CN102215833B - 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 - Google Patents
苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 Download PDFInfo
- Publication number
- CN102215833B CN102215833B CN200880117660.0A CN200880117660A CN102215833B CN 102215833 B CN102215833 B CN 102215833B CN 200880117660 A CN200880117660 A CN 200880117660A CN 102215833 B CN102215833 B CN 102215833B
- Authority
- CN
- China
- Prior art keywords
- cell
- ref
- cancer
- angiogenesis
- reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000033115 angiogenesis Effects 0.000 title claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 title abstract description 23
- 201000011510 cancer Diseases 0.000 title abstract description 14
- 230000036952 cancer formation Effects 0.000 title abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 title description 6
- 229940127089 cytotoxic agent Drugs 0.000 title description 4
- 150000004057 1,4-benzoquinones Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000005764 inhibitory process Effects 0.000 claims abstract description 9
- AALSSIXXBDPENJ-FYWRMAATSA-N (2e)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylidene]undecanoic acid Chemical group CCCCCCCCC\C(C(O)=O)=C/C1=C(C)C(=O)C(OC)=C(OC)C1=O AALSSIXXBDPENJ-FYWRMAATSA-N 0.000 claims description 101
- 239000003153 chemical reaction reagent Substances 0.000 claims description 29
- 101100452003 Caenorhabditis elegans ape-1 gene Proteins 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 230000007850 degeneration Effects 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 208000035719 Maculopathy Diseases 0.000 claims description 4
- 229960000397 bevacizumab Drugs 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 73
- 230000000694 effects Effects 0.000 abstract description 23
- 230000004083 survival effect Effects 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 15
- 108091023040 Transcription factor Proteins 0.000 abstract description 6
- 102000040945 Transcription factor Human genes 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 101150059062 apln gene Proteins 0.000 abstract description 5
- 230000005012 migration Effects 0.000 abstract description 5
- 238000013508 migration Methods 0.000 abstract description 5
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000004568 DNA-binding Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 206010027476 Metastases Diseases 0.000 abstract 1
- 230000009401 metastasis Effects 0.000 abstract 1
- 230000004565 tumor cell growth Effects 0.000 abstract 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 21
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 21
- 230000006907 apoptotic process Effects 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 230000006870 function Effects 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 238000012545 processing Methods 0.000 description 15
- 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 13
- 229960001924 melphalan Drugs 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 230000012010 growth Effects 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- 208000034578 Multiple myelomas Diseases 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 7
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 7
- 206010021143 Hypoxia Diseases 0.000 description 7
- WJAJPNHVVFWKKL-UHFFFAOYSA-N Methoxamine Chemical compound COC1=CC=C(OC)C(C(O)C(C)N)=C1 WJAJPNHVVFWKKL-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 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 7
- 229960005277 gemcitabine Drugs 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 230000007954 hypoxia Effects 0.000 description 7
- 229960005192 methoxamine Drugs 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 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 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 102100034533 Histone H2AX Human genes 0.000 description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 239000004037 angiogenesis inhibitor Substances 0.000 description 6
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 102000000412 Annexin Human genes 0.000 description 5
- 108050008874 Annexin Proteins 0.000 description 5
- 208000032612 Glial tumor Diseases 0.000 description 5
- 206010018338 Glioma Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 210000001525 retina Anatomy 0.000 description 5
- 229960001727 tretinoin Drugs 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 101001067891 Homo sapiens Histone H2AX Proteins 0.000 description 4
- -1 Tetramethyl azo azoles salt Chemical class 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 201000008275 breast carcinoma Diseases 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940120638 avastin Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 229940102223 injectable solution Drugs 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 239000012099 Alexa Fluor family Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- 101710195517 Histone H2AX Proteins 0.000 description 2
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 2
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- 208000002260 Keloid Diseases 0.000 description 2
- 206010023330 Keloid scar Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 210000003725 endotheliocyte Anatomy 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000001117 keloid Anatomy 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001915 proofreading effect Effects 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 201000001514 prostate carcinoma Diseases 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 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 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 102100037373 DNA-(apurinic or apyrimidinic site) endonuclease Human genes 0.000 description 1
- 101710109420 DNA-(apurinic or apyrimidinic site) endonuclease Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 208000000527 Germinoma 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
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000222065 Lycoperdon Species 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000768494 Polymorphum Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-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
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 231100000045 chemical toxicity Toxicity 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000027832 depurination Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000010046 negative regulation of endothelial cell proliferation Effects 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000000007 visual effect Effects 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K31/13—Amines
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明披露了用于治疗癌症和血管生成的新方法。酶Ape I/Aef-1通过其氧化还原功能，增强与癌症演进相关的转录因子的DNA结合活性。本发明阐述了应用这些试剂来选择性抑制Ape I/Aef-1的氧化还原功能从而减弱肿瘤细胞的生长、存活、迁移和转移。Ape I/Aef-1的抑制活性已证实可增强其他治疗剂的疗效并保护正常细胞免遭毒性。此外，Ape I/Aef-1抑制已证实可减少血管生成，可用于治疗癌症以及其他那些血管生成改变是组分之一的病理学症状。
Description
相关申请的交叉引用
本申请要求于2007年11月21日提交的60/989,566号美国临时专利申请和于2007年9月26日提交的美国临时专利申请60/975,396的优先权，其全部内容均结合于此供参考。
技术领域
本发明通常涉及分子生物学、生物化学和病理学领域。较具体的，在某些方面，本发明涉及Ape1/Ref-1氧化还原抑制剂在癌症治疗及血管生成抑制方面的应用。
背景技术
脱嘌呤/脱嘧啶核酸内切酶(Ape1)，也称为氧化还原效应因子(Ref-1)(以下均写为Ape1/Ref-1)，是一种具有双重作用的酶。除了其DNA碱基切除修复(BER)活性之外，Ape1/Ref-1还可作为一种氧化还原效应物保持转录因子呈一种活化的还原状态而发挥作用(见图1)。
Ape1/Ref-1已证实可刺激几种转录因子如HIF-1α、NFkβ、AP-1和p53以及其他已知和未知的与肿瘤存活和演进相关因子的DNA结合活性(Evans et al.，Mutat Res 2000，461，83)。已证实Ape1/Ref-1在多种癌症包括乳腺癌、宫颈癌、生殖细胞瘤、成人和儿童胶质瘤、骨肉瘤、横纹肌肉瘤、非小细胞性肺癌以及多发性硬化症中表达发生改变(Puglisi et al.，Oncol Rep 2002，9，11；Thomson et al，Am JPediatr Hematol Oncol 2001，23，234；Roberston et al.，cancer Res 2001，61，2220；Puglisi et al.，Anticancer Res 2001，21，4041；Koukourakis et al.，Int J Radiat OncolBiol Phys 2001，50，27；Kakolyris et al.，BrJCancer 1998，77，1169；Bobola et al.，Clin CancerRes 2001，7，3510)。Ape1/Ref-1高表达与放化疗效果差、完全应答率低、局部无复发间隔较短、生存较差以及血管生成较多有关 (Koukourakis et al.，Int J Radiat Oncol Biol Phys 2001，50，27；Kakolyris et al.，BrJCancer 1998，77，1169；Bobola et al.，Clin Cancer Res 2001，7，3510).
血管生成是癌症生长、存活、迁移和转移的一个重要要素。癌性肿瘤的部位形成新血管为肿瘤加速生长和扩散提供营养源，并为肿瘤细胞进入血流并扩散至身体的其他部分提供路径。因此，有效抑制血管生成是一种减缓或防止癌症生长及扩散的有效机制。Ape1/Ref-1活性的增加与血管生成有关。血管内皮生长因子(VEGF)是血管发生和血管生成中牵涉到的重要信号传导蛋白。Ape1/Ref-1是在血管内皮生长因子(VEGF)基因的缺氧反应元件上形成的低氧诱导性转录复合体的一个组分(Ziel et al.，Faseb J 2004，18，986)。
除了癌症，血管生成改变促进了与心血管疾病、慢性感染性疾病、风湿性关节炎、糖尿病性视网膜病、退行性黄斑病变、视网膜后纤维增生、特发性肺纤维变性、急性成人呼吸窘迫综合征、哮喘、子宫内膜异位症、银屑病、瘢痕瘤以及全身性硬化症相关的病理学症状。对于减缓或预防涉及过量血管生成的疾病，抑制血管生成是一种理想的临床结局。
发明内容
靶向抑制Ape1/Ref-1的氧化还原功能是一种治疗癌症和血管生成的新途径。在一个实施方式中，本发明涉及到应用抑制Ape1/Ref-1氧化还原功能的抗癌治疗剂。在另一个实施方式中，本发明涉及Ape1/Ref-1氧化还原功能的抗血管生成试剂。
附图说明
图1：Ape1/Ref-1在调节肿瘤存活中非常重要的转录因子方面的氧化还原功能。
图2：VEGF的酶联免疫吸附试验(ELISA)。
图3A-3B：VEGF ELISA检测。
图4A-4B：VEGF ELISA检测。
图5：VEGF ELISA检测。
图6：VEGF ELISA检测。
图7：VEGF ELISA检测。
图8：利用铺种于基质胶上的CB-ECFC细胞实施的毛细管形成试验。
图9：限制性稀释试验(LDA)。
图10：在用或不用碱性纤维母细胞生长因子(bFGF)处理的细胞中对视网膜内皮细胞增殖进行MTS增殖检测。
图11：E3330(RN-3)对视网膜血管内皮细胞(RVEC)-野生型/sv40细胞的作用。
图12：利用源自人乳腺癌的MCF-7肿瘤细胞进行MTS检测。四甲基偶氮唑盐(MTS)试验用于细胞存活/生长分析。
图13：利用源自人卵巢腺癌的OVCAR-3肿瘤细胞进行MTS检测。
图14A-14D：E3330(RN-3)和化疗药物美法仑联合应用对多发性骨髓瘤细胞的作用。
图15：MTS检测中，72小时后E3330(RN-3)和化疗药物美法仑联合应用对多发性骨髓瘤细胞的作用。
图16：在24和48小时，E3330(RN-3)和吉西他滨(0..25μM)对胰腺肿瘤细胞的作用。
图17：MTS细胞活性检测。
图18：MTS细胞活性检测。
图19：给药E3330(RN-3)(0-50mg/kg)的雄性小鼠体重。
图20：以不同量RN-3(E3330)处理的小鼠在处理后第2、3、4或5天观察到的存活数据。
图21A-21B：E3330(RN-3)在24hr时程的实验过程中的药物动力学数据。
图22：E3330(RN3-3)的药物动力学数据。
图23：E3330(RN-3)和视黄酸对促进细胞分化的作用。
图24：如图23所述利用Annexin/PI试验进行HL-60细胞的凋亡分析。
图25：RN-3(E3330)和不同剂量RA的作用。
图26：E3330(RN-3)和RA对正发生凋亡(Annexin/PI试验)的HL-60细胞的作用。
图27A-27D：E3330(RN-3)和小分子甲氧胺联合应用对多发性骨髓瘤细作用。
具体实施方式
本发明涉及到应用选择性抑制Ape1/Ref-1氧化还原功能的抗癌和抗血管生成试剂。这种选择性抑制包括特异性抑制，或者，换句话说，对Ape1/Ref-1的BER功能无影响或者无可估计到的影响，且相对于BER功能而言，主要对氧化还原功能产生影响。本发明还涵盖了这些试剂与其他化疗/治疗性试剂的联合应用。最好所述其他试剂以与那些选择性抑制Ape1/Ref-1氧化还原功能的试剂不同的方式作用于患者。
与血管生成发生改变相关的生理性疾病涵盖那些与血管生成不当(其直接或间接有害于患者)相关的疾病。除了其他疾病，血管生成改变促进与癌症(包括生长、存活、迁移、微环境和转移)以及心血管疾病、慢性感染性疾病、风湿性关节炎、糖尿病性视网膜病、退行性黄斑病变、视网膜后纤维增生、特发性肺纤维变性、急性成人呼吸窘迫综合征、哮喘、子宫内膜异位症、银屑病、瘢痕瘤和全身性硬化症相关的病理学症状。
术语患者包括脊椎动物，优选人类患者。术语抑制及其衍生语，包括其通常公认的含义，其包括阻止、防止、遏制和减慢、中断或逆转进程或严重程度。因此，本发明所述方法既包括内科治疗性给药又包括预防性给药，视情况而定。就其本身而言，当涉及到本文所述的治疗性应用时，需要该治疗的患者是经鉴定需要或希望医学干预的个体。有效量是抑制本文所述病理性疾病和病症所需试剂的量。当给药患者至少一种其他治疗剂时，这些试剂可依次、并列(concurrently)或同时(simultaneously)给药，以实现这些试剂的优势。
人们已发现Ape1/Ref-1的氧化还原功能可被3-[(5-(2，3-二甲氧基-6-甲基1，4-苯并喹啉基)]-2-壬基-2-丙烯酸选择性抑制，见下图(下文的“E3330”，本申请中也称为“RN3-3”)。
关于E3330的其他信息可在Abe et al.，U.S.Patent 5,210,239中查到，其全部内容均结合于此供参考。特别的，其中阐述了用于制备的过程、制剂以及药学可接受的盐。
有趣的是，我们的研究表明，在正常细胞中选择性阻断Ape1/Ref-1的氧化还原功能不会引起凋亡或不会引起任何可估计的凋亡。人们很可能会认为，可引起癌细胞中凋亡增加的选择性阻断也将损害正常细胞。然而，我们发现这一点并非事实。
如果计划在患者特别是人体内应用，将有必要以适于预期应用的形式制备药物组合物。通常，这将使得有必要制备基本不含对患者有害杂质的组合物。
试剂可基于患者体重和疾病进展程度而经口服、静脉内、肌内、胸腔内或腹膜内给药，且可每天一次、两次甚至四次给药。
人们通常将希望采用恰当的盐和缓冲液而使试剂稳定并适于靶细胞吸收。本发明所述水性组合物包含有效量的该试剂，溶解于或分散于药学可接受的载体或水性培养基中。这种组合物还可称为无毒的或无害的。术语药学或药理可接受的指当给药患者时，不会引起副反应、过敏反应或其他不良反应的分子实体和组合物。如本文中使用的，药学可接受载体包括任何以及所有溶剂、分散介质、涂层、抗细菌和抗真菌试剂、等张试剂和活性吸收剂等。本领域中，这些介质和试剂用作药学活性物质已经为人熟知。 还可将补充性的有效成分整合入组合物中。
用于本发明中的组合物可包含经典的药学制剂。给药本发明所述的这些组合物将通过任何常用途径，只要其借助该途径可到达靶组织，包括经口、经鼻、口腔、直肠、阴道或局部。可替代的，可通过常位、皮内、皮下、肌内、腹膜内或静脉内注射给药。这些组合物通常将作为药学可接受的组合物而给药，如上文所述。
例如，所述化合物可用常用的赋形剂、稀释剂或载体进行配制，并制成片剂、胶囊、悬液、粉末等。适用于赋形剂、稀释剂和载体的实例包括下列试剂：填充剂和增量剂如淀粉、糖、甘露醇和硅衍生物；结合剂如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；保湿剂如甘油；崩解剂如碳酸钙和碳酸氢钠；用于延缓溶解的试剂如石蜡；再吸收加速剂如季铵化合物；表面活化剂如十六烷醇、单硬脂酸甘油酯；吸附载体如高岭土和膨润土；以及润滑剂如滑石、硬脂酸酸钙和硬脂酸镁和固态聚乙二醇。
所述活性化合物可肠外或肠内给药。活性化合物的游离碱溶液或药理学可接受盐的溶液可在恰当混有表面活性剂如羟丙基纤维素的水中制备。分散液可在甘油、液态聚乙二醇及其混合物以及油中制备。在普通的贮存和应用条件下，这些制剂包含防腐剂，以防止微生物的生长。
适于注射性应用的药学形式包括无菌水性溶液或分散液以及用于无菌注射溶液或分散液的临时制剂的无菌粉末。在所有的情形下，该形式必须无菌，且必须达到易于注射程度的液态，在生产及储存条件下必须稳定，且必须能够抵抗微生物如细菌和真菌的污染作用而保存。载体可以为包含例如水、乙醇、聚醇(如甘油、聚乙醇以及液态聚乙醇等)、其恰当的混合物以及植物油的溶剂或分散介质。恰当的流动性可通过例如采用涂层如卵磷脂、通过在分散液中保持所需的颗粒大小以及通过采用表面活性剂而维持。防止微生物作用可通过多种抗细菌和抗真菌试剂而实现，例如对羟基苯甲酸酯、氯丁醇、酚、山梨酸、硫柳汞等。在多种情况下，将优选包括等张剂例如糖或氯化钠。可注射性组合物的延时吸收可通过在组合物中应用延缓吸收的试剂如单硬脂酸铝和明胶而实现。
无菌注射溶液通过将所需量的活性化合物以及上文列举的多种其他成分整合入恰当溶剂中，然后进行过滤除菌而制备。通常，分散液通过将多种无菌活性成分整合入无菌介质中，其中包含基础分散介质以及所需来自上文所列举的其他成分。在用于制备无菌注射溶液的无菌粉末中，优选的制备方法是真空干燥和冷冻干燥技术，可从其前述无菌过滤溶液中得到活性成分以及任何其他所需成分。
对于口服给药，本发明所述试剂可与赋形剂整合，并以非注射性漱口水和洁牙品的形式应用。漱口水可通过将所需量的活性成分整合于恰当溶剂如硼酸钠溶液(Dobell’s溶液)中而制备。可替代的，活性成分可整合入含硼酸钠、甘油和碳酸氢钾的抗菌洗液中。活性成分还可分散于洁牙品中，包括凝胶、膏剂、粉末和浆料。活性成分可以治疗有效量加入膏状洁牙品中，其包括水、粘合剂、研磨剂、调味剂、发泡剂和润湿剂。
用于本发明中的组合物可配制成中性或盐形式。药学可接受盐包括酸加成盐(通过蛋白的游离氨基形成)，且可通过无机酸形成，例如氯酸或磷酸，或有机酸诸如乙酸、草酸、酒石酸、苦杏仁酸等。用游离羧基形成的盐还可源自无机碱如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁以及有机碱诸如异丙胺、三甲胺、组氨酸、普鲁卡因等。
制备后，溶液可以与剂型配方相匹配的方式以及治疗有效量而给药。该制剂可易于以多种剂型如可注射性溶液、药物缓释胶囊等给药。对于水性溶液中的肠外给药，例如，如有必要溶液应恰当缓冲，液体稀释剂应首先用足量盐或葡萄糖变为等张。这些特殊的水性溶液尤其适于静脉内、肌内、皮下和腹膜内给药。在这个方面，按照本披露案，可采用的无菌水性介质为本领域的熟练技术人员所知。例如，可将一剂量(one dosage)溶解于1ml的等张NaCl溶液中，然后加入1000ml的皮下灌注液体中或者在所拟定的灌注部位进行注射(见例如，“Remington’s Pharmaceutical Sciences”第15版，第1035-1038页和1570-1580页)。根据待治疗患者的症状，将有必要对剂量加以调整。在任何情况下，负责给药的人员均将决定用于个体患者的恰当剂量。而且，用于人类给药时，制剂应该符合FDA和外国相应机构规定的无菌性、通用安全(general safety)和纯度标准。
抑制Ape1/Ref-1氧化还原功能已证实可减少VEGF释放、损害毛细管形成并抑制大细胞量克隆的生长，表明其抗血管生成活性。下列实例仅用于说明的目的而非限制本发明的范围。
VEGF释放的抑制。VEGF酶联免疫吸附检测(ELISA)。将多种癌细胞系铺种于24孔板中，并在常氧(约21％氧气)或低氧(约2％氧气)的条件下处理约24小时。收集细胞上清，并利用特异于人VEGF的试剂盒并按照生产商(R&D Systems，Minneapolis，MN)建议的方法进行ELISA检测。VEGF ELISA检测的结果在96孔形式的板式读数仪中通过测定450nm处的吸光度并用540nm处的吸光度进行校正而读数。低氧诱发VEGF释放增加(图2)。(对于图2-7，黑色棒＝常氧；灰色棒＝低氧)
VEGF ELISA检测。将Hey-C2(卵巢癌)、SKOV-3X(卵巢癌)、Pancl(胰腺癌)、PaCa-2(胰腺癌)以及Igrov(卵巢癌)细胞铺种于24孔板中，并在常氧(约21％氧气)或低氧(约2％氧气)的条件下用E3330(RN3-3e)以不同浓度平行处理约24小时。收集细胞上清，并利用特异于人VEGF的试剂盒并按照生产商(R&D Systems，Minneapolis，MN)建议的方法进行ELISA检测。VEGF ELISA检测的结果在96孔板式读数仪中通过测定450nm处的吸光度并用540nm处的吸光度进行校正而读数。在常氧(约21％氧气)和低氧(约2％氧气)的条件下，E3330(RN3-3e)均通过抑制Apel/Ref-1氧化还原功能而降低所述细胞的VEGF释放(图2-7)。
毛细管形成的抑制。毛细管形成试验利用铺种于基质胶上的CB-ECFC细胞并通过E3330或对照培养基处理而实施。ECFC的培养如前所述(Blood，1November 2004，Vol.104，N0.9，pp.2752-2760)。ECFC克隆在培养5天至22天时出现。采用倒置显微镜(Olympus，Lake Success，NY)，在40倍的放大倍数下通过肉眼观察计数克隆。细胞如前所述进行传代(Blood，1November 2004，Vol.104，N0.9，pp.2752-2760.)。
毛细管形成试验如前所述实施(J.Biol.Chem.274(1999)，pp.35562-35570)。室温下将不同浓度的E3330给药CB-ECFC约30分钟，然后以约1x104细胞/孔的密度接种并铺于基质胶层上。约8小时后，从随机抽取的视野计数完整管的闭合网，并在显微镜下照相。E3330及其类似物 抑制毛细管形成，这是抗血管生成和生长抑制的一个指标(图8)。
限制性稀释试验。在限制性稀释试验(LDA)中，E3330抑制大细胞数克隆的生长，这也是一个抗血管生成的指标(图9)。ECFC如前所述进行培养(Blood，1November 2004，Vol.104，N0.9，pp.2752-2760)。ECFC克隆在培养5天至22天时出现。采用倒置显微镜，通过肉眼观察计数克隆以及每个克隆的细胞数。在限制性稀释试验(LDA)中，E3330抑制大细胞数克隆的生长，这也是一个抗血管生成的指标。增加E3330(RN3-3)的量，引起含大细胞数克隆数的减少，且仅具有较少细胞数的克隆增加，表明细胞生长受到抑制(图9)。(在图9中，从左至右，棒bar表示剂量为25μM、37.5μM和50μM的EtOH和E3330。)
内皮细胞增殖的抑制。在用或不用碱性成纤维生长因子(bFGF)处理的细胞中，约10-100μM的E3330降低视网膜内皮细胞的增殖。分离出幼年小鼠视网膜组织并进行消化。将细胞铺种于24孔板中，并培养至汇合，然后接种至96孔板进行分析。接种3天后，通过MTS检测(Promega)测定细胞总数。按照生产商的说明计算增殖率，并比较不同组REC增殖是否具有统计学显著性。E3330(RN3-3)阻断REC增殖，表明其抗血管生成效应。(图10)
10-100μM的E3330降低肾血管内皮细胞(RVEC)的增殖(图11)。在基础培养基中，E3330在所检测的全部4个浓度均抑制REVC细胞增殖，10μM-57％，25μM-93％(p＜0.01)。向培养基中加入bFGF后，REC增殖显著提高。在10、25和更高的E3330浓度时，也在bFGF培养基中观察到了类似的抑制性效应。
体外管形成试验。另外还观察到，在一个观察体外管形成的试验中，E3330如同Avastin，也能以剂量依赖性方式防止内皮细胞中形成血管样小管。在该试验中，还观察到联合应用Avastin和E3330比单用任何一种的效果呈协同性增加。
Vldlr-/-敲除小鼠试验中的SNV。已经观察到，E3330眼内处理显著减少vldlr-/-视网膜中的视网膜下新生血管(SNV)数量。实验在极低密度脂蛋白(vldr)敲除小鼠中实施，以测定E3330对vldlr-/-突变体中SNV形成 抑制的效应。每一只动物均接受单次眼内注射1μ1体积的BSS作为介质对照，另一只眼睛则接受1μl 200μM的E3330。视网膜中的最终E3330浓度相当于约20μM。处理后一周，凝集素-FITC染色后，在整个视网膜标本中进行SNV的定量测定。结果表明，17/20个体中，用E3330处理的眼睛中，SNV数量降低约30％。相反，Avastin(VEGF抗体)或bFGF抗体处理均未出现任何SNV数量抑制的征象。抗体注射后，SNV的明显增加可能是由于外来蛋白触发的免疫应答，之前曾有报道(Tator et al.，2008)。E3330以统计学显著性水平降低SNV的数量(p＜0.001，配对t检验)。这些数据极其鼓舞人心，因为该视网膜血管瘤增殖(RAP)模型与人类似，难以治疗，且对现有治疗包括抗VEGF和抗bFGF试剂均应答较差。Ape1/Ref-1抑制剂提供了一种新的控制血管生成的途径，用于晚期黄斑变性(AMD)的治疗。
本发明还涵盖了那些抑制Ape1/Ref-1氧化还原功能的试剂作为抗癌治疗剂的用途。这些癌症包括乳腺癌、前列腺癌、胰腺癌、结肠癌、宫颈癌、生殖细胞肿瘤、成人和儿童胶质瘤、骨肉瘤、横纹肌肉瘤、非小细胞肺癌、白血病和多发性骨髓瘤。Ape1/Ref-1已证实可刺激几种与肿瘤存活和演进相关的转录因子如HIF-1α、NFkβ、AP-1和p53的DNA结合活性。通过E3330选择性抑制Ape1/Ref-1的氧化还原功能，可降低转录因子与DNA的结合，并损害癌细胞旺盛生长的能力。下面的实例仅为了说明而非限制本发明的范围。
癌细胞存活减少。将MCF-7或OVCAR-3细胞(约2000-4000)分入96孔板的每一个孔内，并使其过夜贴壁。将E3330(RN3-3)加入培养物中。约24或72h后，向每一个孔内加入0.05mg/mL的四甲基偶氮唑盐(MTS)试剂，并在约37℃孵育约4h，随后测定490nm处的吸光度，并将吸光度的值以仅含培养基的孔进行标准化。独立的，E3330剂量依赖性杀死源于人乳腺癌的MCF-7肿瘤细胞(图12)和源于人卵巢腺癌的OVCAR-3肿瘤细胞(图13)。类似的效应还可在多发性骨髓瘤、前列腺癌、非小细胞肺癌、结肠癌和胶质瘤源性细胞中观察到。相反，在我们的研究中，采用正常细胞如造血胚胎细胞时或在人CD34+祖细胞中，均未观察到显著的生长 抑制。这些数据的新颖之处在于，其牵涉到癌症中Ape1/REF-1的氧化还原作用而非“正常的”细胞存活。
胶质瘤细胞迁移试验。这个试验是为了测定E3330是否抑制SF767胶质瘤细胞的迁移能力。为了实施该试验，我们在60mm组织培养皿中接种1.5X106个SF767细胞，使其过夜贴壁，并形成汇合的单层。用200μl的吸头，沿着板进行划痕或创伤，如前所述(Liang 2007)。随后冲洗细胞去除漂浮的细胞，培养基包含25、50、75或100μM E3330或恰当的介质对照，DMSO。24h后去除含药物的培养基，并加入新鲜培养基。加入药物0、24、36和48小时，沿着划痕在3个做标记的位置照相。对于所拍摄的每一幅照片，均利用Spot软件(Diagnostic Instruments，Sterling Heights，MI)在10个相同的位置测量划痕前缘之间的距离(微米)来量化迁移。每一组数据(每一个数据点的总数均为30)均针对0h时介质对照的迁移进行标准化，并用来测定标准差。结果表明E3330抑制SF767细胞迁移的能力，且与48h的介质对照相比，用100μM的E3330处理的细胞可表现出多达4.0倍的抑制。
我们的结果支持对微环境或间质的影响。微环境不同于癌细胞本身，可在肿瘤演进包括转移中发挥作用，其可限制治疗药物进入肿瘤、改变药物代谢并促成耐药。很显然，能够影响微环境即可辅助在肿瘤中达到最终的治疗性结局。
在另一个实施方式中，本发明涉及到与其他治疗剂联合应用抑制Ape1/Ref-1氧化还原功能的试剂。这些治疗剂包括但不限于美法仑、吉西他滨、顺铂、甲氧胺、沙利度胺及其衍生物以及视黄酸(RA)。选择性Ape1/Ref-1抑制可与其他治疗剂协同发挥作用以增加抗癌效果。因此，可给药低剂量的治疗剂(较高剂量时，其可引起sickness且对正常细胞有毒)而不降低抗癌效果。应用选择性抑制Ape1/Ref-1氧化还原功能的试剂可保护正常细胞免受顺铂和其他化学毒性化合物的损害。下列实施例仅为了说明而非限制本发明的范围。
E3330与化疗剂美法仑联合应用。E3330与化疗药物美法仑协同增加对多发性骨髓瘤细胞的杀伤(图14)，协同效应的图利用CalcuSyn软件制作。 E3330可单独给药或与美法仑联合给药。作为DNA双链断裂(DSB)的指示剂，组蛋白H2AX 在Ser139处的磷酸化利用来自Upstate Cell Signaling Solutions(Waltham，MD)的磷酸化特异性H2AX抗体进行检测。细胞仅用美法仑处理或用美法仑与E3330一起处理。药物处理后，收集指数生长的细胞，在冷PBS中清洗，并在100μl RIPA检测缓冲液中裂解，如前所述。蛋白定量后，在12％SDS聚丙烯酰胺凝胶上于SDS凝胶上样缓冲液中进行电泳。小鼠单克隆抗磷酸-组蛋白H2AX(约1∶1000)或抗肌动蛋白抗体(约1∶1000；作为上样对照，LabVision Corp.，NeoMarkers，Fremont，CA)用来检测蛋白水平，如前所述。条带利用购自Roche Applied Biosciences(Indianapolis，IN)的化学发光试剂盒进行检测。条带利用Bio-Rad Chemidoc XRS(Hercules，CA)进行显色并利用Chemidoc软件，Quantity One 4.6.1进行定量。相比于仅给药美法仑，美法仑与E3330(RN3-3)时，出现了DSB增加。
E3330(RN3-3)与化疗药物美法仑联合应用，72小时后，在MTS试验中，发现可协同增加对多发性骨髓瘤细胞的杀伤(图15)。E3330(RN3-3)单独给药或与美法仑联合给药，根据CalcuSyn软件，针对对照的百分比绘制ED50，该软件基于Chou-Talalay 算法(Chou-Talalay；Advances in Enzyme Regulation 22，27-55)。美法仑加E3330(RN3-3)比单用二者中每一种都更为有效。
E3330与化疗剂吉西他滨联合应用。E3330增强吉西他滨(约0.25μM)在胰腺肿瘤细胞中的凋亡诱导效应(图16)。为了分析细胞凋亡，铺种细胞并使其贴附过夜。细胞单用E3330或与吉西他滨一起处理。处理后约24和48小时检测凋亡。细胞用胰酶消化、沉淀、在冷PBS中清洗并重悬于1x结合缓冲液[约10mmol/L HEPES/NaOH(pH 7.4)，140mmol/L NaCl，2.5mmol/L CaCl2]中。凋亡利用来自Vybrant凋亡检测试剂盒的Alexa Fluor 488Annexin V与碘化丙啶(Molecular Probes，Eugene，OR)进行分析，如之前在Clinical Cancer Research 13，260-267，January 1，2007中描述的。Annexin强阳性的细胞可认为是凋亡阳性。样品在Indiana大学癌症中心流 式细胞中心通过流式细胞仪进行分析。
E3330与化疗剂顺铂联合应用。浓度高达约120μM的E3330未损害培养基中生长的大鼠后根神经节细胞的存活，达约72小时，如通过MTS细胞存活试验测定的(图17)。E3330(RN3-3)对有丝分裂后的DRG细胞无影响，表明E3330(RN3-3)对非分裂细胞无毒性作用。
DRG细胞的培养和处理类似于之前发表的步骤，仅利用E3330而实施(DNA Repair Volume 4，Issue 3，2March 2005，pp 367-379)。另外，当给药大鼠后根神经节细胞时，E3330保护细胞免受化疗剂顺铂的神经毒性作用(图18)。这就证实，尽管E3330(RN3-3)增强某些化疗剂，但其对未分裂、有丝分裂后的细胞具有保护性作用，即使是在化疗剂存在的情况下。
E3330与化疗剂视黄酸联合应用。E3330增强视黄酸促进细胞分化的作用(图23)。HL-60细胞用指定浓度的介质(EtOH；对照)、E3330、视黄酸(RA)或E3330和RA进行处理，并在第6天测定形态。形态学分析表明，用E3330(RN3-3)处理的HL-60细胞的分化增加。第6天时，HL-60细胞的凋亡分析表明，与单用E3330处理的细胞相比，联合应用E3330和RA时，表现出发生凋亡的细胞数量增加，E3330剂量为25μM时，相比单用RA时增加约1.5倍(图24)。
在RA剂量低1000倍时，E3330可增加RA的效应，但RA剂量较高时，则得到的分化水平类似。CD11是HL-60分化的标志物，已证实将E3330加入RA中(图25)可使比所需剂量低约1000倍的RA达到较高RA时相同的分化水平(图25)。
在RA剂量较低时，E3330未显著增加HL-60细胞发生凋亡的水平(annexin/PI分析)，即使分化水平大大增加，达1000倍(图26)。
这些结果表明，RA剂量降低时，E3330加RA可引起这些细胞和模型系统中的细胞分化但未导致这些凋亡增加。
E3330与化疗剂吉西他滨联合应用-多发性骨髓瘤细胞。E3330与小分子甲氧胺联合应用促进多发性骨髓瘤细胞的杀伤，如通过MTS检测的(图27)。数据利用CalcuSyn软件进行计算，该软件基于Chou-Talalay算法 (Chou-Talalay；Advances in Enzyme Regulation 22，27-55)。E3330单独给药或与甲氧胺联合给药。
作为DNA双链断裂(DSB)的指示剂，组蛋白H2AX在Ser139处的磷酸化利用来自Upstate Cell Signaling Solutions(Waltham，MD)的磷酸化特异性H2AX抗体进行检测。细胞单用E3330处理或用E3330与甲氧胺一起处理。药物处理后，收集指数生长的细胞，在冷PBS中清洗，并在100μl RIPA检测缓冲液中裂解，如前所述。蛋白定量后，在12％SDS聚丙烯酰胺凝胶上于SDS凝胶上样缓冲液中进行电泳。小鼠单克隆抗磷酸-组蛋白H2AX(约1∶1000)或抗肌动蛋白抗体(约1∶1000；作为上样对照，LabVision Corp.，NeoMarkers，Fremont，CA)用来检测蛋白水平，如前所述。条带利用购自Roche Applied Biosciences(Indianapolis，IN)的化学发光试剂盒进行检测。条带利用Bio-Rad Chemidoc XRS(Hercules，CA)进行显色并利用Chemidoc软件，Quantity One4.6.1进行定量。
E3330与化疗剂吉西他滨联合应用-胰腺细胞。E3330增强甲氧胺在胰腺肿瘤细胞中的凋亡诱导效应。为了分析细胞凋亡，铺种细胞并使其贴附过夜。细胞单用E3330或与甲氧胺一起处理。处理后约24和96小时检测凋亡。细胞用胰酶消化、沉淀、在冷PBS中清洗并重悬于1x结合缓冲液[约10mmol/L HEPES/NaOH(pH 7.4)，140mmol/L NaCl，2.5mmol/L CaCl2]中。凋亡利用来自Vybrant凋亡检测试剂盒的Alexa Fluor 488Annexin V与碘化丙啶(Molecular Probes，Eugene，OR)进行分析，如之前在Clinical Cancer Research13，260-267，January 1，2007中所描述的。Annexin强阳性的细胞可认为是凋亡阳性。样品在Indiana大学癌症中心流式细胞机构利用流式细胞仪进行分析。
体内预实验。实施小鼠体内预实验是为了探索安全谱并测定E3330的药动学特征(图19-22)。
图19。给药E3330(RN3-3)(0-50mg/kg)的雄性小鼠体重。在E3330(RN3-3)低于50mg/kg时，未观察到小鼠毒性。小鼠用RN3-3(E3330)处理并在处理前2天或用3个化合物剂量处理后称重。
图20。以不同量RN3-3(E3330)处理并在处理后第2、3、4或5天 观察的小鼠存活数据。存活小鼠数量占总数的比例以存活/总数表示。
图21。24小时时程的实验中，E3330(RN3-3)的药动学数据。小鼠用E3330(RN3-3)处理，随后在临床药理学和分析中心(CPAC)检测血液浓度。对E3330(RN3-3)的时间vs.浓度绘图，将所估计的浓度示于表中。每一个时间点均采用3只小鼠，数据表示每一个时间点绘制的均值和SD(未示出)。
图22。E3330(RN3-3)的药动学数据。收集来自存活、体重和PK研究的数据并示于该表中。测定雄性、雌性和组合的小鼠中RN3-3(E3330)的半衰期以及其体重和浓度。
Claims (8)
1.一种制备用于抑制与改变的血管生成相关的生理疾病的药物中选择性抑制Ape1/Ref-1的氧化还原功能的试剂的用途，其中所述疾病选自糖尿病性视网膜病、退行性黄斑病变和晶状体后纤维组织增生症，其中所述试剂是E3330或其药学可接受的盐。
2.根据权利要求1所述的用途，其中所述试剂是E3330。
3.根据权利要求1所述的用途，其中所述试剂是E3330药学可接受的盐。
4.根据权利要求1所述的用途，其中所述疾病是糖尿病性视网膜病。
5.根据权利要求1所述的用途，其中所述疾病是退行性黄斑病变。
6.根据权利要求1所述的用途，其中所述疾病是晶状体后纤维组织增生症。
7.根据权利要求1-6中任一项所述的用途，其中至少一种其他的治疗剂与所述试剂联合使用。
8.根据权利要求7所述的用途，其中所述一种其他的治疗剂是贝伐单抗。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US98956607P | 2007-11-21 | 2007-11-21 | |
| US60/989,566 | 2007-11-21 | ||
| PCT/US2008/077210 WO2009042542A1 (en) | 2007-09-26 | 2008-09-22 | Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410499746.1A Division CN104666286A (zh) | 2007-11-21 | 2008-09-22 | 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102215833A CN102215833A (zh) | 2011-10-12 |
| CN102215833B true CN102215833B (zh) | 2014-11-05 |
Family
ID=44746714
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410499746.1A Pending CN104666286A (zh) | 2007-11-21 | 2008-09-22 | 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 |
| CN200880117660.0A Expired - Fee Related CN102215833B (zh) | 2007-11-21 | 2008-09-22 | 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410499746.1A Pending CN104666286A (zh) | 2007-11-21 | 2008-09-22 | 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN104666286A (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2825162B1 (en) * | 2012-03-14 | 2018-09-12 | Indiana University Research and Technology Corporation | Compounds and methods for treating leukemia |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030229004A1 (en) * | 2002-03-20 | 2003-12-11 | Pangene Corporation | Modulation of tumor cells using BER inhibitors in combination with a sensitizing agent and DSBR inhibitors |
-
2008
- 2008-09-22 CN CN201410499746.1A patent/CN104666286A/zh active Pending
- 2008-09-22 CN CN200880117660.0A patent/CN102215833B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102215833A (zh) | 2011-10-12 |
| CN104666286A (zh) | 2015-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220184016A1 (en) | Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis | |
| US20210186993A1 (en) | Combination therapies targeting mitochondria for cancer therapy | |
| CN102427814A (zh) | 激酶蛋白结合抑制剂 | |
| JP2014515390A (ja) | Ｐｉ３ｋ阻害剤化合物を用いた中皮腫の治療法 | |
| CN102215833B (zh) | 苯醌衍生物e3330联合化疗剂用于治疗癌症和血管生成 | |
| CN108703968B (zh) | 左旋千金藤啶碱用于抑制或治疗转移性乳腺癌的用途 | |
| CN107708682A (zh) | 以ape1/ref‑1为靶标抑制缺氧传输信号基因的方法 | |
| WO2008086008A1 (en) | Method of treating multidrug resistant cancers | |
| CN108743591A (zh) | 用于治疗癌症的药物组合物及其应用 | |
| CN112336864A (zh) | 原黄素在肺癌治疗中的应用 | |
| CN104434948A (zh) | 一种抗胰腺癌的药物组合物及其应用 | |
| CN116057071B (zh) | 重组灵芝免疫调节蛋白新突变体及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141105 Termination date: 20190922 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |