明内文中之選擇的蛋白質酪胺 酸激酶受雔括抗劑包括所有可藉由蛋白質酪胺酸激酶受體 92580.doc -18- 1378795 之配體來抑制蛋白質酪胺酸激酶受體激發或活化之物質。 以屬於生長因子受體家族之蛋白質酪胺酸激酶受體而言, 該激發或活化之抑制作用抑制了表現受體細胞之生長。 一些與腫瘤生成有關之生長因子受體之實例為表皮生長 因子党體(EGFR)、血管内皮生長因子(VEGFRs)、血小板衍 生生長因子(PDGFR)、類胰島素生長因子(IGFR)、神經生 長因子(NGFR)及纖維細胞生長因子(FgfR)。 蛋白質酷胺酸激酶受體激發或活化之抑制作用係指減少 任何受體之活化’其不需要完全阻礙或阻止受體之活化。 再者,受體激發或活化之抑制作用,如本發明之定義, 係指因拮抗劑與受體或其配體交互作用所產生之抑制作 用。交互作用係指拮抗劑及受體間之有效的物理或化學作 用,因而抑制了蛋白質酪胺酸激酶之活性。熟習此項技藝 者應了解,包括聯合或結合之化學作用的實例已為本項技 藝所熟知,且包括在拮抗劑與受體或其配體間之共價鍵 結、離子鍵結、氫鍵結等等。 可由向暈的配體、受體基因擴增、增加受體轉錄或突變, 造成不規則受體訊號來增加蛋白質酪胺酸激酶激發或活 化。編碼受體基因之擴增使結合至受體的配體增加,其更 進一步激發了細胞增生作用。在缺乏基因擴增下,蛋白質 路胺酸激酶激受體亦可過度表現,或許經由突變增加其轉 錄、mRNA轉譯或蛋白質的穩定性。EGFR型之蛋白質路胺 酉文激S#激受體犬變體已於神經膠質瘤(gli〇mas)、非小細胞 肺癌、卵巢癌及前列腺癌中辨識出,其具有一構成活性之 92580.doc •19- 1378795 蛋白質絡胺酸激酶激,顯示其在這些癌症中為高量egfr活 性而非EGFR過度表現(見例如pe(jersen等人,Ann 〇nc〇i·,
Vol. 12(6),ρρ·745-60, 2001)。 在一根據本發明之實施例中,選擇的蛋白質酪胺酸激酶 激受體拮抗劑抑制了蛋白質酪胺酸激酶激與其配體之結 合。 配體與受體之外部的胞外區域結合激發了受體二聚化作 用、受體自磷酸化作用、受體内部活化作用、細胞質内蛋 白質路胺酸激酶激區域及與DNA合成調節作用有關之多訊 號傳導路徑起始作用、細胞分裂、血管新生或血管生成。. 藉由拮抗劑的存在所產生的抑制作用將因而降低了此種激 發作用。 在另一根據本發明之實施例中,選擇的蛋白質酪胺酸激 酶激受體拮抗劑直接與受體結合。該拮抗劑可從外部結合 至受體的胞外部份(其可能或不能抑制配體之結合),或從内 部結合至蛋白質路胺酸激酶激區域。該拮抗劑之實例包括 (但不限於)生物分子例如該受體之專一性抗體(及其功能相 當之同等物)’及可直接作用在受體細胞質區域之合成的激 酶抑制劑(例如稱為「小分子酪胺酸激酶激抑制劑」)。小分 子路胺酸激酶激抑制劑之非詳盡列表請參見Laid &
Cherrington之 Expert Opinion Invest. Drugs,Vol. 12 No 1 2003文獻,其内容係以引用的方式併入本文中。 其他蛋白質酪胺酸激酶激受體拮抗劑可容易的使用熟知 之方法來螂定。本發明所用之選擇的受體拮抗劑抑制了一 92580.doc •20- 1378795 般與磷酸化有關.之受體之蛋白質酪胺酸激酶激活性。因 此,磷酸化分析可作為實例有效的用於測定本發明内文所 用之拮抗劑。此外,亦可利用·偵測受體表現之特定方法。 這些方法包括偵測蛋白質表現之免疫組織化學、偵測基因 擴增之螢光原位雜合、放射配體結合分析、固定式基質墨 點技術(例如北方墨點及南方墨點法)、反轉錄酶聚合酶連鎖 反應及ELISA。 根據本發明,蛋白質酪胺酸激酶激受體拮抗劑較佳的為 至少一種選自 VEGFR 1 至 3、PDGFRa及 jS、FGFR1、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑,及另 一種src酪胺睃激酶家族成員之拮抗劑,特別是src、lck、lyn 或fyn,或其同質異形物、代謝物或醫藥上可接受之鹽類。 選擇的蛋白質酪胺酸激酶激受體拮抗劑,另外可為週期素 依賴性激酶與其特定的週期素或與病毒週期素(例如 CDia、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8 及CDK9與特定的週期素 A、Bl、B2、C、Dl、D2、D3、E、 F、G卜G2、Η、I及K)所形成之至少一種複合物之拮抗劑, 及/或另一種旁泌素(paracrine)IL_6分泌作用之抑制劑。 在根據本發明另一實施例中,將該等活性物質組合係希 望用於治療涉及血管生成之腫瘤疾病。 腫瘤的血管生成在人類的惡性腫瘤發展上扮演一個重要 的角色。其抑制過程在癌症的治療上被認為是最佳的治療 涉入點。經由血管内皮生長因子受體2(VEGFR-2)之訊號傳 導,顯示了其在腫瘤血管生成中内皮細胞之增生、存活及 92580.doc •21 · 1378795 移動上扮演一個重要角色。 就本項而言’有效及可口服的低分子量VEGFR-2拮抗劑 已發展出’其可有效的作為供治療涉及細胞增生、骨髓癌 細胞之移動或凋零或血管生成之疾病之新穎化合物,特別 是作為一種新穎的癌症治療劑,這些拮抗劑因此亦為受體 活性之抑制劑。有些該等拮抗劑亦可為其他生長因子受體 之结抗劑’例如VEGFR 3、PDGFRa及卩、FGFR1、2及3、 HER2、IGF1R、HGFR或c-Kit,有些亦可為src酪胺酸激酶 家族成員src ' lck、lyn或fyn之括抗劑。
這些化合物係揭示於W〇 02/36564、WO 99/52869、WO 00/18734、WO 00/73297、WO 01/27080、WO 01/27081 及 WO 01/32651中。任何與揭示這些相關之特定化合物各方面 有關之引用文件,係以引用的方式併入本文中。 下列化合物特別具代表性且為VEGFR-2及lck之組合抑 制劑,其在本發明定義中可作為蛋白質酪胺酸激酶激受體 拮抗劑。 (A) (Ζ)-3-(1-(4-(Ν-(2-二甲基胺基-乙基)_N-曱基磺醯基·胺 基)-笨基胺基)-1 -苯基-伸甲基)_2_。引„朵酉同; (Β) (Ζ)-3-(1·(4-(Ν-(3-二曱基胺基_丙基)_N_丙醯基·胺基)· 苯基胺基)-1-苯基-伸甲基)_2-吲哚酮; (C) (Z)-3-(l-(4-(二曱基胺基-甲基)_苯基胺基苯基伸 曱基)-5-(丁基胺甲酿基)_2-d引π朵酉同; (D) (Ζ)-3-(1·(4-(二甲基胺基-甲基)笨基胺基笨基伸 甲基)-5-(環己基甲基-胺甲醒基)_2_0引0朵酮; 92580.doc •22- 1378795 (E) (Z)-3-(l-(4-(二甲基磺醯基)-N-(2-二甲基胺基-乙基)· 胺基)-苯基胺基)-1-苯基-伸甲基)-5-(環己基甲基-胺甲 酿基)-2 -引0朵嗣; (F) (Z)-3-(l-(4-(丁基胺基甲基)-苯基胺基苯基-伸甲 基)-5-(環己基甲基-胺甲酿基)-2 -α引β朵酮; (G) (Ζ)-3-(1-(4-(η比咯啶-1-基-曱基)_苯基胺基卜丨—苯基-伸 甲基)-5-(環己基甲基-胺甲醯基)-2-吲哚酮; (Η) (Z)-3-(l-(4-(二乙基胺基曱基)-笨基胺基)_ι·苯基-伸曱 基)-5-(環己基甲基-胺甲醯基)_2_吲哚酮; ⑴(2)-3-(1-(4-(二乙基胺基甲基)-笨基胺基)_1_苯基_伸甲 基)-5-(N-(3-氯苄基)-胺甲醯基)-2-吲哚酮; (J) (Z)-3-(l-(4-(二乙醇胺基甲基)-苯基胺基)苯基_伸甲 基)-5-( 丁基胺甲醯基)-2-吲哚酮; (K) (Z)-3-(l-(4-(二曱基胺基甲基)-笨基胺基)苯基-伸曱 基)-5-(N-(3-氯苄基)-胺甲醯基)-2-吲哚酮; (L) (Ζ)-3-(1-(4-(Ν-乙醯基-N-(2-二甲基胺基-乙基)·胺基)-苯基辟基)-1-苯基-伸曱基)-5-(N-(3 -氣苄基)-胺甲醯 基)-2-吲哚酮; (Μ) (Z)-3-(l-(4-(丁基胺基曱基)-苯基胺基卜苯基-伸甲 基)-5-(N-(3-氯苄基)-胺曱醯基)-2-吲哚酮; (Ν) (Ζ)-3-(1·(4-(二甲基胺基曱基)-笨基胺基)小苯基_伸曱 基)-6 -甲氧魏基-2 - °引。朵酮; (0)〇3-(1-(4-(]^-(3-二甲基胺基-丙基)-]^-乙醯基-胺基)-苯基释基)-1-苯基-伸甲基)-6-甲氧羰基-2-吲哚酮; 92580.doc •23· 1378795 (Ρ) (Ζ)-3-(1·(4-(乙基胺基甲基)-苯基胺基)_卜苯基_伸f 基)-6-甲氧羰基-2-吲哚酮; (Q) (Z)-3-(l-(4-(卜甲基米唑-2-基)-苯基胺基)小苯基·伸甲 基)-6-曱氧羰基-2-吲哚酮; (R) (Ζ)-3-(1-(4-(Ν-二曱基胺基曱基羰基)-N-甲基-胺基)_苯 基胺基)-1-苯基-伸甲基)-6 -曱氧幾基-2-0弓丨η朵酮; (S) (Z)-3-(l_(4-(曱基胺基甲基)-苯胺基)-1-苯基-伸甲基)_6_ 甲氧羰基-2-吲哚酮; .(T) (Ζ)-3-(1,(4-(Ν-(4-甲基-〇底 β井-1-基)-曱基幾基)_n-曱基 _ 胺基)-苯基胺基)-1-苯基-伸甲基)-6-甲氧幾基·2_弓丨嗓 酮;及 (U) 4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基派咬_4_基甲氧 基)-啥嗤淋 及其同質異形物、代謝物或醫藥上可接受之鹽類。 化合物(A)至(B)係描述於W0 00/18734中,化合物至 (M)係描述於WO 00/73297中,化合物(N)至(T)係描述於W〇 01/27081中.,化合物(u)係描述於w〇 01/32651中。 特別具代表性的為有效及可口服之低分子量VEGFr 1至 3、PDGFRof及沒、FGFR1、2及 3、eGFR、HER2、IGF1R、 HGFR及c-Kit拮抗劑,其為另一種src酪胺酸激酶家族成員之 拮抗劑,另一種由週期素依賴性激酶與其特定的週期素或與 病毒週期素所形成之複合物之拮抗劑,及另一種旁泌素 (paracrine)IL 6刀/必作用抑制劑,例如揭示於w〇 〇 1/27081 中作為例箄之473號化合物及其同質異形物、代謝物或醫藥 92580.doc 24- 1378795 上可接受之鹽類。該化合物係指如上表中(τ). f n_(4_(N_(4.f基則·ι·基)·甲基縣)_基嘯t 苯胺基)小苯基·伸甲基]冬甲氧幾基-2令朵酮。 " 相較於上述其他作為實例之化合物,因為其作為抑制 高效用及較㈣毒理性質,該化合物為特佳之化合物。"之 特佳的為該化合物之單乙基磺酸鹽,稱為O 甲基-娘畊-1-基)-甲基羰基)_N•甲基·胺基)_苯胺基)小笨基_ 伸甲基]_6_甲氧幾基·2令朵酮之單乙基續酸鹽,係、揭示於土未 公開之德國專利申請案DE 1〇2 33 500」、未公開的. PCT/03/07822及未公開的美國專利申請案1〇/623,97i中。 根據未公開之德國專利申請案DE 102 33 500.1、未公開的 PCT/03/07822及未公開的美國專利申請案1〇/623,971中所揭 示的,3-Ζ-[1-(4-(Ν-(4-甲基-哌畊墓)_甲基羰基)·Ν•甲基_ 胺基)-苯胺基)-卜苯基-伸甲基]-6-甲氧羰基-2-吲哚酮之單乙 基磺酸鹽具有下列結構:
化合物MES(T) (化合物(T)之單乙基磺酸鹽) 92580.doc -25- 1378795 該化cr物可經由選擇一適合的製造條件來選擇性製得,較 佳的係以其結晶半水合物之形式。 遠化合物特徵為熔點T=305±5°C(以DSC=微差掃瞄熱卡 計’使用梅特勒-托利多(METTLER_T〇LED〇)DSC82裝置來 測量’加熱速率:1〇 K/min)。 可使用根據下列之製程來製造曱基_哌畊 -1-基)-甲基羰基)-N-甲基-胺基)-苯胺基苯基_伸甲基]_6_ 甲氧羰基-2-吲哚酮之單乙基磺酸鹽。 用於製備該3·Ζ-[1-(4·(Ν-(4·曱基 〇底喷_ 1 _基)·甲基叛籲 基)-Ν-甲基-胺基)_苯胺基)_ι_苯基_伸甲基]_6_曱氧羰基_2_吲 。朵_之單乙基續酸鹽的起始物質可為3-Ζ-[1-(4-(Ν-(4-甲基-哌畊-1-基)-甲基羰基)-Ν-甲基-胺基)-笨胺基)]-苯基-伸甲 基]-6-甲氧羰基-2-吲哚酮之游離鹼,其可根據先前技術中 (例如WO 01/27081中所述)已知之方法來製得。 因此,第一步驟及根據WO 01/27081中所描述的, 3-Ζ-[1-(4-(Ν-(4-甲基-哌畊-1-基)-曱基羰基)-N-甲基-胺基)-_ 笨胺基)-1'苹基-伸甲基].-6 -曱氧幾基- 2- n引η朵酮之製備如下。 將10.5 g (30.0 mmol)l-乙醯基-3-(1-乙氧基-1-苯基伸甲 基)-6-曱氧羰基-2-吲哚酮(如WO 01/27081中所述製備)及 8.60 g (33.0 mmol)的N-[(4-甲基-哌畊-1-基)-曱基羰基]-N-曱 基-對-苯二胺(如W0 01/27081中所述製備)溶於80 ml二甲基 ^ 甲醯胺中,並於80°C下混合1小?夺。待冷卻後’加入6.50 ml 的哌啶,然後於室溫下混合2小時。加入水,將所產生之沉 澱上的水嗲完,將沉澱以少量的水再次沖洗。將殘餘物懸浮. 92580.doc -26- 1378795 於200 ml甲醇中,將液體抽乾,並將剩餘的殘餘物以冷水及 乙醚沖洗》將所得到的產物於110°C下真空乾燥。 回收產物:12.4 g (理論値之77%) 紅外線光譜學:1610, 1655, 1711 cm·1
Tsmp =253〇C 分子式:C31H33N504 電喷霧質譜儀:m/z = 540 [M+H] + 元素分析: 計算結果:C 68.99 Η 6.16 Ν 12.98 C 68.32 Η 6.29 Ν 12.85 第二步驟’根據DE 102 33 500.1中所揭示的, 3-Z-[l-(4-(N-(4-f基-派畊-1-基)-甲基羰基)_N甲基-胺基)· 苯胺基)-1-苯基-伸曱基]-6-甲氧羰基-2-吲哚酮之單乙基石蔷 酸鹽製備如下。 將 605 g (1.12 mol)的 3-Ζ-[1-(4-(Ν-(4-甲基-哌畊 基)_甲 基羰基)-N-曱基·胺基)-苯胺基)-1_苯基-伸甲基]_6_甲氧幾 基-2-吲哚酿1懸浮於9公升的甲醇中,並加熱至5〇<^。加入 183.7 g (1.121 mol)之70%的乙基磺酸鹽水溶液。將所產生 溶液冷卻至40°C並與4.5公升的第三丁基曱基醚混合。數分 鐘後有結晶作用產生。將整個溶液於室溫下混合16小時, 以達到完全沉澱。待冷卻至1〇。〇時,將液體抽出,並以2公 升的第三丁基曱基醚沖洗沉澱並於4〇。〇下真空乾燥。 回收產物:63 8 g (理論値之87.6%)
Tsmp =305±5〇C (DSC 10 K/min) 92580.doc -27- 1378795 純度(以HPLC測量):99.4% 水含量:1.0 bis 2.0%(KF) 3-Ζ-[1-(4-(Ν-(4-甲基-痕啡 1 -基)-甲基域基)-N-甲基-胺 基)_苯胺基)-1-苯+基-伸甲基]-6-甲氧幾基- 2-°引0朵嗣之早乙 基磺酸鹽非常易於溶於生理上可接受溶解劑中。 此外,化合物MES(T)在小鼠中為口服、生物可利用之化 合物。 3-Ζ-[1-(4-(Ν-(4-甲基-哌畊-1-基)-甲基羰基)-N-曱基-胺 基)-苯胺基)-1-苯基-伸甲基]-6-甲氧羰基-2-吲哚酮之單乙 基磺酸鹽抑制人類VEGFR-2激酶(huVEGFR-2)之IC5G為21 nM,小鼠 VEGFR-2 激酶(muVEGFR-2)之 IC5〇 為 13 nM,及 VEGFR刺激内皮細胞之增生作用(HUVEC: IC50 = 9 nM, HSMEC: IC50 = 12 nM)。 再者,血管生成訊號傳遞中重要的兩個受體分裂激酶區 域家族中的成員,FGFR-1及PDGFRa另外可被該化合物抑 制,IC5G分別為69 nM及59 nM。 因此當對許多不同的激酶進行試驗時,化合物MES(T)具 高度選擇性,如下表I所示。 表I_ 激酶_1C.η ΓηΜΙ huVEGFR-2 21 mu VEGFR-2 13 VEGFR-3 13 InsR >4000 92580.doc -28- 1378795 >1000 >50000 >50000 69 137 59 >10000 >10000
IGF1R
EGFR HER2 FGGR1 FGFR3 PDGFRa CDK1 CDK2 CDK3 >10000
Lck 16
Lyn 195
Src_156_ 另外値得注意的是該拮抗劑對受體VEGFR-2具有長續性 的抑制作用。在分子及細胞上,將化合物MES(T)短暫的暴 露於細胞(例如内皮細胞)便足以抑制受體激酶本身及往下 傳遞信號分子(例如MAP激酶,MAPK)之活化及細胞增生作 用,至少違32小時。 下列之實驗結果證實此種長續性抑制效果。爲了測定由 MES(T)在受體上所引發之抑制作用的持續性,進行了沖刷 (washout)實驗。將HUVEC及NIH 3T3 KDR細胞暴露於 MES(T)中一段限定的時間,將MES(T)沖掉,並在一段不同 的時間後分析細胞增生作用(HUVEC)或VEGFR-2活化/磷 酸化作用。如圖1所示,在暴露於50 nM MES(T)1小時後, VEGFR-2 士自磷酸化作用被阻斷了至少32小時。在無 92580.doc -29- 1378795 MES(T) 8小時、24小時及32小時後,細胞再度以VEGF激發 並分析受體活化現象。即使在3 2小時後,仍無觀測到受體 活性。由此強烈的顯示出即使在MES(T)血漿濃度非常低 時,MES(T)對受體激酶仍具有持續性的效用》 下列在活體器官移植實驗結果證實了化合物MES(T)在 腫瘤細胞上之效用。爲了測定此效用,以化合物MES(T) 口 服治療帶有皮下FaDu腫瘤(FaDu腫瘤係由人類的鱗狀腫瘤 細胞所構成)之裸鼠。如圖2所示,當以100 mg/kg之劑量每 週二次治療小鼠時’腫瘤生長降低之τ/c(腫瘤/控制)値為 3 1 %。若增加至200 mg/kg每週二次之口服劑量,預計其抗 腫瘤效果會更好。 其指出了該拮抗劑特別適合與其他化學治療劑或或天 然、半合成或合成治療劑,及/或放射線治療或放射免疫治 療連續共同投藥及/或共同治療。該拮抗劑之治療時程的安 排可為,例如一天給藥/ 一天不給藥、一天給藥/二天不給 藥、一星期給藥/一星期不給藥或甚至二星期給藥/二星期不 給藥之間隔治療。 因此’ 3-Ζ-[1-(4-(Ν-(4-曱基-哌畊-1·基)_甲基羰基)_\_曱 基-fe基)-本胺基)-1-苯基-伸曱基]-6-甲氧幾基-2-0引朵酮之 單乙基磺酸鹽顯然是一種有效用及可口服之VEGFR-2激酶 抑制劑及抗腫瘤劑。 有關於本發明之各個方面,適合之選擇的蛋白質酪胺酸 激S#受體结抗劑在活體中亦為選擇的蛋白質酷胺酸激酶受 體拮抗劑表活化代謝物。例如,在活體中蛋白質赂胺酸激 92580.doc -30- 1378795 酶受體拮抗劑之活化代謝物3_Ζ·Π·(4_(Ν·(4_甲基-哌畊-卜 基)-甲基羰基)-Ν-甲基-胺基)_苯胺基)_i_苯基_伸甲基]·6甲 氧羰基·2-弓丨哚酮可為未酯化之化合物3-Ζ-[1-(4-(Ν-(4-甲基 -哌畊-1-基)基羰基)_Ν•甲基_胺基)_笨胺基)“··苯基·伸甲 基]-6-幾基-2-,嗓_。 在本發明定義中,所有上述作為例證之化合物,特別是 化合物(Τ)及其單乙基磺酸鹽]^]£8(丁),亦可用作治療上述疾 病之單方治療,亦即所有涉及細胞增生、骨髓癌細胞之移 動或凋零或血管生成之疾病,其可為腫瘤性質,例如所有 類型的惡性腫瘤或癌症,或非腫瘤性質例如糖尿病視網膜 病變、類風濕關節炎或牛皮癣。在癌症中,作為單方治療 之選擇的特定目標疾病為實體腫瘤,例如泌尿生殖器癌症 (例如則列腺癌、腎細胞癌、膀胱癌)、婦科癌症(例如卵巢 癌、子宮頸癌、子宮内膜癌)、肺癌、腸胃道癌症(例如大腸 直腸癌、胰臟癌、胃癌、食道癌、肝癌、膽管細胞癌)、頭 及頸癌、惡性間皮瘤、乳癌 '惡性黑色素瘤或骨頭及軟組 織肉瘤、及血液腫瘤,例例如多發性骨髓癌 '急性非淋巴 陡白血病、慢性非淋巴性白血病、骨髓發育不良徵候群及 急性淋巴性白血病。其中特別有利的為治療荷爾蒙敏感性 或荷爾豕抗性之前列腺癌、卵巢癌、非小細胞肺癌、小細 胞肺癌或、或多發性骨髓癌。上述作為例證之化合物對於 抑制腫瘤生長、存活及轉移特別有效。 •其他化學治療劑或或天然、半合成或合成治療劑 該化合物較佳的可選自下列化合物之種類及實例,而該 92580.doc •31 - 1378795 列項不應視為一種限制。 >合成小分子VEGF受體拮抗劑 特別有利之合成小分子VEGF受體拮抗劑為第2型之 VEGF受體拮抗劑,其亦為VEGF受體、纖維母細胞生長因 子(bFGF)及血小板衍生生長因子(PDGF)之拮抗劑。代表性 的化合物,例如α引°朵_衍生物,係描述於W0 02/36564、 WO 99/52869、WO 00/18734、WO 00/73297、WO 01/27080、 WO 01/27081及WO 01/32651中。另外代表性的小分子VEGF 受體拮抗劑如描述於WO 01/60814、WO 99/48868及WO 98/35958之化合物,及特別是伐他拉尼(vatalanib)化合物 (PTK-787/ZK222584) ' SU-5416、SU-6668、SU-111248、 SU-14813、AZD-6474、AZD-2m、CP-547632、CEP-7055、 AG-013736、IM-842(L-麩胺醯胺及L-色胺酸)或 GW786034。 >小分子生長因子(GF)受體拮抗劑 特別有利之小分子生長因子(GF)受體拮抗劑為蛋白質酪 胺酸激酶(PTK)受體拮.抗劑,特別是表皮生長因子(EGF)拮 抗劑及表皮生長因子(EGF)和2型(2型之HE)人類表皮生長 因子(EGF)受體之雙重拮抗劑,或有絲分裂原活化蛋白激酶 (MAPK)拮抗劑。代表性的EGFR及HER-2雙重拮抗劑化合物 為,例如描述於WO 00/78735及WO 02/50043之喹唑啉衍生 物、吉非替尼(gefitinib)、爾羅替尼(erlotinib)、CI-1033及 GW-2016。代表性的EGFR單一拮抗劑之化合物為艾瑞沙 (iressa)(ZD-1839)、阿瓦斯丁(OSI-774)、PKI-166、 EKB-569、HKI-272及贺赛汀(herceptin)。代表性的有絲分 92580.doc -32- 1378795 裂原活化蛋白激酶(MAPK)拮抗劑之化合物為 ΒΑΥ-43-9006(—種Raf蛋白質激酶家族之抑制劑)及 BAY-57-9006(—種Kdr酪胺酸激酶抑制劑)。 在此類中較佳的化合物為揭示於w〇 〇2/5〇〇43實例1(1〇) 中作為例證之喹唑啉衍生物,即4-[(3_氯_4氟苯基)胺 基]-6-{[4-(N,N-二T基胺基)小氧_2-丁烯小基]胺 基}-7-((S)-四氫呋喃-3-基氧基)_喹唑啉或其互變異構物、立 體異構物及鹽類,特別是帶有無機或有機酸或鹼之其生理 上可接受之鹽類。最佳的為該化合物之二馬來酸鹽,其可 容易的以下列製程來製得。將6.0 kg (12 35 111〇1)之4_[(3_氯 -4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基卜卜氧」·丁烯_卜 基]胺基}-7-((S)-四氫呋喃-3-基氧基)_喹唑啉於84公升的乙 醇中加熱至70°C。加入2.94 kg(25.31 mol)馬來酸之36公升 乙醇溶液。在開始結晶時’將反應混合物冷卻至2 〇並擾 拌2小時。將反應混合物冷卻至〇 c並授掉3小時。將沉澱抽 氣過濾。將濾倂以19公升的乙醇沖洗並於40。(:下真空乾燥。 在此類t.另一較佳的化合物為4-[(3-氯-4-氟苯基)胺 基]-6-{[4-(4·[(3-氯-4-氟苯基)胺基]·6·{[4-(Ν,Ν·二甲基胺 基)-1-氧-2·丁烯-1-基]胺基}-7-((S)-四氫呋喃-3-基氧基喹 嗤啉-4-基)-1-氧_2_ 丁烯-1-基]胺基}-7-[ (S)-四氫呋喃_3_ 基])氧基]-喹唑啉或其鹽類。該化合物之化學結構為 92580.doc -33- 1378795
使用下列製造條件以三個步驟可得到該化合物。 •起始化合物I : 4-[(3-氣-4-氟笨基)胺基]_6·[(二乙氧基·碟 酸基)-乙醯基胺基]-7-[ (S)-四氫呋喃_3·基])氧基]_喹唑 啉之製備 將60.07 g之二乙氧磷酸基醋酸置於750 ml的Ν,Ν-二甲義 甲醯胺中’並於環境溫度下與48.67 g的Ν,Ν,-羰基二咪。坐藏 合。待氣體停止產生後,加入90.00 g的4-[(3-氣-4-氟-笨基) 胺基]-6-胺基-[(S)-四氫吱喃-3-基])氧基]_啥吐淋,並於學 境溫度下授拌反應混合物4-5小時,直到反應完成》然後將 反應混合物以水浴緩慢加熱,並加入750 ml的水兩次。將 該濃稠的懸浮液攪拌至隔夜,隔天早晨另外加入35〇…的 水。將懸浮液以冰浴冷卻’攪拌一小時並抽氣過濾。將濾 餅以240 ml的N,N-二甲基甲醯胺/水(1 : 2)及240 ml異丙醚 再次沖洗,並以循環式空氣乾燥機於4(TC下乾燥。 產率:117.30 g (理論值之88%)
Rf值:0.37 (石夕膠,二氣曱烷/甲醇=9 : u 質譜(ESI+) : m/z = 553, 555 [m+H] + •起始化合物II:高嗎啉_4_基-乙醛_鹽酸之製備 於80°C下攪拌(2.5小時)4-(2,2-二甲氧基-乙基)-高嗎啉 92580.doc -34- 1378795 與半濃鹽酸。將得到的溶液直接如下述進一步反應。 •最終化合物:4_[(3·氯_4·氟苯基)胺基]·6-{[4-(高嗎啉-4- 基)小氧I 丁烯基]胺基卜7_[你四氫呋味小·基])氧 基]-喹唑啉之製備 於環境溫度下將3.9 g的4-[(3_氯_4_氟苯基)胺 基]-6-[2-(二乙氧基-磷酸基)_乙醯基胺基]_7_[ (s)_四氩呋 喃-3-基])氧基]•喹唑啉(起始化合物1}之2〇 ml四氫呋喃溶 液加到300 mg氯化鋰之20…水溶液中。然後加入2 35 g的 氫氧化鉀薄片,並以冰/丙酮冷卻浴將反應混合物冷卻至_3 °c。然後於〇°c.下將上步驟所得的高嗎啉_4_基-乙醛-鹽酸 (起始化合物II)溶液,於五分鐘内逐滴的加入。加完後於 0 C下另外授摔反應混合物1 〇分鐘,並於環境溫度下另授掉 1小時。後續加入100 ml的乙酸乙酯並將水相分離出。將有 機相以飽和的氯化鈉溶液沖洗’以硫酸鎂乾燥並蒸發。以 色層分析法於矽膠管柱使用乙酸乙酯/甲醇/濃氨甲醇液為 溶離液純化粗產物。將獲得的產物與少許異丙崎擾掉、抽 氣過遽並乾燥。 產率:2.40 g (理論值之68%)
Rf值:0.09 (矽膠,二氯甲烷/乙酸乙酯/甲醇/濃氨水溶液 =90 : 10 : 1) 質譜(ESI+) : m/z = 542, 544 [M+H] + >不屬於合成小分子之egf受體及/或受體及/戍敕 合素(integrin)受體或任何其他蛋白質酪胺酸激酶受體 之抑制劑 92580.doc •35· 1378795 不屬於合成小分子之EGF受體及/或VEGF受體及/或整合 素受體或任何其他蛋白質酪胺酸激酶受體之抑制劑,特別 有利的為EGF受體及/或VEGF受體及/或整合素(integrin)受 體或任何其他蛋白質酪胺酸激酶受體之單株抗體。代表性 的化合物,例如有艾措森塔(atrasentan)(整合素括抗劑)、利 妥昔(rituximab)、西妥昔(cetuximab)、阿瓦斯丁 (AvastinTM)(貝瓦昔(bevacizumab))、ICM-1C11、艾比特思 (erbitux)(C-225)、DC-101、EMD-72000(人化之 EGF 受體專 一性單株抗體)、維他辛(vitaxin)(a、)S3整合素之抗體)及伊 馬替尼(imatinib)(c-kit抑制劑)。在適當的受體上可特別辨 識其抗原表位之單株抗體,在此方面特別有利。可成功的 用於體外及動物模型之該等抗體,作為單方藥物治療時對 病人並無令人滿意的功效。於臨床試驗上使用其他非抗體 之抗血管生成或EGF受體拮抗劑,得到相似的結果。若一 些特定位置被阻斷,腫瘤似乎可使用其他細胞表面分子來 補償該原有的阻斷。因此,腫瘤在各種抗血管生成或抗增 生治療期間並非真正的縮小。基於這些理由,在本情況下, 針對這項問題而提出組合治療,例如使用單株抗體與特定 的細胞毒性劑或化學治療劑或與放射治療或放射免疫治療 併用。事實上,臨床試驗已顯示這些組合治療比同等的單 方投藥更為有效。 >融合蛋白之EGF受體及/或VEGF受體及/或整合素受體 或任何其他蛋白質酪胺酸激酶受體抑制劑 本項之作表化合物,例如Regeneropn and Aventis醫藥公 92580.doc -36- 1378795 司所開發名稱為VEGFtrap之化合物。 >與核酸相互作用之化合物,及分類為烷化劑之化合物 或始化合物 對與核酸相互作用之化合物,及分類為烷化劑之化合物 或鉑化合物其用於治療腫瘤性質疾病,已有描述。該類化 合物之代表種類及實例有美法侖(melphalan)、環磷酸胺 (cyclophosphamide)、咢沙膦酸(oxazaphosphorine)、順銘 (cisplatin)、卡始(carboplatin)、奥沙利翻(oxaliplatin)、沙 銘(satraplatin)、四麵(tetraplatin)、異丙始(iproplatin)、絲 裂黴素(miton^ycin)、鏈佐星(streptozocin)、卡莫司汀 (carmustine)(BCNU)、洛莫司汀(lomustine)、布沙分 (busulfan)、 異環填酰胺(ifosfamide)、 鏈佐星 (streptozocin)、塞替派(thiotepa)、苯丁 酸氮芥 (chlorambucil)、氮芥氣(nitrogen nmstards)(例如甲基氮芬 (mechlorethamine))、次乙亞胺(ethyleneimine)化合物及烧基 續酸鹽。 >與核轉相互作用之化合物,及分類為蒽環類 (anthracycline)、DNA驗基結合劑(intercalator)或DNA 交鏈劑之化合物 與核酸相互作用之化合物,及分類為惹環類 (anthracycline)、DNA驗基結合劑(intercalator)(包括DNA 副溝槽面(minor-groove)結合化合物)或DNA交鏈劑之化合 物亦可有效用於治療腫瘤性疾病。該化合物之代表種類及 實例有柔紅黴素 (daunorubicin)、 阿黴素 92580.doc -37- 1378795 (doxorubicin)(adriamycin)、微脂體阿黴素(liposomal doxorubicin)(doxil)、表阿黴素(epirubicin)、伊達比星 (idarubicin)、米托蒽酿(mitoxantrone).、安0丫咬(amsacrine)、 多汀黴素(dactinomycin)、迪塔黴素(distamycin)及衍生物、 纺錘菌素(netropsin)、皮本利莫(pibenzimol)、絲裂黴素 (mitomycin)、CC-1065(鏈黴菌(Streptomyces zelensis)發酵 產物)、道卡黴素(duocarmycin)、光輝黴素(mithramycin)、 色黴素(chromomycin)、撖欖 f數素(olivomycin)、 phtalanilide(丙脒替(propamidine)、二脒替(stilbamidine))、 氨茴黴素(anthr.amycin)、氮元(aziridine)或亞靖腺及其衍生 物。 >抗代謝物 有利的抗代謝物代表種類有嘧啶及嘌呤類似物或拮抗 劑,例如氟嘧啶及硫嘌呤,或核苷酸二磷酸還原酶抑制劑》 代表性化合物有,例如阿糖胞普(cytarabine)、5 -氣尿嘴淀 (5-FU)、烏拉莫司汀(uracil mustard)、氟達拉濱 (fludarabine) ' 二氣胞嘴咬(gemcitabine)、卡培他濱 (capecitabine)、疏嗓吟(mercaptopurine)、克拉屈濱 (cladribine)、硫鳥嗓呤(thioguanine)、甲氨螺吟 (methotrexate)、喷司他丁(pentostatin)、經脲(hydroxyurea) 或葉酸。 >天然、半合成或合成博萊黴素(bleomycin)抗生素 (BLM-群之抗生素) 有利的代表種類及化合物有芬萊黴素(phleomycin)、博萊 92580.doc -38- 1378795 黴素、博萊黴素衍生物及鹽類、CHPP、BZPP、ΜΤΡΡ、B APP、 利博黴素(liblomycin)。咸信這些藥劑係經由染色體DNA之 降解作用或RNA之降解作用(特別是選擇性的tRNA股裂解) 來傳遞其治療效果。 > DNA轉錄酵素抑制劑,特別是拓撲異構酶 I(topoisomerase I)或拓撲異構酶II(topoisomerase II)抑 制劑。
有利的化合物代表種類及實例有°丫咬(acridine)及。丫咬衍 生物、利發黴素(rifamycin)、放線菌素(actinomycin)、阿卓 黴去(adramyc.in)、喜樹驗(camptothecin)(依立替康 (irinotecan)或卡托沙(camptosar)、拓撲替康(topotecan)、安 吖咬(amsacrine)及類似物及三環甲醢胺(tricyclic carboxamides) ° >染色質(chromatin)修飾劑
有利的化合物代表種類及實例有組織蛋白去乙醯酶抑制 劑例如 SAHA(皮脂醯胺將酸(suberoylanilide hydroxamic acid))、Ml^-275、三克斯他,;丁(trichostatin A)、CBHA(M-缓基肉桂酸雙經醯胺(M-carboxycinnamic acid bishydroxamide)、LAQ824或丙戊酸(valproic acid)。 >有絲分裂抑制劑、抗有絲分裂劑或細胞週期抑制劑 有利的化合物代表種類及實例有植物性抗癌劑,例如紫 杉烷類(taxane)(派克紫杉醇(paclitaxel)或泰素(taxol)、多西 他赛(docetaxel)或泰索帝(taxotere))、長春生物鹼類(長春瑞 賓(navelb}ne)、長春驗(vinblastin)、長春新驗(vincristin)、 92580.doc -39- 1378795 長春地辛(vinde'sine)或·諾維班(vinorelbine))、托酴ϋ (t ropolone)生物驗(秋水仙素及衍生物)、大環内酉旨 (macrolide)(美登素(maytansine)、安絲菌素(ansamitocin)、 瑞挫辛(rhizoxin)),抗有絲分裂胜肽(氟摩辛(phomopsin)、 多拉斯坦汀(dolastatin))、表鬼臼毒素(epipodophyllotoxin ) 或鬼臼毒素衍生物(依託泊苷(et〇P〇side)、替尼泊苷 (teniposide))、史坦佳納辛(steganacin)及抗有分裂胺基甲酸 酉旨衍生物(康布雷他斯汀(c〇mbretastatin)、amphetinile)或丙 卡巴肼(procarbazine)。這些化合物為cdk抑制劑、微小管 (tubulin)結合劑或類波羅激酶(polo-like kinase)抑制劑。 >蛋白質降解體(Proteasome)抑制劑 屬於該類之代表性化合物有例如VelcadeTM(波替單抗 (brotezomib)或 PS-341)。 >酵素 有利的化合物代表種類及實例有例如天門冬醯胺酶 (asparaginase)、聚乙二醇化天門冬醯胺酶(pegaspargase)及 胸腺嘧啶-礙酸酶抑制劑。 >荷爾蒙、荷爾蒙拮抗劑或荷爾蒙抑制劑、或類固醇生 物合成抑制劑 有利的荷爾蒙代表種類及實例有’例如雌激素及黃體助 孕素(gestagen),例如雌莫司汀(estramustine)或T-66、或甲 地孕酮(megestrolp有利的荷爾蒙拮抗劑代表種類及實例 有,例如抗雄激素如氟他米特(flutamide)、康士得casodex、 安南隆(ar^ndron)及醋酸環丙孕酮(cyproterone acetate),芳 92580.doc -40· 1378795 香酶抑制劑例如amonogluthetimide 、阿那曲。坐 (anastrozole)、福美司坦(formestan)及來曲唾(ietroz〇ie)、 GNrH類似物如亮丙瑞林(leuprorelin)、博司靈(busereiin)、 戈瑞舍林(goserelin)及曲普瑞林(triptorelin),抗雌激素劑如 塔莫昔芬(tamoxifen)或其檸檬酸鹽、屈落昔芬 droloxifene)、粹洛昔芬(trioxifene)、雷洛昔芬(rai〇xifene)、 辛多昔芬(zindoxifene)、17/3-雌二醇衍生物(ici 164,384 及 ICI 182, 780)、aminoglutethimide、福美司坦(f〇rmestane)、 法倔嗤(fadrozole)、非那雄安(finasteride) '或酮康嗤 (ketoconazole)或LH-RH拮抗劑亮丙瑞林。類固醇荷爾蒙抑 制劑特別適合作為乳癌及前列腺癌之治療。 >類固醇 有利的代表化合物,例如潑尼松龍(prednisone)、潑尼松 龍(prednisolone)、甲基潑尼松龍(methylprednisolone)、地 塞米松(dexamethasone) '布登若普(budenoside)、氟可龍 (fluocortolone)及曲安縮松(triamcinolone)。類固醇可用於 治療某些瘅症之理由及以類固醇治療癌症所得到的效果係 依所欲治療之癌症的類型而定。以實體腫瘤的治療而言, 類固醇首先係用於控制症狀。以轉移性腦瘤而言,類固醇 係屬於降低水腫之標準治療。其亦可用於控制腫瘤病變周 圍之發炎現象。在治療淋巴細胞株之血液惡性腫瘤(所有, 非何杰金士淋巴瘤、骨髓癌),因其細胞溶解效應,類固醇 可單獨或與傳統化學治療劑組合用於抗腫瘤治療。天然類 固醇四氫腎上線皮脂素、合成的環狀糊精衍生物十四基硫 92580.doc -41 · 1378795 酸/3-環狀糊精及·四環黴素衍生物米諾環素(minocycline),因 為其抗血管生成活性已建議與細胞毒性標準抗癌治療(例 如#、美法命(melphalan)、環璃酿胺、阿黴素 (adriamycin)、博萊黴素(bleomycin)或放射線基本治療)作為 組合治療(Teicher 等人,Cancer research, vol. 52,pp. 6702-6704, 1992)。類固醇地塞米松(dexamethasone)已試驗 作為多發性骨聽癌之初級治療(Dimopoulos等人,Blood, Vol. 80(4),ρρ· 887-890,1992)。再者,使用地塞米松 (dexamethasone)與沙利竇邁(thalidomide)組合治療之評估 研究中,已揭示一種已知其活性為TNF-α合成抑制劑及細胞 激素拮抗劑之物質。這些研究係集中在先前無法治療之多 發性骨體癌(Weber等人,Journal of Clinical Oncology, Vol. 21, No. 1,pp. 16-19, 2003)、新診斷出的骨髓癌(Rajkumar 等人,Journal of Clinical Oncology, Vol· 20,No. 21,pp. 4319-4323, 2002)及強烈化療後之多發性骨髓癌(Ann. Oncol.,Vol. 13, No· 7, pp. 1116-1119, 2002)。 有關本發明之所有方面,適合作為組合治療之類固醇應 非限制地包括潑尼松(prednisone)、潑尼松龍 (prednisolone)、甲基潑尼松龍(prednisolone)、地塞米松 (dexamethasone)、布登若苦(budenoside)、氟可龍 (fluocortolone)及曲安縮松(triamcinolone)。較佳的類固醇 為地塞米松。 >細胞激素、缺氧選擇性細胞毒素、細胞激素抑制劑、 淋巴敏素、細胞激素抗體或口服及非經腸耐受誘導劑 92580.doc -42- 1378795 有利的化合物代表種類及實例,例如干擾素(特別是干擾 素/3)、介白素(特別是IL-10及12)、抗TNF-α抗體(西那依普 (etanercept))、免疫調節藥劑(或IMiDs,特別是TNF-α生成 抑制劑,例如沙利竇邁(thalidomide),其R-及S-對掌異構物 及其衍生物,或瑞維敏(revimid)(CC-5013))、白細胞三烯 (leukotrien)拮抗劑、絲裂黴素C 、 亞胺西昆 (aziridoquinone)(BMY-42355, AZQ,EO-9)、2-硝基咪唑(米 索硝唑(misonidazole)、NLP-1、NLA-1)、硝基吖啶 (nitroacridine)、硝基喧琳、頌基β比°坐σ丫唆、「雙官能」确基 芳香物(RSU-1069、RB-6145、經硝基芳族物減活之芥氣 (CB-1954)、氮芬氣之Ν-氧化物例如尼特羅明(nitromin)、氣 芥氣之金屬錯合物、抗-CD3或抗-CD25抗體、具忍受性之 基因性修改的腸内細菌。 >載劑 有利的化合物代表種類,例如二膦酸鹽及其衍生物,例 如米諸膦酸(minodronic acid) (YM-529、Ono-5920 ' ΥΗ·529)、°舉來膦酸(zoledronic acid)單水合物、伊班膦酸鈉 水合物(ibandronate sodium hydrate)、氣膦酸二鈉 (cl 〇 dronate di sodium)。這些化合物在臨床發展上及最近已 證明可治療從乳癌/肺癌轉移的骨癌及多發性骨髓癌(Drugs of the Future 2002, 27(10), pp. 935-941) ° >化學放射敏化劑及保護劑 有利的化合物代表種類,例如硝基味嗤(甲£肖唾 (metronidazole)、米索硝 °坐(misonidazole)、苯硝吐 92580.doc -43- 1378795 (benznidazole)、頌基嗎咪唾(nimorazole))及其他硝芳基化合 物,例如RSU-1069、硝醯基及N-氧化物,如SR-4233、鹵化 β密咬類似物(溴化去氧尿嘴咬核苷(bromodeoxyuridine)、埃 化去氧尿0f咬核普(iododeoxyuridine))或硫填酸鹽(如 WR-2721)作為放射線保護劑。 >光化學活化藥物 有利的代表化合物及種類,例如普分莫(porfimer)、光敏 素(photofrin)、苯基紫質(benzoporphyrin)衍生物、脫鎮葉 綠醋(pheoghorbide)衍生物、美羅花青(merocyanin540, MC-540)、及錫.依替泊嗓吟(tin etioporpurin)。 >合成聚或寡核苷酸 視需要可經修改或改變之聚核苷酸或募核苷酸亦為有利 的。代表的聚核苷酸或寡核苷酸種類,例如反模板RNA及 DNA(合成或經化學修改之寡核苷酸,本身不具活性但能與 功能性模板引體競爭在酵素上特定的結合位置,因而阻斷 其功能)、反義RNA及DNA(特定序列之蛋白質合成抑制 劑,可與m-RNA之互補鹼基序列雜交,例如歐布美森 (oblimersen)),特別是針對癌基因、生長因子基因或腫瘤抑 制基因、抗基因聚或寡核苷酸(能形成三鏈DNA結構之寡核 苷酸,可選擇性抑制標地基因之轉錄)及酵素性核酸 (ribozyme) ° >非類固醇抗發炎藥物 在本發明定義中,非類固醇抗發炎藥物亦為一種可用於 組合治療之有利的化合物種類。特別有利的為環氧化酶 92580.doc 1378795 (cox)抑制劑,例如非選擇性COX抑制劑乙醯柳酸、美沙拉 秦(mesalazin)、布洛芬(ibuprofen)、普生(naproxen)、氟. 比洛芬(flurbiprofen)、菲諾洛芬(fenoprofen)、芬布芬 (fenbufen)、酮洛芬(ketoprofen)、°引 °朵洛芬(indoprofen)、 0比洛芬(pirprofen)、卡洛芬(carprofen)、咢丙°秦 (oxaprozine)、普拉洛芬(pranoprofen)、米羅洛芬 (miroprofen)、替号洛芬(tioxaprofen)、舒洛芬(suprofen)、 阿明洛芬(alminoprofen)、嘆洛芬酸(tiaprofenic acid)、氣 洛芬(fluprofen)、吲 °朵美辛(indomethacin)、舒林酸 (sulindac)、托美丁(tolmetin)、佐美酸(zomepirac)、萘丁美 酮(nabumetone)、氯芬酸(diclofenac)、芬氯芬酸 (fenclofenac)、阿氯芬酸(alclofenac)、漠芬酸(bromfenac)、 布芬酸(ibufenac)、醋氯芬酸(aceclofenac)、阿西美辛 (acemetacin)、芬提咢酸(fentiazac)、環氯茚酸(clidanac)、 依託度酸(etodolac)、咢品酸(oxpinac)、美芬那酸(mefenamic acid)、甲氣芬那酸(meclofenamic acid)、氣芬那酸 (flufenamic acid)、尼氟米酸(nifluminic)、托芬那酸 (tolfenamic acid)、二氟尼柳(diflunisal)、氟芬尼柳 (flufenisal)、°比囉昔康(piroxicam)、替諾昔康(tenoxicam)、 氯諾昔康(lomoxicam)及尼美舒利(nimesulide)或其醫藥上 可接受之鹽類,或選擇性的COX抑制劑美洛昔康 (meloxicam)、西樂標(celecoxib)或羅菲西保(rofecoxib)。特 佳的為選擇性的COX-2抑制劑美洛昔康。 >其他牝學治療劑或天然、半合成或合成治療劑 92580.doc -45- 1378795 在本發明定義中,其他可作為組合治療之有利的化合物 種類及實例,例如細胞毒性抗生素、癌細胞表面分子抗體 (特別是HLA-DR抗體,例如阿波利單抗(ap〇iizumab)及 1D09C3)、金屬蛋白酶抑制劑(TIMP-I ' TIMP-2)、鋅、癌 基因(oncogene)抑制劑(特別疋 c-myc、Ras、v-raf或 c-src抑 制劑,如P53及Rb)、基因轉錄抑制劑(特別是,例如描述於 W0 03/097855中,控制Her-2表現之轉錄因子複合物 ESX/DRIP130/Sur-2之抑制劑)或RNA轉譯或蛋白質表現抑 制劑(特別是Her-2表現抑制劑,如熱緊迫蛋白HSP90調節劑 格爾德黴素(geldanamycin)及其衍生物17_烯丙基胺基格爾 德黴素或17-AAG)、稀土元素複合物例如描述於德國專利 Nr. 101 38 538實例中之鑭系雜環複合物、光化學治療劑 (PUVA,補骨脂内酯(psoralen)(p)與長波紫外線放射線 (UVA)之組合)、IM-842、四硫钥酸鹽(tetrathiomolybdate )、 絞第:胺(squalamine)、康布雷他斯汀(combrestatin) A4、 TNP-470、馬立馬司他(marimastat)、癌立消(neovastat)、比 卡魯胺(bicalutamide)、阿巴瑞利(abarelix)、奥瑞氟單抗 (oregovomab)、米他莫單抗(mitumomab)、TLK-286、阿來 組單抗(alemtuzumab)、依布莫(ibritumomab)、替莫°坐胺 (temozolomide)、戴尼白介素(denileukin diftitox)、阿地白 介素(aldesleukin)、達卡巴。秦(dacarbazine)、氟腺嘴咬脫氧 核普(floxuridine、普卡徽素(plicamycin)、米托坦 (mitotane)、旅泊漠烧(pipobroman)、泰羅西芬(tamloxifen)、 睪内 S旨(testolactone)。 92580.doc -46- 1378795 根據本發明一較佳的實施例,另一化學治療劑或天然、 半合成或合成治療劑係選自合成小分子VEGF受體拮抗 劑、不分類為合成小分子之小分子生長因子受體拮抗劑 EGF受體及/或VEGF受體及/或整合素受體或任何其他蛋白 質酪胺酸激酶受體之抑制劑、融合蛋白之EGF受體及/或 VEGF受體及/或整合素受體或任何其他蛋白質酪胺酸激酶 受體之抑制劑、與核酸相互作用及分類為烷化劑之化合物 或鉑化合物、與核酸相互作用,及分類為蒽環類 (anthracycHne)之化合物、作為DNA驗基結合劑 (intercalator)或DNA交鏈劑(包括DNA副溝槽面 (minor-groove)結合化合物)、抗代謝物、天然、半合成或合 成博萊黴素(bleomycin)類抗生素、DNA轉錄酵素抑制劑(特 別是拓撲異構酶I或拓撲異構酶II抑制劑)、染色質 (chromatin)修飾劑、有絲分裂抑制劑、抗有絲分裂劑或細 胞週期抑制劑、蛋白質降解體(proteasome)抑制劑、酵素、 荷爾蒙、荷爾蒙拮抗劑、荷爾蒙抑制劑、類固醇生物合成 抑制劑、類固醇、細胞激素、缺氧選擇性細胞毒素、細胞 激素抑制劑、淋巴激素、細胞激素抗體、口服及非經腸耐 受誘導劑、載劑、化學放射敏化劑及保護劑、光化學活化 藥物、合成聚核苷酸或寡核苷酸(視需要可經修飾或改變)、 非類固醇抗發炎藥、細胞毒性抗生素、癌細胞表面分子抗 體,特別是HLA-DR抗體,例如,金屬蛋白酶抑制劑、金屬、 癌基因(oncogene)抑制劑、基因轉錄或RNA轉譯或蛋白質表 現抑制劑、稀土元素複合物或光化學治療劑。 92580.doc -47- 1378795 根據本發明另一較佳的實施例,其他化學治療劑或天 然、半合成或合成治療劑係選自小分子VEGF受體拮抗劑, 例如伐他拉尼(vatalanib)化合物(PTK-787/ZK222584)、 SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474、 AZD-2171、CP-547632、CEP-7055、AG-013736、IM-842 或GW-786034 ; EGFR/HER2雙重拮抗劑,例如吉非替尼 (gefitinib)、爾羅替尼(erlotinib)、CI-1033 或 GW-2016; EGFR 拮抗劑,例如艾瑞沙(iressa)(ZD-1839)、塔賽伐 (tarceva) (OSI-774)、PKI-166、EKB-569、HKI-272 及賀賽汀 (herceptin);有絲分裂原活化蛋白激酶拮抗劑例如 BAY-43-9006 或 BAY-57-9006;喹唑啉衍生物,例如 4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧-2-丁烯 -1-基]胺基}-7-((S)-(四氫呋喃-3-基氧基)-喹唑啉或4-[(3-氯 -4-氟-苯基)胺基]-6-{[4-(高嗎啉-4-基)-1-氧-2-丁烯-1-基] 胺基}-7-[(S)-四氫呋喃-3-基)氧基]-喹唑啉,或其醫藥上可 接受之鹽類;不分類為合成小分子之蛋白質激酶受體拮抗 劑,例如艾措森塔(atrasentan)、利妥昔(rituximab)、西妥昔 (cetuximab)、阿瓦斯丁(AvastinTM)(貝瓦昔(bevacizumab))、 IMC-1C11 、艾比特思(erbitux)(C-225)、DC-101 、 EMD-72000、維他辛(vitaxin)及伊馬替尼(imatinib);融合 蛋白之蛋白質酪胺酸激酶抑制劑,例如VEGFtrap ;烷化劑 或始化合物,例如美法舍(melphalan)、環填酸胺 (cyclophosphamide)、咢沙膦酸(oxazaphosphorine)、順翻 (cisplatin).、卡翻(carboplatin)、奥沙利始(oxaliplatin)、沙 92580.doc -48- 1378795 翻(satraplatin)、四链(tetraplatin)、異丙銘(iproplatin)、絲 裂黴素(mitomycin) '鏈佐星(streptozocin)、卡莫司汀 (carmustine)(BCNU)、洛莫司汀(lomustine)、布沙分 (busulfan)、異環鱗醯胺(ifosfamide)、 鏈佐星 (streptozocin)、塞替派(thiotepa)、苯丁 酸氮芥 (chlorambucil)、氮芥氣(nitrogen mustard)(例如甲基氮芥 (mechlorethamine))、次乙亞胺(ethyleneimine)化合物、烧基 續酸鹽、柔紅黴素(daunorubicin)、 阿黴素 (doxorubicin)(adriamycin)、微脂體阿黴素(liposomal doxorubicin)(doxil)、表阿黴素(epirubicin)、伊達比星 (idarubicin)、米托蒽 g昆(mitoxantrone)、安 σ丫咬(amsacrine)、 多ί丁黴素(doctinomycin)、迪塔黴素(distamycin)或其衍生 物、紡鐘菌素(netropsin)、皮本利莫(pibenzimol)、絲裂黴 素(mitomycin)、CC-1065、道卡黴素(duocarmycin)、光輝黴 素(mithramycin)、色黴素(chromomycin)、橄禮黴素 (olivomycin) ; phtalanilide(例如丙脉替(propamidine)、二脉 替(stilbamidine))、氨茴黴素(anthramycin)、氮 元(aziridine) 或亞硝腺或其衍生物;11密11定及嗓吟類似物或拮抗劑或核苦 酸二填酸還原酶抑制劑,例如阿糖胞苷(cytarabine)、5 -氟 尿嘧0定(5-FU)、烏拉莫司汀(uracil mustard)、氟達拉濱 (fludarabine)、二氟胞。密 °定(gemcitabine)、卡培他濱 (capecitabine)、疏嗓吟(mercaptopurine)、克拉屈濱 (cladribine)、硫鳥嗓吟(thioguanine)、甲氨蝶呤 (methotrexate)、噴司他丁(pentostatin)、經脲(hydroxyurea) 92580.doc -49- 1378795 或葉酸;芬萊黴素(phleomycin)、博萊黴素、博萊黴素衍生 物或其鹽類、CHPP、BZPP、MTPP、BAPP、利博黴素 (liblomycin)、吖啶(acridine)或其衍生物、利發黴素 (rifamycin)、玫線菌素(actinomycin)、阿卓黴素 (adramycin)、喜樹驗(camptothecin)(例如依立替康 (irinotecan)卡托沙(camptosar)或拓撲替康(topotecan))、安 吖啶(amsacrine)或其類似物、三環甲醯胺(tricyclic carboxamide);組織蛋白去乙酿酶抑制劑例如SAHA、 MD-275、三克斯他汀(trichostatin A)、CBHA、LAQ824或 丙戍酸(valproic acid);植物性抗癌劑,例如派克紫杉醇 (paclitaxel)(泰素(taxol))、多西他賽(docetaxel)或泰索帝 (taxotere)),長春生物驗類,例如長春瑞賓(navelbine)、長 春驗(vinblastin)、長春新驗(vincristin)、長春地辛 I _ i (vindesine)或諾維班(vinorelbine)),托紛酮(tropolone).生物 驗,例如秋水仙素或其衍生物;大環内S旨(macrolide)(美 登素(maytansine)、安絲菌素(ansamitocin)、瑞挫辛 (rhizoxin).),抗有絲分裂胜肽,例如氟摩辛(phomopsin)、 多拉斯坦汀(dolastatin))、表鬼臼毒素(epipodophyllotoxin ) 或鬼臼毒素衍生物,例如依託泊普(etoposide)、替尼泊苷 (teniposide)、史坦佳納辛(steganacin)、抗有絲分裂胺基曱 酸酯衍生物,例如康布雷他斯汀(combretastatin)或 amphetinile 、丙卡巴肼(procarbazine);蛋白質降解體抑制 劑例如VelcadeTM(波替單抗(bortezomib)或PS-341);酵素例 如天門冬酿胺酶(asparaginase)、聚乙二醇化天門冬酿胺酶 92580.doc -50- 1378795 (pegaspargase)及胸腺嘧咬-填酸酶抑制劑;黃體助孕素 (gestagen)及雌激素,例如雌莫司;丁(estramustine)(T-66)或 甲地孕酿1 (megestrol);抗雄激素例如氟他米特(flutamide)、 康士得(casodex)、安南隆(anandron)或醋酸環丙孕酮 (cyproterone acetate); 芳香 酶抑制 劑例 如 (aminogluthetimide)、阿那曲唑(anastrozole)、福美司坦 (formestan)或來曲唑(letrozole) ; GNrH類似物如亮丙瑞林 (leuprorelin)、博司靈(buserelin)、戈瑞舍林(goserelin)及曲 普瑞林(triptorelin),抗雌激素劑如塔莫昔芬(tamoxifen)或 其檸檬酸鹽.,屈落昔芬(droloxifene)、粹洛昔芬 (trioxifene)、雷洛昔芬(raloxifene)或辛多昔芬 (zindoxifene),17/5-雌二醇衍生物例如ICI 164,384及1(:1 182,780、aminoglutethimide、福美司坦(formestane)、法倔 σ坐(fadrozole)、非那雄安(finasteride)、酮康嗤 (ketoconazole)、LH-RH结抗劑例如亮丙瑞林;類固醇例如 例如潑尼松(prednisone)、潑尼松龍(prednisolone)、甲基潑 尼松育i (me.thylprednisolone)、地塞米松(dexamethasone)、 布登若苷(budenoside)、敗可龍(fluocortolone)及曲安縮松 (triamcinolone);干擾素例如干擾素/3;介白素例如IL-10及 IL-12、抗TNF-α抗體例如西那依普(etanercept )、免疫調 節藥劑例如沙利竇邁(thalidomide),其R-及S-對掌異構物及 其衍生物,或瑞維敏(revimid)(CC-5013))、白細胞三烯 (leukotrien)拮抗劑、絲裂黴素 C ;亞胺 S昆(aziridoquinone) 例如BMY-42355、AZQ或EO-9 ; 2-硝基咪唑例如米索硝唑 92580.doc •51 · 1378795 (misonidazole)、.NLP-1、NLA-1 ;.硝基 σ丫咬(nitroacridine)、 硝基喹啉、硝基吡唑吖啶、「雙官能」硝基芳香物例如 RSU-1069或RB-6145、CB-1954、硝基芳香衍生氮芥 (CB-1954)、氮芥氣之N-氧化物(尼特羅明(nitromin))、氮芥 氣之金屬錯合物、抗-CD3或抗-CD25抗體、具忍受性誘發 劑;二膦酸鹽及其衍生物,例如米諾膦酸(minodronic acid) 或其衍生物 (YM-529 ' Ono-5920、YH-529)、唑來膦酸 (zoledronicacid)單水合物、伊班膦酸納水合物(ibandronate sodium hydrate)、氯膦酸二納(clodronate disodium);硝基 0米°坐例如甲石肖唾(metronidazole)、 米索端°坐 (misonidazole)、苯确嗤(benznidazole)或硝’基嗎味 0坐 (nimorazole);确芳基化合物,例如RSU-1069、硝酿基及N-氧化物,如SR-4233 ;鹵化喷咬類似物例如演化去氧尿喷咬 核苷(bromodeoxyuridine)、峨化去氧尿。密咬核苷 (iododeoxyuridine);硫墻酸鹽例如WR-2721 ;光化學活化 藥物,例如普分莫(porfimer)、光敏素(photofrin)、苯基紫 質(benzoporphyrin)衍生物、脫鎂葉綠酯(pheophorbide)衍生 物、美羅花青(merocyanin 540, MC-540)、錫依替泊嘌呤(tin etioporpurin)、反模板或反義RNA及DNA例如歐布美森 (oblimersen);非類固醇抗發炎藥物例如乙醯柳酸、美沙拉 秦(mesalazin)、布洛芬(ibuprofen)、普生(naproxen)、I t匕 洛芬(flurbiprofen)、菲諾洛芬(fenoprofen)、芬布芬 (fenbufen)、酮洛务(ketoprofen)、β引 °朵洛芬(indoprofen)、 啦洛芬(pirprofen)、卡洛芬(carprofen)、咢丙嗪(〇xapr〇zin)、 92580.doc -52· 1378795 普拉洛芬(pranoprofen)、米羅洛芬(miroprofen)、替咢洛芬 (tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)、 噻洛芬酸(tiaprofenic acid)、氟洛芬(flUprofen)、吲哚美辛 (indomethacin)、舒林酸(sulindac)、托美丁(tolmetin)、佐美 酸(zomepirac)、萘 丁美酮(nabumetone)、氣芬酸 (diclofenac)、芬氯芬酸(fenci〇fenac)、阿氯芬酸 (alclofenac)、溴芬酸(bromfenac)、布芬酸(ibufenac)、醋氯 芬酸(aceclofenac)、阿西美辛(acemetacin)、芬提咢酸 (fentiazac)、環氯茚酸(clidanac)、依託度酸(etodolac)、咢 品酸(oxpinac)、美芬那酸(mefenamic acid)、甲氯芬那酸 (meclofenamic acid)、氟芬那酸(flufenamic acid)、尼氟米酸 (nifluminic acid)、托芬那酸(tolfenamic acid)、二氟尼柳 (diflunisal)、氟芬尼柳(flufenisal)、吡囉昔康(piroxicam)、 替諾昔康(tenoxicam)、氯諾昔康(l〇rnoxicam)及尼美舒利 (nimesulide)' 美洛昔康(meloxicam)、西樂葆(celecoxib)或 羅菲西保(rofecoxib)或非類固醇抗發炎藥物之醫藥上可接 受之鹽類;細胞毒性抗生素、癌細胞表面分子抗體例如阿 波利單抗(apolizumab)及1D09C3)、金屬蛋白酶抑制劑例如 TIMP-1、TIMP-2、辞、癌基因(oncogene)抑制劑例如 P53 及Rb ;稀土元素複合物例如鋼系雜環複合物、光化學治療 劑如PUVA ;轉錄因子複合物ESX/DRIP130/Sur-2之抑制 劑、HER-2表現抑制劑例如熱緊迫蛋白HSP90調節劑格爾德 黴素(geldanamycin)及其衍生物17-烯丙基胺基格爾德黴素 或17-AAG ; 或選自IM-842 、 四硫钥酸鹽 92580.doc -53- 1378795 (tetrathiomolybdate)、鮫黨胺(squalamine)、康布雷他斯汀 (combrestatin) A4 ' TNP-470、馬立馬司他(marimastat) ' 癌 立消(neovastat)、比卡魯胺(bicalutamide)、阿巴瑞利 (abarelix)、奥瑞氟單抗(oregovomab)、米他莫單抗 (mitumomab)、TLK-286、阿來組單抗(alemtuzumab)、依布 莫(ibritumomab)、替莫°全胺(temozolomide)、戴尼白介素 (denileukin diftitox)、阿地白介素(aldesleukin)、達卡巴嗪 (dacarbazine)、氟脲嘧唆脫氧核苷(floxuridine)、普卡黴素 (plicamycin)、米托坦(mitotane)、派泊溴烧(pip.obroman)、 泰羅西芬(tamlpxifen)或睪内醋(testolactone)之治療劑。 根據本發明另一較佳的實施例,另一化學治療劑或天 然、半合成或合成治療劑係選自植物性抗癌藥劑,例如派 克紫杉醇(paclitaxel)(泰素(taxol))、多西他賽(docetaxel)或 泰索帝(taxotere)),長春生物驗類,例如長春瑞賓 (navelbine)、長春驗(vinblastin)、長春新驗(vincristin)、長 春地辛(vindesine)或諾維班(vinorelbine),烧化劑或始化合 物,例如美法余 (melphalan)、 環_ 酸胺 (cyclophosphamide)、夸沙膦酸(oxazaphosphorine)、川頁翻 (cisplatin)、卡始(carboplatin)、奥沙利銘(oxaliplatin)、沙 始(satraplatin)、四翻(tetraplatin)、異丙翻(iproplatin)、絲 裂黴素(mitomycin)、鏈佐星(streptozocin)、卡莫司;丁 (carmustine)(BCNU)、洛莫司汀(lomustine)、布沙分 (busulfan)、 異環填醯胺(ifosfamide)、 鍵佐星 (streptozocin)、塞替派(thiotepa)、苯丁 酸氮芬 92580.doc -54- 1378795 (chlorambucil)、氮芥氣(nitrogen mustard)例如曱基氮芥 (mechlorethamine),免疸調節樂劑例如沙利竇邁 (thalidomide),其R-及S-對掌異構物及其衍生物,或瑞維敏 (revimid)(CC-5013)),次乙亞胺(ethyleneimine)化合物、烷 基磺酸鹽、柔紅黴素(daunorubicin)、阿黴素 (doxorubicin)(adriamycin) ' 微脂體阿徽素(liposomal doxorubicin)(doxil)、表阿徽素(epirubicin)、伊達比星 (idarubicin)、米托蒽醌(mitoxantrone)、安吖啶(amsacrine)、 多汀黴素(dactinomycin)、迪塔黴素(distamycin)或其衍生 物、纺錘菌素(netropsin)、皮本利莫(pibenzimol)、絲裂黴 素(mitomycin)、CC-1065、道卡黴素(duocarmycin)、光輝黴 素(mithramycin)、色黴素(chromomycin)、橄欖黴素 (olivomycin) ; phtalanilide,例如丙脒替(propamidine)、二 脉替(stilbamidine)、敦茴黴素(anthramycin)、氣 11 元(aziridine) 或亞硝脲或其衍生物;嘧啶及嘌呤類似物或拮抗劑或核苷 酸二填酸還原酶抑制劑,例如阿糖胞穿(Cytarabine)、5 -敦 尿嘴唆(5-.FU) '烏拉莫司;丁(uracil mustard)、氧達拉濱 (fludarabine) > 二氟胞嘧啶(gemcitabine)、卡培他濱 (capecitabine)、巯嘌呤(mercaptopurine)、克拉屈濱 (cladribine)、硫鳥嘌呤(thioguanine)、曱氨蝶呤 (methotrexate)、喷司他丁(pe.nt〇statin)、經脲(hydroxyurea) 或葉酸;吖啶(acridine)或其衍生物、利發黴素(rifamycin)、 放線菌素(actinomycin)、阿車黴素(adramycin)、喜樹鹼 (camptothecin)例如依立替康(irinotecan)、卡托沙 92580.doc •55. 1378795 (camptosar)或拓撲替康(topotecan)、安 B丫咬(amsacrine)或其 類似物、三環曱醯胺(tricyclic carboxamide);組織蛋白去 乙酿酶抑制劑例如SAHA、MD-275、三克斯他汀(trichostatin A)、CBHA、LAQ824或丙戊酸(valproic acid);蛋白質降解 體抑制劑例如VelcadeTM(波替單抗(bortezomib)或 PS-341);小分子VEGF受體拮抗劑,例如伐他拉尼 (vatalanib) (PTK-787/ZK222584) ' SU-5416、SU-6668、 SU-11248、SU-14813、AZD-6474、AZD-2m、CP-547632、 CEP-7055、AG-013 736、IM-842 或 GW-786034 ;有絲分裂 原活化蛋白激酶拮抗劑例如BAY-43-9006或BAY-57-9006 ; EGFR/HER2雙重拮抗劑,例如吉非替尼(gefitinib)、爾羅替 尼(erlotinib)、CI-1033 或 GW-2016 ; EGFR拮抗劑,例如艾 瑞沙(iressa)(ZD-1839)、塔赛伐(tarceva) (OSI-774)、 PKI-166、EKB-569、HKI-272及贺赛汀(herceptin);喹唑淋 衍生物,例如4-[(3-氣-4-氟苯基)胺基]-6-{[4-(N,N-二甲基 胺基)-1-氧-2-丁烯-1-基]胺基}-7-((S)-四氫呋喃-3-基氧基)-喧坐琳或4.-[(3 -氣-4-敗-苯基)胺基]-6-{[4-(南嗎琳-4-基)-1-氧-2-丁烯-1-基]胺基}-7-[ (S)-四氫呋喃-3-基)氧基]-喹唑 啉,或其醫藥上可接受之鹽類;轉錄因子複合物 ESX/DRIP130/Sur-2之抑制劑、HER-2表現抑制劑例如熱緊 迫蛋白HSP90調節劑格爾德黴素(geldanamycin)及其衍生物 17-烯丙基胺基格爾德黴素或17-AAG ;不分類為合成小分 子之蛋白質激酶受體拮抗劑,例如艾措森塔(atrasentan)、 利妥昔(rituximab)、西妥昔(cetuximab)、阿瓦斯丁 92580.doc -56· 1378795 (AvastinTM)(貝瓦昔(bevacizumab))、IMC_1C11、艾比特思 (erbhUX)(C-225)、DC-101、EMD_72〇〇〇、維他辛(vitaxin) 及伊馬替尼(imatinib);癌細胞表面分子抗體例如阿波利單 抗(apolizumab)及 1D09C3 » 根據本發明另一較佳的實施例,另一化學治療劑或天 然、半合成或合成治療劑係選自上述揭示於w〇 〇2/5〇〇43 貫例1(10)中例證化合物之喹唑啉衍生物,即4_[(3•氯_4-氟 苯基)胺基]-6-{[4-(N,N-二甲基胺基)_卜氧_2_丁烯_丨基]胺 基}-7-((S)-四氫呋喃_3_基氧基)_喹唑啉或其互變異構物、立 體異構物及鹽類,特別是帶有無機或有機酸或鹼之其生理 上可接受之鹽類。 根據本發明另一較佳的實施例,另一化學治療劑或天 然、半合成或合成治療劑係選自4_[(3_氯_4_氟苯基)胺 基]-6-{[4-(N,N-二甲基胺基)_卜氧_2_ 丁烯卜基]胺 基} 7 ((S)四氫吱喃_3_基氧基)_啥β坐琳之二馬來酸鹽或其 互變異構物或立體異構物。 根據本發明另一較佳的實施例,另一化學治療劑或天 然、半合成或合成治療劑係選自4_[(3_氯_4_氟-苯基)胺 基]-6-{[4-(两嗎啉_4_基)]•氧_2_丁烯·丨基]胺基} 7 [⑻_ 四氫夫$ 3幻氧基]-啥唾琳或帶有無機或有機酸或驗之 生理及醫藥上可接受之鹽類。 •放射線治療 '放射免疫治療或預設標㈣射免疫治療. 放射線/α療、放射免疫治療或預設標乾放射免疫治療係 用於治療準瘤性質之疾病。「放射治療」或放射線治療係指 92580.doc •57· 1378795 以游離放㈣治療録及其他㈣。㈣放射㈣存能量 在欲治療的區域(標地組織),藉由破壞其基因物質來毀壞或 摧毀細胞,使這些細胞無法繼續生長。放射治療可用於治 療局部性的實體腫瘤,例如皮膚癌、舌癌、喉癌、腦癌、 乳癌、肺癌或子宮頸癌。其亦可用於治療血癌或淋巴癌, 亦即非別為形成血液細胞及淋巴系統之癌症。通常用於放 射線治療之一種類型係涉及光子,例如X—光◊依照其所具 有能量的多寡,該光線可用於摧毁身體表面或深層之癌細 胞。X-光的能量越高,X-光所能進入的標地組織就越深。 直線加速器及電子加速器(betatron)係為產生加速較大能量 之X-光的機器。該等機器使用時係將放射線(如又_光)集中 在癌細胞的位置’稱為體外放射線治療。7射線為另一種用 於放射治療之光子形式。γ射線係某些元素(如鐳、鈾及鈷 60)當其分解或衰變時釋出放射線而自然產生的。另一種傳 送放射線至癌細胞之技術係將放射性植入物直接置於腫瘤 或身體内腔中。該方法稱為體内放射治療。近接放射治療 (brachytherapy) ’ 組織内照射治療(interstitial irradiation) 及腔内照射治療(intracavitary irradiation)為體内放射治療 的類型。在此項治療中’放射線劑量係集中在一小區域中, 病患只需住院幾天。體内放射治療常用於舌癌、子宮癌及 子宮頸癌。另一種技術為手術放射治療,其中係於手術中 將大劑量的體外放射線針對腫瘤及周圍組織照射。另一種 為粒子放射線治療。此種類型治療與光子放射治療不同, 其係涉及像用快速移動之亞原粒子(subatomic particle)去 92580.doc -58- 1378795 治療局部性癌症。一些粒子(中子、π介子(pion)及重離子) 儲存比X-光或γ射線更多能量,沿著其路徑穿過組織,因而 對其撞擊到的細胞造更大的破壞。這類的放^線通常係指 高直線能量轉移(高LET)放射線。放射敏化劑使腫瘤更易被 破壞,而放射保護劑則保護正常組織免於放射線傷害。高 熱療法(hyperthermia),使用熱,亦可用於敏化組織對放射 線的敏感性。另一種選擇係關於使用放射性標定抗體傳送 針對癌症位置之放射線劑量(放射免疫治療)。在本項技藝中 有許多可用的方法,可連接放射性同位素至抗體上。例如, 抗體之放射碘化處理法、如W0 93/05 804中所揭示的方法亦 可運用。另一種選擇係在抗體及放射性同位素間使用一種 連結分子,例如 MAG-3(US 5,082,930、EP 0 247 866)、MAG-2 GABA(US 5,681,927、EP 0 284 071)及 N2S2(phenthioate, US 4,897,255、US 5,242,679、EP 0 188 256)。另一種選擇 為預設標靶放射免疫治療,其可用於藉由將長循環抗體與 快速清除的放射核種分開使放射線毒性最小化。(Drugs of the future 2003,28(2),pp. 167-173)。詳細的放射治療方案 為專家所熟知(Cancer Radiotherapy : Methods and Protocols (Methods in Molecular Medicine),Huddart RA Ed.,Human Press 2002)。依照疾病的性質及病人的體質,專家了解如 何決定適當的劑量及應用的時程。特而言之,因而專家了 解如何取用劑量限定毒性(DLT)及如何決定最大耐受劑量 (MTD)。 •共同投筹或共同治療之療法 92580.doc -59- 1378795 選擇的蛋白質酪胺酸激酶受體拮抗劑及另—種化學治療 劑或天然 '半合成或合成治療劑之共同投藥,及/或與放射 線治療或放射免疫治療之共同治療’係包括於時間内連續 或同時投藥及/或治療。以連續投藥及/或治療而言,選擇的 蛋白質酪胺酸激酶受體拮抗劑可在另一種化學治療劑或天 然、半合成或合成治療劑投予前或投予後給藥,及/或在放 射線治療或放射免疫治療前或治療後給藥。 該活性物質可以口服、舌下含服(bucally)、非經腸、經 由吸入喷霧、直腸或局部給藥,口服投要為較佳的。非唆 腸給藥包括皮下、靜脈、肌肉内及胸腔内注射及注輸技術。 該活性物質可以各種不同劑型口服投藥,亦即可與各種 醫藥上可接受之惰性载劑-起調配成錠劑、膠囊、含"、 =二糖劑:散劑、喷劑、水性懸浮劑、_、㈣及 ;生媒二及:形式。載劑包括固體稀釋劑或填充劑、無菌水 物可、商^ 有機卜再者’該等°服醫藥調配 物了適备的以該項目中當 般而言,本發明化八P用的料加入甜味及/或調味。一 έ入 。物口服劑型之濃度範圍約從0.5%至約 90%之總組合物的 其他本發明化合物二足以提供所欲的單位劑量。 熟習本項技藝者所::::劑型包括控制性釋放調配物及 以口服投藥之目 一- 鈉、碳酸詞、碟酸#而:’♦有各種賦形劑(例如,檸檬酸 佳的馬鈴薯㈣之⑮射與各種碎解劑(例如澱粉及較 及與結著劑(例如薯叔粉、海藻酸及某些複合矽酸鹽), ,乙烯吡咯酮、蔗糖、明膠及阿拉伯膠) 92580.doc 1378795 一起應用。此外-,潤滑劑,例如硬脂酸鎮、月桂基硫酸納 及滑石或相同形態之組合物亦可置於軟式或硬式明膠膠囊 中作為填充劑之用;乳糖或牛乳中糖分及高分子量聚乙二 醇亦可包括。當希望以水性懸浮劑或酏劑作為口服投藥 時,其中基本的活性成份可與各種甜味劑或調味劑、調色 劑或色素混合,及若需要可與乳化劑及/或水、乙醇、丙二 醇、甘油及各種其類似組合物混合。 以口服投藥之目的而言,特別適合根據本發明之選擇的 蛋白質酪胺酸激酶受體拮抗劑之醫藥調配物為軟式明膠膠 囊。適合作為醫藥調配物包膠之軟式明膠膠囊及其製備方 法系描述於例如英國專利第395546號、美國專利第 2,720,463號、美國專利第2,870,062號、美國專利第 4,829,057 號及下歹ij 出版品中· ANON(Verpack-Rundsch., Vol. 21,NO. 1, Jan 1970, pp. 136-138)、Lachman等人(The Theory and Practice of Industrial Pharmacy,第 13 章,Lea & Febiger出版,1970年)、Ebert (Soft Gelatine Capsules: A Unique Dosage Form, reprint from Pharmaceutical Technology, Oct. 1977)及 R. F· Jimerson (Soft Gelatine
Capsule Update, Drug Development and Industrial Pharmacy Vol. 12 (8 & 9),pp. 1133-1 144, 1986)。 以非經腸投藥之目的而言,可使用化合物之芝麻油或花 生油溶液或丙二醇水溶液以及同等的醫藥上可接受之鹽類 之無菌水溶液。若需要,該等水溶液應經適當的缓衝,及 液體稀釋劑應以足量的食鹽或葡萄糖給予等張滲透。這些 92580.doc -61 - 1378795 特別的水溶液特別適合作為靜脈'肌肉内及皮下注射。在 此項中,所用的無菌水性媒液可以熟習本項技藝者所熟知 之標準技術來製得。例如蒸财料最f使㈣液體稀釋 劑亚將最終的製備物通過適合的細菌過濾器,例如燒結玻 璃過濾器或矽藻土或無釉的陶瓷過濾器。此種形態中較適 合的過滤器為伯克菲爾德(Berkefeld)、張伯倫 (Chamberland)及石棉賽氏過濾器(Disk_Meui filter),其中5亥》谷液係以抽器幫浦抽到一無菌容器中。整個 可注射溶液製備中所必須作之步驟係要確定所得到最終產 物是否為無菌狀態。 以滲透皮膚投藥之目的而言,該特定化合物或化合物之 劑型可包括’例如溶液、乳液、軟膏、乳霜、凝膠、栓劑、 速度限制之持續釋放調配物及其裝置。該等劑型包括該特 疋化合物或化合物及可包括乙醇、水、促滲劑及惰性載劑, 例如產生膠體物質' 礦物油、乳化劑、苯甲醇及其類似物。 根據一貫施例,選擇的蛋白質酪胺酸激酶受體拮抗劑, 或其同質異形物或醫藥上可接受之鹽類,每日投藥劑量在 24小時的劑量區間内,至少12小時可使血漿中活性物質的 含量位於10及500 ng/ml間。 根據另一實施例,選擇的蛋白質酪胺酸激酶受體拮抗 劑,或其同質異形物或醫藥上可接受之鹽類,每日投藥劑 量可藉於每公斤體重2 mg至20 mg間。 另一種化學治療劑或天然、半合成或合成治療劑可以適 當的劑型找藥,劑量及劑型已為熟習此項技藝者所熟知。 92580.doc •62- 1378795 根據—實施例,若該化學治療劑或天然、半合成 户 療劑為類固醇時,該類固醇之每日投藥劑量為5至二二 如前文中所提到的,詳細的放射治療方案為專家所熟 ^。依照疾病的性質及病人的體f,#家了解如何決定適 當的劑量及應用的時程。特而言之,目而專家了解如何取 用劑里限疋毒性(DLT)及如何決定最大耐受劑量(mtd)。 體内及體外組合研究顯示可有效抑制腫瘤細胞增生及/或 弓丨發腫瘤細胞之凋亡 在下列組合實例中,係以代表細胞株進行體外實驗,或 以帶有特定腫瘤之裸鼠進行體内實驗,其證實了選擇的蛋 白質酪胺酸激酶受體拮抗劑與另一化學治療劑及/或與放 射治療之有效組合,抑制了内皮增生或腫瘤細胞,及/或引 發腫瘤細胞的凋亡。因此,這些實例係為本發明之例證。 組合實例 1.至少一種選自 VEGFR1 至 3、PDGFRa及 /3、FGFR1、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑組合, 其為另广種src酪胺酸激酶家族成員之拮抗劑,或其同質 異形物、代謝物或醫藥上可接受之鹽類,用於治療難治 的或復發的多發性骨髓癌。 在進行3-Ζ·[1-(4-(Ν-(4-甲基-η底啫-1-基)_甲基羰基)_N_曱 基-胺基)-苯胺基)-1-苯基·伸甲基]_6_甲氧羰基_2-吲哚酮 (化合物MES(T))之單乙基續酸鹽之體外研究中顯示,這個 特定化合物具有令人意外的特性使其特別適於治療根據本 發明之疾婷’特別是當與類固醇組合時,更特別是與地塞 92580.doc •63- 1378795 米松(dexamethasone)組合時。 在這些令人意外的特性中,下列為與本項標地組合之特 別關聯:VEGFR1至3、FGFR1及3、PDGFRo:酪胺酸激酶抑 制作用;src酪胺酸激酶家族成員抑制作用及骨髓癌細胞 增生之潛在抑制作用;由VEGF及bFGF引發之neo-血管生成 抑制作用;旁泌素IL-6分泌作用之抑制;傳導IL-6分泌作用 之細胞連接抑制;自體分泌VEGF及bFGF效應之抑制作 用;以t(4; 14)於細胞株上直接導致細胞凋亡。 該特定化合物似乎另外特別適合治療多發性骨髓癌。下 列新進的發現建構了 一連串的證據作為選擇該特定化合 物之指標:在小鼠多發性骨隨癌模型中骨髓之血管生成平 行滲透(Yaccoby 等人,Blood 1998, Vol. 92(8) pp. 2908-2913)及在多發性骨隨癌病人之病情惡化(Vacca等人, Blood 1999, Vol. 93(9) pp.3064-3073; Blood 2002, Blood First Edition Paper, Pre-published Online October 17, 2002, DOI 10.1182/Blood-2002-08-2441);已顯示VEGF為一有效 的 jk 管生成刺激物(Toi等人,Lancet Oncol. 2001,Vol. 2,pp. 667-673) ; VEGF係表現在多發性骨隨癌細胞上並由多發性 骨隨癌細胞所分泌(Dankbar等人,Blood 2000,Vol. 95(8), pp. 2630-2636; Bellamy等人,Cancer Res. 1999,Vol. 59(3), pp. 728-33) ; VEGF從骨髓基質細胞引發IL-6分泌作用,其 輪流從細胞株血漿細胞擴大VEGF表現(Dankbar等人, Blood 2000, Vol. 95(8), ρρ· 263 0-2636);在活體中 IL-6被認 為是一種f發性骨隨癌細胞之主要的生長因子(Klein等人, 92580.doc -64 - 1378795
Blood 1995, Vol· 85(4),ρρ· 863-872) ; IL-6抑制了地塞米松 (dexamethasone)引發的多發性骨隨癌細胞死亡(Hardin等 人,Blood 1994, Vol. 84(9),pp_ 3063-3070) ; VEGF引發多發 性骨隨癌細胞之增生及觸發移動(Podar等人,Blood 2001, Vol. 98(2),pp. 428-435) ; VEGF促進了溶骨作用,其為多發 性骨隨癌主要特性(Nakagawa等人,FEBS Lett. 2000,Vol. 473(2), ρρ· 161-164; Niida等人,J. Exp. Med. 1999,Vol. 190(2),pp. 293-298) ; FGGR3引發增生作用,抑制細胞凋亡 並與骨髓癌細胞的發展有關(Chesi等人,Blood 2001, Vol. 97(3), pp. 729-736; Plowright等人,Blood 2000, Vol. 95(3), pp. 992-998);在骨隨癌病患的次組群中FGFR3被不正常及 組成性活化(Chesi 等人,Blood 2001,Vol. 97(3),pp. 729-736; Chesi等人,Nat. Genet. 1997,Vol. 16(3),pp. 260-264) ; Src家族激酶與骨隨癌中引發的增生反應有關 (Ishikawa等人,Blood 2002, Vol· 99(6),pp. 2172-2178)。 下列體外實驗結果證實化合物MES(T)之特性使其特別 適合治療多發性骨隨癌。
在第一實驗中,化合物MES(T)對骨髓基質細胞(BMSC細 胞)之IL-6分泌作用之抑制效果係在不同的MES(T)濃度下 (0, 10, 50, 125, 250及500 nM),在原來狀況下(本身)及在以 bFGF(+bFGF)或以VEGF(+VEGF)生長因子刺激細胞的狀況 下測量。為了作比較,亦測量抗-bFGF(+抗-VEGF)、抗 -VEGF(+ 抗-bFGF)及-bFGF 與抗-VEGF(+ 抗-bFGF + 抗-VEGF)組合之抑制作用的抑制效果。實驗結果如下表II 92580.doc • 65· 1378795 所示。
表II BMSC細胞之IL-6分泌作用之抑制 MES(T) 濃度 本身 +bFGF +VEGF +抗 -bFGF + 抗 -VEGF + 抗-VEGF + 抗-bFGF OnM 124.2 216.9 107.4 77.7 118.9 71.1 ΙΟηΜ 130.2 150.5 122.3 68.9 148.6 68.1 50 nM 170.4 179.7 130.7 81.3 155.2 63.4 125 nM 97.5 91.2 141.0 42.4 166.7 86.1 250 nM 76.5 76.9 65.5 33.0 89.4 45.0 500 nM 39.6 43.3 14.8 20.2 16.2 13.5 該項實驗結果顯示化合物MES(T)在濃度匕250 nM時抑制 了基本(本身)及bFGF/ VEGF所刺激之骨髓基質細胞(BMSC 細胞)之IL-6分泌作用,且該抑制作用比抗體的抑制作用更 有效。因為bFGF及VEGF生長因子(由骨髓癌細胞所釋放) 先前已顯示可刺激BMSC細胞及微血管内皮細胞產生及分 泌IL-6,其本身刺激骨髓癌細胞產生bFGF及VEGF生長因 子,以根據本發明化合物抑制IL-6分泌作用,顯示其可有 效的治療多發性骨髓癌。 在另一項實驗中,於不同的MES(T)濃度(0, 5 0,125, 250 及5 00 nM),測量化合物MES(T)在骨髓癌細胞(U-266骨髓癌 細胞株)與骨髓基質細胞(BMSC細胞)的轉移盤(transwell) 及接觸共培養中對分泌IL-6之抑制效果。為了作比較,亦 測試BMSC單培養(本身)之抑制作用及(作為控制)U266單 培養之分泌量。實驗結果如下表III所示。 92580.doc -66- 1378795 表in IL-6分泌作用之抑制 MES(T) 濃度 BMSC 單 培養 轉移盤 U-266 + BMSC共培 養 接觸 U-266 + BMSC 共培養 U-266 單培養 0 nM 153.5 336.1 348.1 2.0 50 nM 213.4 354.5 125 nM 192.1 297.6 259.6 250 nM 69.9 231.1 199.4 500 nM 38.6 123.9 114.7 該項實驗結果顯示化合物MES(T)能降低在轉移盤及接 觸共培養中由骨髓癌細胞刺激BMSC培養之IL-6分泌量基 礎(本身)值。因此,可斷定藉由大幅減少NFkB依賴之IL_6 產生,化合物MES(T)妨礙了以骨髓微觀環境為目標之骨髓 基質交互作用。其又另外顯示根據本發明化合物對治療多 發性骨髓癌之效用。 在另一實驗中,可能顯示化合物MES(T)提供了在t(l4; 16)MMl.s骨髓癌細胞(帶有易位染色體t(14;16)之MMl.s骨 髓癌細胞)之自然凋亡效應,化合物MES(T)促進由地塞米松 (dexamethasone)引發的細胞调亡。 因為這些特性,可斷定化合物MES(T)特別適合與類固醇 (特別是地塞米松)組合治療難治的或復發的多發性骨髓 癌。 2.至少一種選自 VEGFR1 至3、PDGFRce 及/3、FGFRJ、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑,其 92580.doc -67- 1378795 為另一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類,及表皮生長因子 (EGF)受體及第2型人類表皮生長因子(第2型HE)受體之 雙重拮抗劑之組合’用於治療前列腺癌、非小細胞肺癌 或直腸癌。 下列實驗係為了分析較低的拮抗劑劑量之組合.治療效 果,其在減緩腫瘤生長上,與相同劑量之單方治療之比較。 該拮抗劑為至少一種選自VEGFR1至3、PDGFRa及/3、 FGFR1、2及 3、EGFR、HER2、IGF1R、HGFR或 c-Kit 受體 之拮抗劑,其為另一種src酪胺酸激酶家族成員之拮抗劑, 即(Ζ)-3-(1-(4-(Ν-((4-曱基-哌畊-1-基)-曱基羰基)-N-甲基-胺基)-苯基胺基)-1-苯基-伸曱基)-6_甲氧羰基-2-吲哚酮之 二氯化物鹽類(C12(T)化合物),其為上述例證化合物(T)之 二氣化物鹽類,及表皮生長因子(EGF)受體及第2型人類表 皮生長因子(第2型HE)受體之雙重拮抗劑’即化合物4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧-2-丁烯 -1-基]胺基}-7-((S)-四氳呋喃-3-基氧基)-喹唑啉 (EGFR/HER2抑制化合物,並描述於WO 02/50043作為實例 1(10)之例證化合物)。 就此項目的而言,將SKOV-3細胞(人類卵巢腫瘤)以皮下 注射到裸鼠(NMRI nu/nu)身上。將帶有建立性腫瘤之小鼠 任意分配到控制組及治療組(N= 10)。在控制組的小鼠只接 受載體溶液(0.5%納脫羅梭經乙基纖維素(natrosol)),第二 組每天以15 mg/kg EGFR/HER2抑制劑口服治療,第三組每 92580.doc -68- 1378795 天接受一次50 mg/kg C12(T) ’第四組的小鼠以15 mg/kg EGFR/HER2抑制劑及50 mg/kg C12(T)組合治療。實驗結果 如圖3所示。 每天口服治療開始進行3 1天。此時控制組中一些腫瘤大 於2000 mm3小鼠因此必須犧牲。此時,計算治療組腫瘤與 控制組腫瘤(T/C)比例,以15 mg/kg EGFR/HER2抑制劑治療 的為35%,以50 mg/kg C12(T)治療的為32%,及以組合治療 的為13%。此項結果清楚的證明VEGFR-2與EGFR/HER2抑 制劑組合在活體中之抗腫瘤效果。持續治療至64天顯示, 相較於單方治療組(事實上其腫瘤長到與控制組的腫瘤大 小相當),組合治療組的腫瘤生長極度緩慢。 從此項實驗結果,可斷言以不同與腫瘤生長有關及重要 的反應機構為目標之化合物,例如VEGFR-2抑制劑C12 (T)(抑制了腫瘤血管生成),及組合EGFR/HER2抑制劑之 EGFR/iiER^抑制劑(抑制經由第1類受體酪胺酸激酶之增生 訊號傳遞),具有協力的抗腫瘤功效。因此,所有腫瘤血管 生成抑制.剛之組合(例如描述於WO 〇2/36564、WO 99/52869、WO 00/18734、WO 00/73297、WO 01/27080、 WO 01/27081及WO 01/32651中之吲哚酮衍生物,描述於 WO 01/60814、WO 99/48868 及 WO 98/35958 之小分子 VEGF 受體拮抗劑,特別是化合物伐他拉尼(vatalanib) (PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、 SU-148 13、AZD-6474、AZD-2m、CP-547632、CEP-705 5、 AG-013 73 0·、IM-842或GW 786034,VEGF受體之單株抗體, 92580.doc -69- 1378795 特別是阿瓦斯丁(AvastinTM)(貝瓦昔(bevacizumab))或 IMC-1C11、與 EGFR 抑制劑(例如艾瑞沙(iressa)(ZD-1839)、 塔賽伐(tarceva) (OSI-774)、PKI-166、EKB-569、HKI-272 及賀賽汀 (herceptin)或組合EGFR/HER-2抑制劑(例如描述 於W0 00/78735及W0 02/50043之喹唑啉衍生物、吉非替尼 (gefitinib)、爾羅替尼(erlotinib)、CI-1033 及 GW-2016),預 計對抗腫瘤治療將具有相同或相似效果。 3. 至少一種選自 VEGFR1 至 3、PDGFRa及/3、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與放射線治療之組合用於治療乳癌或卵巢癌。 4. 至少一種選自 VEGFR1至 3、PDGFRa 及/?、FGFiU、2 及3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit 受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與另一種VEGFR 2、PDGFR 或 bFGFR 拮抗劑(例 如伐他拉尼(vatalanib) (PTK-787、ZD-6474或單株抗體阿 瓦斯丁(AvastinTM))或EGFR拮抗劑(例如塔赛伐 (tarceva) (OS 1-774))之組合,用於治療大腸直腸癌、實體 腫瘤、乳癌、非小細胞肺癌、小細胞肺癌或多發性骨髓 癌。 5. 至少一種選自VEGFR1至3、PDGFRa及尽、FGFIU、2及3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit 受體之拮抗劑,其 92580.doc •70- 1378795 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與抗代謝物(例如二氣胞鳴咬(gemcitabine))及 翻化合物(例如順16 (cisplatin)),或植物性抗癌藥物(例如 派克紫杉醇(paclitaxel))及鉑化合物(例如卡銘 (carboplatin))之組合,用於治療非小細胞肺癌或卵巢癌。 6. 至少一種選自 VEGFR1至 3、PDGFRa 及/5、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 為另一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與荷爾蒙拮抗劑(例如亮丙瑞林(Leuprorelin) 及氟他米特(flutamide))之組合,作為轉移的荷爾蒙敏感 性前列腺癌之持續及/或間歇性治療。 7. 至少一種選自VEGFR1至3、PDGFRa及冷、FGFR1、2及3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與鬼臼毒素衍生物(例如依託泊苷(et〇p〇side)) 及銘化合物(例如卡銘或順韵)之組合,用於治療小細胞 肺癌。 8. 至少一種選自 VEGFR1 至 3、PDGFRa及 /3、FGFR1、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之抬抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、.代謝物或醫藥上可接受之鹽類(例如化合物 92580.doc -71 - 1378795 MES(T)),與植物性抗癌藥物(例如派克紫杉醇或泰素)之 組合,用於治療卵巢癌、小細胞肺癌或前列腺癌。 9. 至少一種選自 VEGFR1 至 3、PDGFRo!及 /3、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit 受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與植物性抗癌藥物(例如泰索帝(taxotere))之組 合,用於治療前列腺癌。 10. 至少一種選自 VEGFR1至 3、PDGFRce及/3、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與鉑化合物(例如卡鉑)及植物性抗癌藥物(例 如派克紫杉醇)之組合,用於治療卵巢癌,特別是減積 手術(debulking surgery)後。 11. 至少一種選自 VEGFR1至3、PDGFRa 及|3、FGFIU、2 及3、 EGFR、.HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與一拓撲異構酶I抑制劑(例如拓撲替康 (topotecan))及一蒽環類(anthracycline)(例如阿黴素 (doxorubicin))之組合,用於治療印巢癌。 12. 至少一種選自 VEGFR1至 3、PDGFRa及尽、FGFRJ、2及 3、 EGFR、HER2、IGF1R、HGFR或 c-Kit受體之拮抗劑,其 92580.doc -72· 1378795 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)) ’與一拓撲異構酶I抑制劑(例如拓撲替康)之組 合,用於治療小細胞肺癌或卵巢癌。 13. 至少一種選自 VEGFR1至 3、PDGFRa及i3、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑,其 為另一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)) ’與植物性抗癌藥物(例如派克紫杉醇)及類固 醇荷爾蒙(例如雌莫司丁(estramustine))之組合,用於治 療荷爾蒙抗·性前列腺癌。 14. 至少一種選自 VEGFR1至 3、PDGFRa 及jS、FGFRJ、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)) ’與一長春生物驗(例如長春瑞賓(navelbine)) 之組合,用於治療肺癌。 15. 至少一種選自 VEGFR1至 3、PDGFRce 及 jS、FGFIU ' 2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit 受體之拮抗劑’其 為另一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與鉑化合物(例如卡鉑或順鉑,較佳的為卡鉑) 之組合,用於治療卵巢癌或非小細胞肺癌。 16_ 至少一種選自 VEGFR1至 3、PDGFRa 及/3、FGFRJ、2及 3、 92580.doc -73- 1378795 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑’其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與COX-2抑制劑(例如西樂標(celecoxib)、羅 菲西保(rofecoxib)或美洛昔康(meloxicam))之組合,用於 治療大腸或直腸癌。 17. 至少一種選自 VEGFR1至 3、PDGFRa 及 |3、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR 或 c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T)),與5-α還原酶抑制劑(例如非那雄安 (finasteride))之組合,用於治療前列腺癌。 18. 至少一種選自 VEGFR1至 3、PDGFRa及/?、FGFIU、2及 3、 EGFR、HER2、IGF1R、HGFR或c-Kit受體之拮抗劑,其 另為一種src酪胺酸激酶家族成員之拮抗劑,或其同質異 形物、代謝物或醫藥上可接受之鹽類(例如化合物 MES(T>.),與光化學治療劑 (PUYA,補骨脂内酯 (卩50131611)(?)與長波紫外線放射線(11\^)之組合))之組 合,用於治療牛皮癬。 本質上,對於腫瘤疾病之治療,根據本發明組合治療之 基本原理為,以下列方式組合特定及機制作用分子與更廣 作用治療觀念對癌症病患有治療上好處: •經由組合治療,目標細胞經由可能逃避的化學作用機制 而存活的機會將更少; 92580.doc -74- 1378795 •與早方治療的劑量相比,因為組合治療之附加及協同作 用,所需藥物的各別劑量可減少; :D ’α療中各別藥劑的時程安排降低了腫瘤細胞產生抗 的可此性,使某些藥物更能傳遞至腫瘤(降低腫瘤内 壓)’並可爲腫瘤細胞另闢死亡路徑。 . 八=此,藉由標定不同細胞結構及間隔,根據本發明之組 口。療係希望在存活率或腫瘤惡化的時間上,對廣大的病 心提供與相當的單方治療同樣之臨床上合適的利益。因 此,以特定抗血管生成治療,例如化合物MES(T),腫瘤似 乎車乂無法從習用化學治療的損傷中復原。並且,藉由阻斷 VEGF在血管滲透性之效應,腫瘤似乎會產生間質壓力下 降,而使細胞毒性藥物更能滲入。以特定的抗血管生成劑 之維持治療’例如化合物刪⑺,在標準細胞減量後,似 乎產生與細胞毒性治療之聯合反應。該現象已由臨床前證 據證實,抗血管生成化合物與細胞毒性治療產生了協力抗 腫瘤活性。 對於治療.非腫瘤疾㉟,根據*發明合理的組合治療亦在 組合特定及機制作用分子與更廣作用治療觀念對病患有治 療上好處°該組合治療之預期效果係避免目標細胞可能逃 避的化學作用機制’與單方治療所用的劑量相&,降低所 需藥物的各別劑量(因為組合治療之附加或協同作用),並降 低目和t細胞對藥物產生抗藥力之可能性。 【圖式簡單說明】 圖1 92580.doc -75- 1378795 暴露於化合物MES(T)後,在NIH3T3 KDR細胞上 VEGFR-2填酸化作用之抑制。上方鑲板為以填酸化酪胺酸 殘基(α-ΡΥ)之專一抗體所作之西方墨點。下方為使用 VEGFR-2〇-KDR)專一抗體所作之西方墨點。 圖2 評估帶有皮下FaDu腫瘤之裸鼠的腫瘤體積,未治療(虛 線),每週二次以50 mg/kg劑量之化合物MES(T) 口服治療 (黑線),或每週二次以100 mg/kg劑量之化合物MES(T)口服 治療(灰線)。 圖3 . 評估帶有皮下卵巢癌SKOV-3腫瘤之裸鼠的腫瘤體積,未 治療(破折線),每天二次以1 5 mg/kg EGFR/HER2抑制劑口 服治療(三角形),每天以50 mg/kg C12(T)治療(正方形),以 15 mg/kg EGFR/HER2抑制劑及 50 mg/kg C12(T)組合治療 (菱形)。 92580.doc 76-
Claims (1)
- 第093111920號專利申請案 中文申請專利範圍替換本;tt /Λ Λ» 挖条赛1 、申請專利範園厂 一種醫藥組合,其特徵在於包括: (0蛋白質酪胺酸激酶受體拮抗劑 (Τ) (Ζ)-3-(1-(4-(Ν-(4-甲基-哌畊-1-基)-甲基羰基)_N_ 曱基-胺基)-苯基胺基)_丨_笨基-伸甲基)_6_甲氧幾 基-2-°引β朵酮,或其醫藥上可接受之鹽類;及 (11)至少另一種化學治療劑或天然、半合成或合成治療 劑’其係選自喹唑啉衍生物4-[(3-氣-4-氟苯基)胺 基]-6-{[4-(Ν,Ν-二甲基胺基)]·氧_2_ 丁烯]•基]胺 *}-7-((S)-(四氫呋喃-3_基氧基)_喹唑啉或其醫藥上 可接受之鹽類、互變異構物或立體異構物。 2.根據請求項1之醫藥組合,其中該蛋白質酪胺酸激酶受體 拮k劑係3-Ζ-Π-(4-(Ν-((4-曱基-哌p井_1_基)_甲基羰*)_N_ 甲基·胺基)-苯胺基)-1-苯基-伸甲基]_6_甲氧羰基_2_吲哚 酮之單乙基磺酸鹽。 3.根據請求項1或2之醫藥組合’其中該另一種化學治療劑 或天然、半合成或合成治療劑係選自化合物4_[(3_氣_4_ 氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)·!·氧_2_丁烯_卜 基]胺基}-7-((S)-四氫咬喃-3-基氧基)_喹唑啉之二馬來酸 鹽,或其互變異構物或立體異構物。 4 ·根據請求項1或2之醫藥組合’其中該組合製備物係用於 治療腫瘤疾病。 5.根據請求項1或2之、醫藥組合,其中該組合製備物係用‘方/ 92580-1001214.doc 治療人類惡性腫瘤。 一 6.根據請求項1或2之醫藥組合,其中該組合製備物係用於 治療實體腫瘤。 .根據清求項1或2之醫藥組合’其中該組合製備物係用於 治療泌尿生殖器癌症、肺癌、腸胃道癌症.、頭及頸癌、 惡性間皮瘤、乳癌、惡性黑色素瘤或骨頭及軟組織肉瘤。 8·根據請求項1或2之醫藥組合,其中該組合製備物係用於 治療血液腫瘤。 9.根據請求項卜戈2之醫藥組合,其中該組合製備物係用於 治療難治的或復發的多發性骨髓癌、急性或慢性非淋巴 ί·生白血病、骨髓發育不良徵候群或急性淋巴性白血病。 以:據請求項…之醫藥植合,其十該組合製備物係用於 ~療非腫瘤疾病,例如糖尿病、視網膜病變、類 節炎或牛皮癬。 "Ί η·根據請求項ί或2之醫藥組合,其中選擇的蛋白質 激酶受體拮抗劑之調配物係用於口服投藥。 夂 12. -種醫藥組合製備物套組’其係用於治療 生、骨髓癌細胞之移動或鴻零或血管生之 胞増 括: 义杀病,其包 (1)蛋白質酪胺酸激酶受 土胺基)-本基胺基)]_苯基-伸甲基)6 基-2-吲哚酮, 苹 或其醫藥上可接受之鹽類;及 92580-1001214.doc (種化學治療劑或天然、半合成或合成治療 基^系選自啥。坐啦衍生物4_[(3_氯_4_氧苯基)胺 4-(N’N-二甲基胺基)-1_氧-2-丁締小基]胺 :_你)-(四氫呋喃_3_基氧基)_啥唑啉或其醫藥上 可接党之鹽類、互變異構物或立體異構物;’、括抗劑係包含在第一隔間中,及該另-種化 ’、月S天然、半合成或合成治療劑係包含在第二隔 間中’因而可同時、分開或連續投藥於需要此種治瘁之 病人。 深心 3.根據請求項12之醫藥組合製備物套組,其中該蛋白質酪 胺酸激酶受體拮抗劑係3_ζ_π_(導((4·甲基“"小 基甲基羰基)-Ν_甲基·胺基)_苯胺基苯基伸甲基]·6_ 甲氧羰基-2·吲哚酮之單乙基磺酸鹽。14.根據請求項12或13之醫藥組合製備物套組,其中該另一 種化學治療劑或天然、半合成或合成治療劑係選自化合 物4_[0氣-4-氟苯基)胺基]_6_{[4_(Ν,Ν二甲基胺基)小氧 2- 丁婦-1-基]胺基}_7_(⑻_四氫吱喃_3_基氧基)_喧唾啉 之二馬來酸鹽,或其互變異構物或立體異構物。 15.根據請求項12或13之醫藥組合製備物套組,其中選擇的 蛋白質酪胺酸激酶受體拮抗劑之調配物係用於口服投 藥。 16.根據請求項12或13之醫藥組合製備物套組,其特徵為經 投藥於需要此種治療之病人,該蛋白質酪胺酸激受體拮 抗劑(Τ)或其醫藥上可接受之鹽類的每日投藥劑量在以小 92580-1001214.doc 1378795 時的劑量區間内,至少丨2小時可使 量位於10至5〇〇 ng/mi間。 17. —種根據請求項1或2之醫藥組合之用途,其係用於製造 治療人類或非人類之哺乳動物t涉及細胞增生、骨趙癌 、.’田胞之移動或凋零或血管生成之疾病之醫藥品。 】8一種根據請求項12或13之醫藥組合製備物套組之用途, ::用於製造治療人類或非人類之哺乳動物中涉及細胞 增生、骨髓癌細胞之移動或、H私藥'周零或企管生成之疾病之醫92580-1001214.doc -4-
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03009587A EP1473043A1 (en) | 2003-04-29 | 2003-04-29 | Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis |
EP04000508 | 2004-01-13 | ||
EP04001171 | 2004-01-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200509931A TW200509931A (en) | 2005-03-16 |
TWI378795B true TWI378795B (en) | 2012-12-11 |
Family
ID=33424438
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099141618A TWI442924B (zh) | 2003-04-29 | 2004-04-28 | 用於治療涉及細胞增生,骨髓癌細胞之移動或凋零或血管生成之疾病之組合 |
TW093111920A TWI378795B (en) | 2003-04-29 | 2004-04-28 | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099141618A TWI442924B (zh) | 2003-04-29 | 2004-04-28 | 用於治療涉及細胞增生,骨髓癌細胞之移動或凋零或血管生成之疾病之組合 |
Country Status (31)
Country | Link |
---|---|
US (7) | US20050043233A1 (zh) |
EP (5) | EP2826480A1 (zh) |
JP (2) | JP4701159B2 (zh) |
KR (1) | KR101150315B1 (zh) |
CN (1) | CN1780627B (zh) |
AR (1) | AR044114A1 (zh) |
AU (2) | AU2004233576B2 (zh) |
BR (1) | BRPI0409919A (zh) |
CA (1) | CA2523868C (zh) |
CL (1) | CL2004000900A1 (zh) |
CO (1) | CO5640112A2 (zh) |
CY (1) | CY1114622T1 (zh) |
DK (1) | DK1622619T3 (zh) |
EA (2) | EA021757B1 (zh) |
EC (1) | ECSP056132A (zh) |
ES (1) | ES2437841T3 (zh) |
HK (1) | HK1091416A1 (zh) |
IL (1) | IL171579A (zh) |
ME (1) | ME00306B (zh) |
MX (1) | MXPA05011656A (zh) |
MY (1) | MY141119A (zh) |
NO (1) | NO333994B1 (zh) |
NZ (1) | NZ543774A (zh) |
PE (1) | PE20050463A1 (zh) |
PL (1) | PL1622619T4 (zh) |
PT (1) | PT1622619E (zh) |
RS (1) | RS52143B (zh) |
SI (1) | SI1622619T1 (zh) |
TW (2) | TWI442924B (zh) |
UY (1) | UY28287A1 (zh) |
WO (1) | WO2004096224A2 (zh) |
Families Citing this family (178)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA71976C2 (en) | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
US7019012B2 (en) * | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
US20050271663A1 (en) * | 2001-06-28 | 2005-12-08 | Domantis Limited | Compositions and methods for treating inflammatory disorders |
WO2003002609A2 (en) * | 2001-06-28 | 2003-01-09 | Domantis Limited | Dual-specific ligand and its use |
US20090197852A9 (en) * | 2001-08-06 | 2009-08-06 | Johnson Robert G Jr | Method of treating breast cancer using 17-AAG or 17-AG or a prodrug of either in combination with a HER2 inhibitor |
DE10221018A1 (de) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie |
JP4563171B2 (ja) | 2002-05-24 | 2010-10-13 | シェーリング コーポレイション | 中和ヒト抗igfr抗体 |
US9321832B2 (en) * | 2002-06-28 | 2016-04-26 | Domantis Limited | Ligand |
US7696320B2 (en) | 2004-08-24 | 2010-04-13 | Domantis Limited | Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor |
CN1678634A (zh) * | 2002-06-28 | 2005-10-05 | 多曼蒂斯有限公司 | 免疫球蛋白单个变体抗原结合区及其特异性构建体 |
EP1578801A2 (en) * | 2002-12-27 | 2005-09-28 | Domantis Limited | Dual specific single domain antibodies specific for a ligand and for the receptor of the ligand |
US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
US7691838B2 (en) | 2003-05-30 | 2010-04-06 | Kosan Biosciences Incorporated | Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics |
PL1663194T3 (pl) * | 2003-08-26 | 2011-01-31 | Merck Hdac Res Llc | Zastosowanie SAHA do leczenia międzybłoniaka |
US7399865B2 (en) | 2003-09-15 | 2008-07-15 | Wyeth | Protein tyrosine kinase enzyme inhibitors |
SI1667992T1 (sl) | 2003-09-19 | 2007-06-30 | Astrazeneca Ab | Kinazolinski derivati |
DE10349113A1 (de) * | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung von Aminocrotonylverbindungen |
US20050096332A1 (en) * | 2003-10-30 | 2005-05-05 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
US7326567B2 (en) | 2003-11-12 | 2008-02-05 | Schering Corporation | Plasmid system for multigene expression |
AR046639A1 (es) | 2003-11-21 | 2005-12-14 | Schering Corp | Combinaciones terapeuticas de anticuerpo anti- igfr1 |
WO2005070020A2 (en) | 2004-01-23 | 2005-08-04 | The Regents Of The University Of Colorado | Gefitinib sensitivity-related gene expression and products and methods related thereto |
US20080113874A1 (en) * | 2004-01-23 | 2008-05-15 | The Regents Of The University Of Colorado | Gefitinib sensitivity-related gene expression and products and methods related thereto |
GB0406446D0 (en) * | 2004-03-23 | 2004-04-28 | Astrazeneca Ab | Combination therapy |
GB0406445D0 (en) * | 2004-03-23 | 2004-04-28 | Astrazeneca Ab | Combination therapy |
US20080113039A1 (en) * | 2004-03-23 | 2008-05-15 | Stephen Robert Wedge | Combination Therapy |
WO2005094823A1 (ja) * | 2004-03-30 | 2005-10-13 | Kyowa Hakko Kogyo Co., Ltd. | Flt-3阻害剤 |
AP2139A (en) | 2004-04-02 | 2010-08-21 | Osi Pharm Inc | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors. |
WO2005117553A2 (en) * | 2004-05-27 | 2005-12-15 | The Regents Of The University Of Colorado | Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by cancer patients |
JP2008521907A (ja) | 2004-12-03 | 2008-06-26 | シェーリング コーポレイション | 抗igf1r治療について患者を予め選択するためのバイオマーカー |
PE20060777A1 (es) * | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
AU2006210572B2 (en) | 2005-02-03 | 2011-08-04 | The General Hospital Corporation | Method for treating gefitinib resistant cancer |
EP1846406B9 (en) | 2005-02-09 | 2012-01-11 | ArQule, Inc. | Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer |
US8152784B2 (en) * | 2005-02-24 | 2012-04-10 | Wisconsin Alumni Research Foundation | Method for treating or preventing steroid-induced glaucoma |
ITRM20050103A1 (it) * | 2005-03-10 | 2006-09-11 | Rocco Savino | Associazione di antagonisti della interleuchina 6 e farmaci antiproliferativi. |
US20080182865A1 (en) * | 2005-03-11 | 2008-07-31 | Witta Samir E | Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors |
CA2600845A1 (en) * | 2005-03-11 | 2006-09-21 | The Regents Of The University Of Colorado | Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors |
PL1874821T3 (pl) * | 2005-04-26 | 2013-09-30 | Trion Pharma Gmbh | Kombinacja przeciwciał i glikokortykoidów do leczenia raka |
CN101175489A (zh) * | 2005-04-29 | 2008-05-07 | 高山生物科学股份有限公司 | 用17-aag或17-ag或其前药治疗多发性骨髓瘤的方法 |
US20060252740A1 (en) * | 2005-04-29 | 2006-11-09 | Johnson Robert G Jr | Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either in combination with a proteasome inhibitor |
US20080032719A1 (en) * | 2005-10-01 | 2008-02-07 | Outland Research, Llc | Centralized establishment-based tracking and messaging service |
WO2007016254A2 (en) * | 2005-07-27 | 2007-02-08 | The Board Of Trustees Of The University Of Arkansas | Antineoplastic activities of ellipticine and its derivatives |
PL1912640T3 (pl) * | 2005-08-03 | 2015-11-30 | Novartis Ag | Zastosowanie inhibitora HDAC panobinostatu w leczeniu szpiczaka |
JP2009514874A (ja) * | 2005-11-04 | 2009-04-09 | メルク エンド カムパニー インコーポレーテッド | Saha及びペメトレキセドを用いて癌を治療する方法 |
JP2009514891A (ja) * | 2005-11-04 | 2009-04-09 | メルク エンド カムパニー インコーポレーテッド | 癌を治療するためのsaha及びエルロチニブを用いる方法 |
CN103110948A (zh) | 2005-11-04 | 2013-05-22 | 惠氏公司 | mTOR抑制剂、赫赛汀和/或HKI-272的抗肿瘤组合 |
EP1792622A1 (en) | 2005-11-11 | 2007-06-06 | GPC Biotech AG | Anti-proliferative combination therapy comprising a platinum-based chemotherapeutic agent and EGFR inhibitors or pyrimidine analogues |
PT1948180E (pt) * | 2005-11-11 | 2013-05-10 | Boehringer Ingelheim Int | Tratamento de combinação de cancro compreendendo inibidores de egfr/her2 |
EP1948179A1 (en) * | 2005-11-11 | 2008-07-30 | Boehringer Ingelheim International GmbH | Quinazoline derivatives for the treatment of cancer diseases |
WO2007057397A1 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer |
US7648976B2 (en) * | 2005-11-23 | 2010-01-19 | Bristol-Myers Squibb Company | 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations |
GB0523810D0 (en) * | 2005-11-23 | 2006-01-04 | Astrazeneca Ab | Pharmaceutical compositions |
US10149889B2 (en) | 2005-11-25 | 2018-12-11 | Rutgers, The State University Of New Jersey | Compositions for the treatment of cancer, and methods for testing and using the same |
US8926990B2 (en) | 2009-10-13 | 2015-01-06 | Rutgers, The State University Of New Jersey | Treatment and diagnosis of inflammatory disorders and HIV |
BRPI0619225A2 (pt) * | 2005-12-01 | 2017-11-07 | Domantis Ltd | monômero de anticorpo de domínio, ligando, ácidos nucleicos isolado e recombinante, vetor, célula hospedeira, método para produzir um monômero de dab de ligando, composição farmacêutica, dispositivo de liberação de medicamento, uso de um monômero de anticorpo de domínio, e, método para tratar uma doença inflamatória, artrite ou doença respiratória |
US8575164B2 (en) * | 2005-12-19 | 2013-11-05 | OSI Pharmaceuticals, LLC | Combination cancer therapy |
WO2007079437A2 (en) * | 2006-01-03 | 2007-07-12 | Kereos, Inc. | Combination antitumor therapies |
JP5241513B2 (ja) * | 2006-01-26 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | アミノクロトニルアミノ置換キナゾリン誘導体の合成方法 |
ES2579762T3 (es) * | 2006-03-01 | 2016-08-16 | Janssen Pharmaceutica N.V. | Tratamiento del cáncer combinando agente linfo - reductor con CLTs y citoquinas |
RU2452492C2 (ru) * | 2006-04-05 | 2012-06-10 | Новартис Аг | КОМБИНАЦИИ, ВКЛЮЧАЮЩИЕ ИНГИБИТОРЫ Bcr-Abl/c-Kit/PDGF-R TK, ДЛЯ ЛЕЧЕНИЯ РАКА |
US20070258976A1 (en) * | 2006-05-04 | 2007-11-08 | Ward Keith W | Combination Therapy for Diseases Involving Angiogenesis |
ZA200809956B (en) * | 2006-05-26 | 2010-07-28 | Celgene Corp | Methods and compositions using Immunomodulatory compounds in combination therapy |
EP2094268A2 (en) | 2006-05-26 | 2009-09-02 | Bayer HealthCare, LLC | Drug combinations with substituted diaryl ureas for the treatment of cancer |
EP1870400A1 (en) * | 2006-06-08 | 2007-12-26 | Boehringer Ingelheim Pharma GmbH & Co. KG | Salts and crystalline salt forms of an 2-indolinone derivative |
CA2656836A1 (en) * | 2006-07-13 | 2008-01-17 | Zymogenetics, Inc. | Interleukin 21 and tyrosine kinase inhibitor combination therapy |
PT2068880E (pt) | 2006-09-18 | 2012-07-12 | Boehringer Ingelheim Int | Método para tratamento do cancro apresentando mutações no egfr |
AU2007317921A1 (en) * | 2006-11-03 | 2008-05-15 | University Of Maryland, Baltimore | Methods of using SAHA and Bortezomib for treating multiple myeloma |
WO2008079849A2 (en) * | 2006-12-22 | 2008-07-03 | Genentech, Inc. | Antibodies to insulin-like growth factor receptor |
US20100047234A1 (en) * | 2007-03-14 | 2010-02-25 | Markovic Svetomir N | Treating skin cancer |
US9358292B2 (en) | 2007-04-08 | 2016-06-07 | Immunolight, Llc | Methods and systems for treating cell proliferation disorders |
JP5563818B2 (ja) * | 2007-05-29 | 2014-07-30 | 北海道公立大学法人 札幌医科大学 | 癌治療剤及び癌の治療方法 |
BRPI0812398A2 (pt) * | 2007-06-06 | 2019-09-24 | Domantis Ltd | domínio variável simples de imunoglobulina anti-vegf, antagonista anti-vegf, domínio variável simples de imunoglobulina resistente à protease, uso do antagonista vegf, método para a dispensação oral ou dispensação de um medicamento ao trato gi de um paciente ou ao pulmão ou tecido pulmonar ou olho de um paciente, dispositivo de dispensação pulmonar, formulação oral, ligando específico duplo, ácido nucleico isolado ou recombinante, vetor, célula hospedeira, método para produzir polipeptídeo, composição farmacêutica, polipeptídeo, e, proteína de fusão |
CN101801969B (zh) | 2007-06-22 | 2014-10-29 | 艾科尔公司 | 治疗癌症的吲哚基吡咯烷 |
JP2010530885A (ja) | 2007-06-22 | 2010-09-16 | アークル インコーポレイテッド | キナゾリノン化合物およびその使用方法 |
EP2170870B1 (en) | 2007-06-22 | 2014-03-05 | ArQule, Inc. | Pyrrolidinone, pyrrolidine-2, 5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer |
WO2009023846A2 (en) * | 2007-08-15 | 2009-02-19 | The Research Foundation Of State University Of New York | Methods for heat shock protein dependent cancer treatment |
WO2009048947A1 (en) * | 2007-10-09 | 2009-04-16 | Board Of Regents, The University Of Texas System | Methods of treatment of opioid tolerance, physical dependence, pain, and addiction with inhibitors of certain growth factor receptors |
US8022216B2 (en) | 2007-10-17 | 2011-09-20 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
US20090131367A1 (en) * | 2007-11-19 | 2009-05-21 | The Regents Of The University Of Colorado | Combinations of HDAC Inhibitors and Proteasome Inhibitors |
WO2009091939A1 (en) * | 2008-01-18 | 2009-07-23 | Osi Pharmaceuticals, Inc. | Imidazopyrazinol derivatives for the treatment of cancers |
ES2456296T3 (es) | 2008-03-27 | 2014-04-21 | Zymogenetics, Inc. | Composiciones y procedimientos para inhibir PDGFR beta y VEGF-A |
WO2009128805A1 (en) * | 2008-04-17 | 2009-10-22 | The Johns Hopkins University | On01910. na enhances chemotherapeutic agent activity in drug-resistant tumors |
JP5993573B2 (ja) * | 2008-06-06 | 2016-09-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 医薬組み合わせ |
UA107560C2 (uk) * | 2008-06-06 | 2015-01-26 | Фармацевтична лікарська форма для негайного вивільнення похідної індолінону | |
EA029996B1 (ru) | 2008-06-06 | 2018-06-29 | Бёрингер Ингельхайм Интернациональ Гмбх | Капсулярная лекарственная форма, содержащая суспензионную композицию производного индолинона |
US20170065529A1 (en) | 2015-09-09 | 2017-03-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
UY31867A (es) * | 2008-06-06 | 2010-01-29 | Boehringer Ingelheim Int | Nuevas formulaciones farmacéuticas sólidas que comprenden bibw 2992 |
CA2725598C (en) | 2008-06-17 | 2013-10-08 | Wyeth Llc | Antineoplastic combinations containing hki-272 and vinorelbine |
EP2138494A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted alkyl pyrimidin-4-one derivatives |
US8338439B2 (en) | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
US8450335B2 (en) | 2008-06-27 | 2013-05-28 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
US11351168B1 (en) | 2008-06-27 | 2022-06-07 | Celgene Car Llc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
EP3266453A1 (en) | 2008-07-03 | 2018-01-10 | Mayo Foundation for Medical Education and Research | Treating cancer |
EP2324012A1 (en) * | 2008-07-29 | 2011-05-25 | Boehringer Ingelheim International GmbH | New compounds |
WO2010017163A1 (en) | 2008-08-04 | 2010-02-11 | Wyeth | Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine |
EP2387401A1 (en) * | 2009-01-14 | 2011-11-23 | Boehringer Ingelheim International GmbH | Method for treating colorectal cancer |
US8802384B2 (en) | 2009-03-12 | 2014-08-12 | Boehringer Ingelheim International Gmbh | Method or system using biomarkers for the monitoring of a treatment |
CN101837129B (zh) * | 2009-03-19 | 2012-12-12 | 鼎泓国际投资(香港)有限公司 | 含cMet抑制剂、HDAC抑制剂与EGFR酪氨酸激酶抑制剂的药物组合物及其应用 |
KR20140036332A (ko) | 2009-04-06 | 2014-03-25 | 와이어쓰 엘엘씨 | 네라티닙을 이용한 유방암의 치료법 |
BRPI1016245A2 (pt) | 2009-04-20 | 2015-09-01 | Osi Pharmaceuticals Llc | Preparação de c-pirazina-metilaminas. |
WO2010129740A1 (en) * | 2009-05-07 | 2010-11-11 | Osi Pharmaceuticals, Inc. | Use of osi-906 for treating adrenocortical carcinoma |
US20120142703A1 (en) * | 2009-05-14 | 2012-06-07 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
US20100316639A1 (en) | 2009-06-16 | 2010-12-16 | Genentech, Inc. | Biomarkers for igf-1r inhibitor therapy |
HUE044629T2 (hu) | 2009-07-06 | 2019-11-28 | Boehringer Ingelheim Int | Eljárás BIBW2992, annak sói, valamint e hatóanyagot tartalmazó szilárd gyógyászati készítmények szárítására |
NZ597695A (en) * | 2009-07-17 | 2014-05-30 | Exelixis Inc | Crystalline forms of n-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl} oxy)phenyl]-n’-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide |
EP2464218B1 (en) * | 2009-08-10 | 2015-05-27 | Board of Regents, The University of Texas System | Treatment of brain metastases with inhibitors of endothelin receptors in combination with a cytotoxic chemotherapy agent |
CA2774999A1 (en) | 2009-09-30 | 2011-04-07 | President And Fellows Of Harvard College | Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products |
US20120107304A1 (en) * | 2010-04-27 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Combination therapy in treatment of oncological and fibrotic diseases |
CN103096716B (zh) | 2010-08-10 | 2016-03-02 | 西建阿维拉米斯研究公司 | Btk抑制剂的苯磺酸盐 |
SI2608792T1 (en) | 2010-08-26 | 2018-02-28 | Boehringer Ingelheim International Gmbh | Methods for the administration of an EGFR inhibitor |
WO2012061299A1 (en) | 2010-11-01 | 2012-05-10 | Avila Therapeutics, Inc. | Heterocyclic compounds and uses thereof |
WO2012061303A1 (en) | 2010-11-01 | 2012-05-10 | Avila Therapeutics, Inc. | Heteroaryl compounds and uses thereof |
EP2637502B1 (en) | 2010-11-10 | 2018-01-10 | Celgene CAR LLC | Mutant-selective egfr inhibitors and uses thereof |
US8951972B2 (en) * | 2010-12-09 | 2015-02-10 | Five Prime Therapeutics, Inc. | FGFR1 extracellular domain combination therapies for lung cancer |
US9352017B2 (en) | 2011-03-16 | 2016-05-31 | Rutgers, The State University Of New Jersey | Combination therapy with leukotoxin |
PL2707030T3 (pl) | 2011-05-09 | 2020-08-24 | Mayo Foundation For Medical Education And Research | Metody leczenia raka |
US8828391B2 (en) | 2011-05-17 | 2014-09-09 | Boehringer Ingelheim International Gmbh | Method for EGFR directed combination treatment of non-small cell lung cancer |
BR112013033836A2 (pt) * | 2011-07-01 | 2017-02-21 | Novartis Ag | terapia de combinação |
US9393224B2 (en) * | 2011-08-26 | 2016-07-19 | Osaka University | Prophylactic and/or therapeutic agent for cardiovascular complications of diabetes |
CA2853498A1 (en) | 2011-10-28 | 2013-05-02 | Celgene Avilomics Research, Inc. | Methods of treating a bruton's tyrosine kinase disease or disorder |
US20130136740A1 (en) * | 2011-11-14 | 2013-05-30 | Thomas Harding | Methods of treating cancer |
SG11201405691WA (en) | 2012-03-15 | 2014-10-30 | Celgene Avilomics Res Inc | Solid forms of an epidermal growth factor receptor kinase inhibitor |
CN104284584B (zh) | 2012-03-15 | 2019-06-04 | 西建卡尔有限责任公司 | 表皮生长因子受体激酶抑制剂的盐 |
KR101386697B1 (ko) * | 2012-06-18 | 2014-04-18 | 아주대학교산학협력단 | 이매티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 치료 또는 예방용 조성물 |
WO2014004543A1 (en) * | 2012-06-25 | 2014-01-03 | Mone Zaidi Consulting, Inc. | Combination cancer therapy using bisphosphonates and anti-egfr agents |
JP2015524400A (ja) | 2012-07-19 | 2015-08-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 9−[4−(3−クロロ−2−フルオロ−フェニルアミノ)−7−メトキシ−キナゾリン−6−イルオキシ]−1,4−ジアザ−スピロ[5.5]ウンデカン−5−オンのフマル酸塩、その薬物としての使用及び調製 |
CN103664737A (zh) * | 2012-09-25 | 2014-03-26 | 杨子娇 | 一类治疗房角狭窄的化合物及其用途 |
US10413606B2 (en) | 2012-10-01 | 2019-09-17 | Mayo Foundation For Medical Education And Research | Methods for treating cancer with nanoparticle complexes of albumin-bound paclitaxel and anti-VEGF antibodies |
WO2014100748A1 (en) | 2012-12-21 | 2014-06-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
KR101911048B1 (ko) | 2013-01-29 | 2018-10-24 | 삼성전자주식회사 | p53 활성화제 및 c-Met 억제제를 포함하는 병용 투여용 약학 조성물 |
MX2015009952A (es) | 2013-02-08 | 2015-10-05 | Celgene Avilomics Res Inc | Inhibidores de cinasas reguladas por señales extracelulares (erk) y sus usos. |
KR20150123250A (ko) * | 2013-03-06 | 2015-11-03 | 제넨테크, 인크. | 암 약물 내성의 치료 및 예방 방법 |
US9376437B2 (en) | 2013-03-13 | 2016-06-28 | Oncoceutics, Inc | 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, salts thereof and methods of using the same in combination therapy |
US9688679B2 (en) | 2013-03-13 | 2017-06-27 | Oncoceutics, Inc. | 7-benzyl-4-(methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidin-5 (1H)-one, salts thereof and methods of using the same in combination therapy |
WO2014160130A1 (en) * | 2013-03-13 | 2014-10-02 | Oncoceutics, Inc. | Combination therapy with 7-benzyl-10-(2-methylbenzyl)-2,6,7,8,9,10-hexahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-5(3h)-one |
RU2524309C1 (ru) * | 2013-04-18 | 2014-07-27 | Государственное бюджетное учреждение здравоохранения Московской области "Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского" (ГБУЗ МО МОНИКИ им. М.Ф. Владимирского) | Способ выбора тактики лечения местно-распространенного рака предстательной железы |
US20140350022A1 (en) | 2013-05-10 | 2014-11-27 | Boehringer Ingelheim International Gmbh | Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment |
US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
US9415049B2 (en) | 2013-12-20 | 2016-08-16 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
CN106604750B (zh) | 2014-06-16 | 2021-05-07 | 梅约医学教育与研究基金会 | 治疗骨髓瘤 |
WO2015200828A1 (en) * | 2014-06-27 | 2015-12-30 | H. Lee Moffit Cancer Center And Research Institute, Inc. | Conjugates for immunotherapy |
EP3179858B1 (en) | 2014-08-13 | 2019-05-15 | Celgene Car Llc | Forms and compositions of an erk inhibitor |
US9446148B2 (en) | 2014-10-06 | 2016-09-20 | Mayo Foundation For Medical Education And Research | Carrier-antibody compositions and methods of making and using the same |
KR102309882B1 (ko) | 2014-11-21 | 2021-10-06 | 삼성전자주식회사 | c-Met 저해제 및 IGF-1R 저해제를 포함하는 병용 투여용 약학 조성물 |
MA55402A (fr) | 2015-01-30 | 2022-02-02 | Oncoceutics Inc | Dérivés de 7-benzyl-4-(2-méthylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, leurs sels et leur utilisation en thérapie |
EP3056202A1 (en) * | 2015-02-16 | 2016-08-17 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Benzopyrrolidone derivatives possessing antiviral and anticancer properties |
CA2982205A1 (en) | 2015-04-10 | 2016-10-13 | David W. Andrews | Methods and compositions for treating cancers and enhancing therapeutic immunity by selectively reducing immunomodulatory m2 monocytes |
TWI664965B (zh) | 2015-06-22 | 2019-07-11 | 新源生物科技股份有限公司 | 酪胺酸激酶抑制劑之眼用調配物、其使用方法、及其製備方法 |
TW201707725A (zh) | 2015-08-18 | 2017-03-01 | 美國馬友醫藥教育研究基金會 | 載體-抗體組合物及其製造及使用方法 |
TW201713360A (en) | 2015-10-06 | 2017-04-16 | Mayo Foundation | Methods of treating cancer using compositions of antibodies and carrier proteins |
US10668068B2 (en) * | 2015-10-07 | 2020-06-02 | The Research Foundation For The State University Of New York | Treating cancer with drug combinations |
US11571469B2 (en) | 2016-01-07 | 2023-02-07 | Mayo Foundation For Medical Education And Research | Methods of treating cancer with interferon wherein the cancer cells are HLA negative or have reduced HLA expression |
CA3014531A1 (en) | 2016-02-12 | 2017-08-17 | Mayo Foundation For Medical Education And Research | Hematologic cancer treatments |
EP3432928A4 (en) | 2016-03-21 | 2019-11-20 | Mayo Foundation for Medical Education and Research | PROCESS FOR IMPROVING THE THERAPEUTIC INDEX FOR CHEMOTHERAPEUTIC |
AU2017238119A1 (en) | 2016-03-21 | 2018-10-11 | Mayo Foundation For Medical Education And Research | Methods for reducing toxicity of a chemotherapeutic drug |
US10618969B2 (en) | 2016-04-06 | 2020-04-14 | Mayo Foundation For Medical Education And Research | Carrier-binding agent compositions and methods of making and using the same |
WO2017178428A1 (en) | 2016-04-13 | 2017-10-19 | Boehringer Ingelheim International Gmbh | Pharmaceutical combination of nintedanib, trifluridine and tipiracil for treating colorectal cancer |
EP3246029A1 (en) | 2016-05-19 | 2017-11-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer |
WO2017203027A1 (en) | 2016-05-27 | 2017-11-30 | Boehringer Ingelheim International Gmbh | Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone |
EP3463353A1 (en) | 2016-06-01 | 2019-04-10 | Boehringer Ingelheim International GmbH | Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone |
CN106393602B (zh) * | 2016-08-31 | 2018-12-07 | 宁波方正汽车模具股份有限公司 | 用于保险杠模具的顶出装置 |
CA3035378A1 (en) | 2016-09-01 | 2018-03-08 | Mayo Foundation For Medical Education And Research | Carrier-pd-l1 binding agent compositions for treating cancers |
JP2019526579A (ja) | 2016-09-01 | 2019-09-19 | マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチMayo Foundation For Medical Education And Research | T細胞癌を標的とする為の方法及び組成物 |
CA3035655A1 (en) | 2016-09-06 | 2018-03-15 | Mayo Foundation For Medical Education And Research | Methods of treating pd-l1 expressing cancer |
EP3509635A1 (en) | 2016-09-06 | 2019-07-17 | Vavotar Life Sciences LLC | Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins |
KR102486055B1 (ko) | 2016-09-06 | 2023-01-09 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 파클리탁셀-알부민-결합제 조성물 및 그의 사용 및 제조 방법 |
CN107970246B (zh) * | 2016-10-21 | 2020-08-28 | 中山大学 | 非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用 |
CN110573608A (zh) * | 2017-02-10 | 2019-12-13 | 施明哲 | 调节纤维母细胞生长因子受体3活化的组合物及方法 |
BR112019018555A2 (pt) | 2017-03-09 | 2020-04-14 | Univ Jefferson | métodos e composições para tratamento de cânceres utilizando antissenso |
CN110573161A (zh) | 2017-03-28 | 2019-12-13 | 勃林格殷格翰国际有限公司 | 用于治疗肌营养不良的方法的尼达尼布 |
CN110662536B (zh) | 2017-03-29 | 2023-06-23 | 普渡研究基金会 | 激酶网络抑制剂及其用途 |
CN109316463B (zh) * | 2018-08-03 | 2021-03-19 | 暨南大学 | 一种复合纳米粒及其制备方法和应用 |
WO2020092682A1 (en) * | 2018-11-02 | 2020-05-07 | Thomas Jefferson University | Methods and compositions for treating hepatocellular carcinoma using antisense |
WO2020232247A1 (en) | 2019-05-14 | 2020-11-19 | Provention Bio, Inc. | Methods and compositions for preventing type 1 diabetes |
US20230135671A1 (en) | 2020-04-01 | 2023-05-04 | Boehringer Ingelheim International Gmbh | Use of biomarkers in the treatment of fibrotic conditions |
CN111454346B (zh) * | 2020-06-04 | 2022-04-08 | 山东农业大学 | 一种来源于大麦的参与硝态氮调控的转录因子HvNLP2及其用途 |
BR112022025381A2 (pt) | 2020-06-11 | 2023-01-24 | Provention Bio Inc | Métodos e composições para prevenir diabetes tipo 1 |
WO2024037982A1 (en) | 2022-08-16 | 2024-02-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical formulations of nintedanib for intraocular use |
Family Cites Families (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US176392A (en) * | 1876-04-18 | Improvement in ironing-tables | ||
US127453A (en) * | 1872-06-04 | Improvement in cultivators | ||
US19819A (en) * | 1858-03-30 | Improvement in lightning-conductors | ||
US108545A (en) * | 1870-10-18 | Improvement in sled-brakes | ||
GB395546A (en) | 1931-10-12 | 1933-07-20 | Robert Pauli Scherer | Method of and apparatus for making capsules |
US2720463A (en) | 1950-11-17 | 1955-10-11 | American Cyanamid Co | Gelatin capsule casting composition preparation |
US2870062A (en) | 1956-04-27 | 1959-01-20 | Scherer Corp R P | Gelatin composition for capsules |
EP0169398B1 (de) | 1984-07-24 | 1990-08-29 | R.P. Scherer GmbH | Oxytetracyclin-HC1-Weichgelatinekapseln und Verfahren zu ihrer Herstellung |
US5242679A (en) | 1985-01-14 | 1993-09-07 | Neorx Corporation | Metal radionuclide labeled proteins for diagnosis and therapy |
DE3680924D1 (de) | 1985-01-14 | 1991-09-26 | Neorx Corp | Metall-radionuklid markiertes protein fuer diagnose und therapie. |
US4897255A (en) | 1985-01-14 | 1990-01-30 | Neorx Corporation | Metal radionuclide labeled proteins for diagnosis and therapy |
US5082930A (en) | 1986-05-29 | 1992-01-21 | Mallinckrodt Medical, Inc. | Coupling agents for joining radionuclide metal ions with biologically useful proteins |
US4861869A (en) | 1986-05-29 | 1989-08-29 | Mallinckrodt, Inc. | Coupling agents for joining radionuclide metal ions with biologically useful proteins |
US4965392A (en) | 1987-03-26 | 1990-10-23 | Neorx Corporation | Chelating compounds for metal-radionuclide labeled proteins |
DE3889956T2 (de) | 1987-03-26 | 1994-12-22 | Neorx Corp | Metall-Radionuklid-markierte Proteine und Glykoproteine zur Diagnose und Therapie. |
WO1993005804A1 (en) | 1991-09-18 | 1993-04-01 | Sloan-Kettering Institute For Cancer Research | Activated stromal fibroblast-specific antibody, f19 and methods of using the same |
ES2326118T3 (es) * | 1993-09-20 | 2009-10-01 | The Trustees Of The University Of Pennsylvania | Regulacion de la expresion del gen bcl-2. |
US6811779B2 (en) * | 1994-02-10 | 2004-11-02 | Imclone Systems Incorporated | Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy |
US20030108545A1 (en) | 1994-02-10 | 2003-06-12 | Patricia Rockwell | Combination methods of inhibiting tumor growth with a vascular endothelial growth factor receptor antagonist |
SE9504661D0 (sv) | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
WO1997041844A1 (en) * | 1996-05-09 | 1997-11-13 | Alcon Laboratories, Inc. | Combinations of angiostatic compounds |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
IL133009A0 (en) * | 1997-05-28 | 2001-03-19 | Aventis Pharm Prod Inc | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
WO1999048868A2 (en) | 1998-03-26 | 1999-09-30 | Sugen, Inc. | Heterocyclic classes of compounds for the modulating tyrosine protein kinase |
DE19816624A1 (de) | 1998-04-15 | 1999-10-21 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
EP1115704B1 (de) | 1998-09-25 | 2003-06-18 | Boehringer Ingelheim Pharma GmbH & Co.KG | Neue substituierte indolinone mit einer inhibierenden wirkung auf verschiedene kinasen und cyclin/cdk-komplexe |
CN1346282A (zh) * | 1998-12-23 | 2002-04-24 | G.D.西尔公司 | 在肿瘤的治疗中使用环加氧酶-2-抑制剂与一种或多种抗肿瘤剂作为联合治疗的方法 |
DE19924401A1 (de) | 1999-05-27 | 2000-11-30 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
UA71976C2 (en) | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
US6762180B1 (en) * | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
UA75054C2 (uk) * | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
DE19949209A1 (de) | 1999-10-13 | 2001-04-19 | Boehringer Ingelheim Pharma | In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
DE10042696A1 (de) * | 2000-08-31 | 2002-03-14 | Boehringer Ingelheim Pharma | In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
BR0014843A (pt) * | 1999-10-19 | 2002-06-11 | Merck & Co Inc | Composto, composição farmacêutica, métodos para tratar ou prevenir o câncer em um mamìfero, uma doença em que a angiogênese está implicada, a vascularização retinal, a retinipatia diabética, a degeneração macular relacionada com a idade, doença inflamatória, uma doença ou condição dependente de tirosina quinase e, patologias relacionadas com o osso, processo para fabricar uma composição farmacêutica, e, método para reduzir ou impedir o dano de tecido que segue um evento isquêmico |
US6794393B1 (en) * | 1999-10-19 | 2004-09-21 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
UA72946C2 (uk) * | 1999-11-05 | 2005-05-16 | Астразенека Аб | Похідні хіназоліну як інгібітори васкулярного ендотеліального фактора росту (vegf) |
SK287142B6 (sk) | 2000-02-15 | 2010-01-07 | Sugen, Inc. | Inhibítory proteínkináz na báze pyrolom substituovaného 2-indolinónu, farmaceutický prípravok s ich obsahom a ich použitie |
WO2001064251A2 (en) * | 2000-03-02 | 2001-09-07 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Combination chemotherapy |
TWI310684B (en) * | 2000-03-27 | 2009-06-11 | Bristol Myers Squibb Co | Synergistic pharmaceutical kits for treating cancer |
AU2001212168A1 (en) * | 2000-10-20 | 2002-05-06 | Bristol-Myers Squibb Pharma Company | Acylsemicarbazides and their use as cyclin dependent kinase (CDK) inhibitors |
US6638965B2 (en) * | 2000-11-01 | 2003-10-28 | Boehringer Ingelheim Pharma Kg | Substituted indolinones, preparation thereof and their use as pharmaceutical compositions |
DE10054019A1 (de) | 2000-11-01 | 2002-05-23 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
DK1365808T3 (da) * | 2000-11-06 | 2011-05-16 | Pharma Mar Sa | Sammensætninger til antitumorbehandling indeholdende ecteinascidin 743 |
AU2002228849A1 (en) * | 2000-12-08 | 2002-06-18 | Bristol-Myers Squibb Pharma Company | Semicarbazides and their uses as cyclin dependent kinase inhibitors |
DE10063435A1 (de) | 2000-12-20 | 2002-07-04 | Boehringer Ingelheim Pharma | Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
CZ299756B6 (cs) * | 2001-05-16 | 2008-11-12 | Novartis Ag | Kombinace s obsahem N-{5-[4-(4-methyl-piperazino-methyl)benzoylamido]-2-methylfenyl}-4-(3-pyridyl)-2-pyrimidin-aminu k lécení proliferativních onemocnení |
US7109204B2 (en) * | 2001-08-01 | 2006-09-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
DE10138538C2 (de) | 2001-08-06 | 2003-12-04 | Faustus Forschungs Cie | Tumorhemmende Lanthanverbindungen |
CA2459879A1 (en) | 2001-09-10 | 2003-03-20 | Sugen, Inc. | 3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene)-2-indolinone derivatives as kinase inhibitors |
JP2005508322A (ja) * | 2001-09-24 | 2005-03-31 | ジェシー エル エス オウ | 併用療法に用いられるスラミンの化学増感用量を決定するための方法及び成分 |
US6998391B2 (en) | 2002-02-07 | 2006-02-14 | Supergen.Inc. | Method for treating diseases associated with abnormal kinase activity |
US20030225079A1 (en) | 2002-05-11 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy |
DE10221018A1 (de) | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie |
WO2003097855A2 (en) | 2002-05-14 | 2003-11-27 | Baylor College Of Medicine | Small molecule inhibitors of her2 expression |
DE10233500A1 (de) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel |
US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
DE10349113A1 (de) | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung von Aminocrotonylverbindungen |
US20060058311A1 (en) | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
EP1948179A1 (en) | 2005-11-11 | 2008-07-30 | Boehringer Ingelheim International GmbH | Quinazoline derivatives for the treatment of cancer diseases |
PT1948180E (pt) | 2005-11-11 | 2013-05-10 | Boehringer Ingelheim Int | Tratamento de combinação de cancro compreendendo inibidores de egfr/her2 |
JP5241513B2 (ja) * | 2006-01-26 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | アミノクロトニルアミノ置換キナゾリン誘導体の合成方法 |
PT2068880E (pt) | 2006-09-18 | 2012-07-12 | Boehringer Ingelheim Int | Método para tratamento do cancro apresentando mutações no egfr |
UY31867A (es) * | 2008-06-06 | 2010-01-29 | Boehringer Ingelheim Int | Nuevas formulaciones farmacéuticas sólidas que comprenden bibw 2992 |
JP5993573B2 (ja) | 2008-06-06 | 2016-09-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 医薬組み合わせ |
-
2004
- 2004-04-22 US US10/830,147 patent/US20050043233A1/en not_active Abandoned
- 2004-04-23 UY UY28287A patent/UY28287A1/es not_active Application Discontinuation
- 2004-04-23 MY MYPI20041495A patent/MY141119A/en unknown
- 2004-04-24 SI SI200432093T patent/SI1622619T1/sl unknown
- 2004-04-24 ME MEP-2008-469A patent/ME00306B/me unknown
- 2004-04-24 CN CN2004800115442A patent/CN1780627B/zh not_active Expired - Lifetime
- 2004-04-24 EA EA200900272A patent/EA021757B1/ru not_active IP Right Cessation
- 2004-04-24 PT PT47293667T patent/PT1622619E/pt unknown
- 2004-04-24 MX MXPA05011656A patent/MXPA05011656A/es active IP Right Grant
- 2004-04-24 NZ NZ543774A patent/NZ543774A/en unknown
- 2004-04-24 EP EP14176946.3A patent/EP2826480A1/en not_active Withdrawn
- 2004-04-24 BR BRPI0409919-2A patent/BRPI0409919A/pt not_active IP Right Cessation
- 2004-04-24 EP EP10184972A patent/EP2359829A1/en not_active Withdrawn
- 2004-04-24 EP EP10184960A patent/EP2361626A1/en not_active Withdrawn
- 2004-04-24 EP EP10184974A patent/EP2409705A1/en not_active Withdrawn
- 2004-04-24 AU AU2004233576A patent/AU2004233576B2/en not_active Expired
- 2004-04-24 EA EA200501555A patent/EA011888B1/ru not_active IP Right Cessation
- 2004-04-24 ES ES04729366.7T patent/ES2437841T3/es not_active Expired - Lifetime
- 2004-04-24 DK DK04729366.7T patent/DK1622619T3/da active
- 2004-04-24 RS YU20050802A patent/RS52143B/sr unknown
- 2004-04-24 PL PL04729366T patent/PL1622619T4/pl unknown
- 2004-04-24 WO PCT/EP2004/004363 patent/WO2004096224A2/en active Application Filing
- 2004-04-24 EP EP04729366.7A patent/EP1622619B1/en not_active Expired - Lifetime
- 2004-04-24 CA CA2523868A patent/CA2523868C/en not_active Expired - Lifetime
- 2004-04-24 JP JP2006500099A patent/JP4701159B2/ja not_active Expired - Lifetime
- 2004-04-27 PE PE2004000415A patent/PE20050463A1/es not_active Application Discontinuation
- 2004-04-28 TW TW099141618A patent/TWI442924B/zh not_active IP Right Cessation
- 2004-04-28 CL CL200400900A patent/CL2004000900A1/es unknown
- 2004-04-28 TW TW093111920A patent/TWI378795B/zh not_active IP Right Cessation
- 2004-04-28 AR ARP040101438A patent/AR044114A1/es active Pending
-
2005
- 2005-10-27 IL IL171579A patent/IL171579A/en active IP Right Grant
- 2005-10-28 KR KR1020057020590A patent/KR101150315B1/ko active IP Right Grant
- 2005-10-31 EC EC2005006132A patent/ECSP056132A/es unknown
- 2005-11-28 NO NO20055605A patent/NO333994B1/no not_active IP Right Cessation
- 2005-11-29 CO CO05121069A patent/CO5640112A2/es not_active Application Discontinuation
-
2006
- 2006-11-06 HK HK06112183.6A patent/HK1091416A1/xx not_active IP Right Cessation
-
2008
- 2008-06-17 US US12/140,661 patent/US7846936B2/en not_active Expired - Lifetime
-
2010
- 2010-05-18 JP JP2010114114A patent/JP2010202658A/ja not_active Withdrawn
- 2010-10-26 US US12/912,090 patent/US20110039863A1/en not_active Abandoned
- 2010-10-28 AU AU2010236075A patent/AU2010236075B2/en not_active Expired
- 2010-11-09 US US12/912,110 patent/US20110171289A1/en not_active Abandoned
- 2010-11-15 US US12/912,098 patent/US20110136826A1/en not_active Abandoned
-
2013
- 2013-11-04 US US14/071,166 patent/US20140057898A1/en not_active Abandoned
- 2013-11-18 CY CY20131101019T patent/CY1114622T1/el unknown
-
2015
- 2015-06-05 US US14/731,722 patent/US20150265610A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI378795B (en) | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis | |
AU2007299080B2 (en) | Method for treating cancer harboring EGFR mutations | |
ZA200506605B (en) | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis | |
CA2946538A1 (en) | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer | |
JP2013512882A (ja) | トリプルネガティブ乳癌の治療に使用するbibw2992 | |
CN103561734A (zh) | 用于治疗头颈部鳞状细胞癌的协同的药物组合 | |
CN101516376A (zh) | 用于治疗携带egfr突变的癌症的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |