JP2021527039A - 悪性リンパ腫性障害の治療法 - Google Patents
悪性リンパ腫性障害の治療法 Download PDFInfo
- Publication number
- JP2021527039A JP2021527039A JP2020567578A JP2020567578A JP2021527039A JP 2021527039 A JP2021527039 A JP 2021527039A JP 2020567578 A JP2020567578 A JP 2020567578A JP 2020567578 A JP2020567578 A JP 2020567578A JP 2021527039 A JP2021527039 A JP 2021527039A
- Authority
- JP
- Japan
- Prior art keywords
- cell
- lymphoma
- inhibitor
- gsk
- ing
- 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.)
- Pending
Links
- 230000003211 malignant effect Effects 0.000 title claims abstract description 129
- 206010025323 Lymphomas Diseases 0.000 title claims description 91
- 238000011282 treatment Methods 0.000 title claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 14
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 claims abstract description 171
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 claims abstract description 169
- 238000000034 method Methods 0.000 claims abstract description 167
- 208000030289 Lymphoproliferative disease Diseases 0.000 claims abstract description 126
- FARXPFGGGGLENU-UHFFFAOYSA-N 3-(5-fluoro-1-benzofuran-3-yl)-4-(5-methyl-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione Chemical compound C12=CC=3OCOC=3C=C2N(C)C=C1C1=C(C=2C3=CC(F)=CC=C3OC=2)C(=O)NC1=O FARXPFGGGGLENU-UHFFFAOYSA-N 0.000 claims abstract description 115
- 239000003112 inhibitor Substances 0.000 claims abstract description 107
- 239000003814 drug Substances 0.000 claims abstract description 41
- 201000001268 lymphoproliferative syndrome Diseases 0.000 claims abstract description 41
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 35
- PMJIHLSCWIDGMD-UHFFFAOYSA-N tideglusib Chemical compound O=C1SN(C=2C3=CC=CC=C3C=CC=2)C(=O)N1CC1=CC=CC=C1 PMJIHLSCWIDGMD-UHFFFAOYSA-N 0.000 claims description 43
- 229950005284 tideglusib Drugs 0.000 claims description 43
- HRJWTAWVFDCTGO-UHFFFAOYSA-N LY-2090314 Chemical compound C1CN(C=23)C=C(C=4C(NC(=O)C=4C=4N5C=CC=CC5=NC=4)=O)C3=CC(F)=CC=2CN1C(=O)N1CCCCC1 HRJWTAWVFDCTGO-UHFFFAOYSA-N 0.000 claims description 42
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 33
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 32
- -1 AT7519 Chemical compound 0.000 claims description 31
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 31
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 30
- ACWKGTGIJRCOOM-HHHXNRCGSA-N 4-(4-fluoro-2-methoxyphenyl)-N-[3-[(methylsulfonimidoyl)methyl]phenyl]-1,3,5-triazin-2-amine Chemical group COc1cc(F)ccc1c2ncnc(Nc3cccc(C[S@](=N)(=O)C)c3)n2 ACWKGTGIJRCOOM-HHHXNRCGSA-N 0.000 claims description 29
- 229960003445 idelalisib Drugs 0.000 claims description 25
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 claims description 25
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 24
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 23
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims description 22
- 239000012828 PI3K inhibitor Substances 0.000 claims description 22
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims description 22
- 239000012664 BCL-2-inhibitor Substances 0.000 claims description 21
- 229940123711 Bcl2 inhibitor Drugs 0.000 claims description 21
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims description 21
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 19
- 229960001183 venetoclax Drugs 0.000 claims description 19
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical group C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 claims description 19
- HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 claims description 16
- 239000002246 antineoplastic agent Substances 0.000 claims description 16
- 230000037361 pathway Effects 0.000 claims description 12
- DKXHSOUZPMHNIZ-UHFFFAOYSA-N 2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one Chemical compound C=1C=2C(=O)NCCC=2NC=1C1=CC=NC=C1 DKXHSOUZPMHNIZ-UHFFFAOYSA-N 0.000 claims description 11
- WJRRGYBTGDJBFX-UHFFFAOYSA-N 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine Chemical compound CC(C)N1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(C)(=O)=O)=N1 WJRRGYBTGDJBFX-UHFFFAOYSA-N 0.000 claims description 11
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 claims description 11
- 229940076005 apoptosis modulator Drugs 0.000 claims description 11
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 10
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 9
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 9
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 claims description 8
- 108091007960 PI3Ks Proteins 0.000 claims description 8
- 201000006966 adult T-cell leukemia Diseases 0.000 claims description 8
- 238000002512 chemotherapy Methods 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 7
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 7
- 206010058314 Dysplasia Diseases 0.000 claims description 7
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 claims description 7
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 7
- HUXYBQXJVXOMKX-UHFFFAOYSA-N N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NC1=NNC(C2(C)C)=C1CN2C(=O)C1CCN(C)CC1 HUXYBQXJVXOMKX-UHFFFAOYSA-N 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 210000004698 lymphocyte Anatomy 0.000 claims description 7
- 229950004847 navitoclax Drugs 0.000 claims description 6
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 claims description 6
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 claims description 5
- 208000000389 T-cell leukemia Diseases 0.000 claims description 5
- 201000003444 follicular lymphoma Diseases 0.000 claims description 5
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 5
- 208000021937 marginal zone lymphoma Diseases 0.000 claims description 5
- 230000002792 vascular Effects 0.000 claims description 5
- 206010007953 Central nervous system lymphoma Diseases 0.000 claims description 4
- 208000017604 Hodgkin disease Diseases 0.000 claims description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 4
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
- 101100289792 Squirrel monkey polyomavirus large T gene Proteins 0.000 claims description 4
- 208000010502 Subcutaneous panniculitis-like T-cell lymphoma Diseases 0.000 claims description 4
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims description 4
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 claims description 4
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 4
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 claims description 4
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 4
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 4
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 4
- 201000005962 mycosis fungoides Diseases 0.000 claims description 4
- 210000000822 natural killer cell Anatomy 0.000 claims description 4
- 210000004287 null lymphocyte Anatomy 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 208000010626 plasma cell neoplasm Diseases 0.000 claims description 4
- 210000004180 plasmocyte Anatomy 0.000 claims description 4
- 208000016800 primary central nervous system lymphoma Diseases 0.000 claims description 4
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 4
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 claims description 4
- JCSGFHVFHSKIJH-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)-4-(1-methyl-3-indolyl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C1=CC=C(Cl)C=C1Cl JCSGFHVFHSKIJH-UHFFFAOYSA-N 0.000 claims description 3
- MDZCSIDIPDZWKL-UHFFFAOYSA-N CHIR-98014 Chemical compound C1=C([N+]([O-])=O)C(N)=NC(NCCNC=2N=C(C(=CN=2)N2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1 MDZCSIDIPDZWKL-UHFFFAOYSA-N 0.000 claims description 3
- AQGNHMOJWBZFQQ-UHFFFAOYSA-N CT 99021 Chemical compound CC1=CNC(C=2C(=NC(NCCNC=3N=CC(=CC=3)C#N)=NC=2)C=2C(=CC(Cl)=CC=2)Cl)=N1 AQGNHMOJWBZFQQ-UHFFFAOYSA-N 0.000 claims description 3
- PQCXVIPXISBFPN-UHFFFAOYSA-N SB 415286 Chemical compound C1=C(Cl)C(O)=CC=C1NC1=C(C=2C(=CC=CC=2)[N+]([O-])=O)C(=O)NC1=O PQCXVIPXISBFPN-UHFFFAOYSA-N 0.000 claims description 3
- 230000001568 sexual effect Effects 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 claims 3
- OOVTUOCTLAERQD-OJMBIDBESA-N 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride Chemical compound Cl.OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O OOVTUOCTLAERQD-OJMBIDBESA-N 0.000 claims 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims 1
- 208000026651 T-cell prolymphocytic leukemia Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 1
- 230000003393 splenic effect Effects 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 238000010586 diagram Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 170
- 101150113453 Gsk3a gene Proteins 0.000 description 30
- 206010028980 Neoplasm Diseases 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 24
- 230000000694 effects Effects 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 21
- 239000008194 pharmaceutical composition Substances 0.000 description 21
- 230000000394 mitotic effect Effects 0.000 description 20
- 238000011287 therapeutic dose Methods 0.000 description 20
- 102000001267 GSK3 Human genes 0.000 description 19
- 210000003793 centrosome Anatomy 0.000 description 17
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 16
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 15
- 230000004083 survival effect Effects 0.000 description 15
- 238000002648 combination therapy Methods 0.000 description 14
- 108060006662 GSK3 Proteins 0.000 description 13
- 239000000546 pharmaceutical excipient Substances 0.000 description 13
- 230000006907 apoptotic process Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 102100022975 Glycogen synthase kinase-3 alpha Human genes 0.000 description 11
- 101000903717 Homo sapiens Glycogen synthase kinase-3 alpha Proteins 0.000 description 11
- 239000003937 drug carrier Substances 0.000 description 11
- 238000001262 western blot Methods 0.000 description 11
- QLUYMIVVAYRECT-OCCSQVGLSA-N 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O QLUYMIVVAYRECT-OCCSQVGLSA-N 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 230000022131 cell cycle Effects 0.000 description 10
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 238000002835 absorbance Methods 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 108090000397 Caspase 3 Proteins 0.000 description 7
- 102100029855 Caspase-3 Human genes 0.000 description 7
- 108010057466 NF-kappa B Proteins 0.000 description 7
- 102000003945 NF-kappa B Human genes 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 6
- 101150097381 Mtor gene Proteins 0.000 description 6
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000002018 overexpression Effects 0.000 description 6
- 230000035899 viability Effects 0.000 description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 5
- 108091033409 CRISPR Proteins 0.000 description 5
- 238000000719 MTS assay Methods 0.000 description 5
- 231100000070 MTS assay Toxicity 0.000 description 5
- 102000029749 Microtubule Human genes 0.000 description 5
- 108091022875 Microtubule Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 102000038030 PI3Ks Human genes 0.000 description 5
- 102100024315 Pericentrin Human genes 0.000 description 5
- 101710179262 Pericentrin Proteins 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 230000005754 cellular signaling Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000016507 interphase Effects 0.000 description 5
- 210000004688 microtubule Anatomy 0.000 description 5
- 230000011278 mitosis Effects 0.000 description 5
- 210000004940 nucleus Anatomy 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 4
- 108020005004 Guide RNA Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000012744 immunostaining Methods 0.000 description 4
- 230000004807 localization Effects 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 239000013610 patient sample Substances 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- 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 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 201000004085 CLL/SLL Diseases 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 230000005778 DNA damage Effects 0.000 description 3
- 231100000277 DNA damage Toxicity 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 229920002527 Glycogen Polymers 0.000 description 3
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 102000000763 Survivin Human genes 0.000 description 3
- 108010002687 Survivin Proteins 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines 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
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 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
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 229940096919 glycogen Drugs 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 230000010287 polarization Effects 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 2
- FHCSBLWRGCOVPT-UHFFFAOYSA-N AZD2858 Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=C(C=2N=C(C(N)=NC=2)C(=O)NC=2C=NC=CC=2)C=C1 FHCSBLWRGCOVPT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 238000010354 CRISPR gene editing Methods 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 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 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101150019946 Gsk3b gene Proteins 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 238000003559 RNA-seq method Methods 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000030570 cellular localization Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 208000021173 high grade B-cell lymphoma Diseases 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 201000003445 large cell neuroendocrine carcinoma Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229960000907 methylthioninium chloride Drugs 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000000069 prophylactic 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
- 238000011002 quantification Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 230000020347 spindle assembly Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003656 tris buffered saline Substances 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-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-GHYRFKGUSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 238000012447 xenograft mouse model Methods 0.000 description 2
- 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 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VOXBZHOHGGBLCQ-UHFFFAOYSA-N 2-amino-3,7-dihydropurine-6-thione;hydrate Chemical compound O.N1C(N)=NC(=S)C2=C1N=CN2.N1C(N)=NC(=S)C2=C1N=CN2 VOXBZHOHGGBLCQ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- QNAQEWTWBYVVSY-UHFFFAOYSA-N 3-(1-benzofuran-3-yl)-4-(1h-indol-3-yl)pyrrole-2,5-dione Chemical class C1=CC=C2C(C=3C(=O)NC(C=3C=3C4=CC=CC=C4NC=3)=O)=COC2=C1 QNAQEWTWBYVVSY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229940124292 CD20 monoclonal antibody Drugs 0.000 description 1
- 101100220616 Caenorhabditis elegans chk-2 gene Proteins 0.000 description 1
- 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 1
- 241000283707 Capra Species 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108090000567 Caspase 7 Proteins 0.000 description 1
- 102000047934 Caspase-3/7 Human genes 0.000 description 1
- 108700037887 Caspase-3/7 Proteins 0.000 description 1
- 102100038902 Caspase-7 Human genes 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 108010025461 Cyclin-Dependent Kinase 9 Proteins 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 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
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 230000037059 G2/M phase arrest Effects 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 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 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.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 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 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 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 108010052419 NF-KappaB Inhibitor alpha Proteins 0.000 description 1
- 102100039337 NF-kappa-B inhibitor alpha Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 208000008425 Protein deficiency Diseases 0.000 description 1
- 238000012180 RNAeasy kit Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 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
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 1
- 101710187743 Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000021375 Xenogenes Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 101150063416 add gene Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000690 anti-lymphoma Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000034720 apoptotic signaling pathway Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- 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 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 1
- 210000004556 brain Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000031080 centrosome localization Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 101150113535 chek1 gene Proteins 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 208000018805 childhood acute lymphoblastic leukemia Diseases 0.000 description 1
- 201000011633 childhood acute lymphocytic leukemia Diseases 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 238000013211 curve analysis Methods 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000012303 cytoplasmic staining Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 229960001251 denosumab Drugs 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 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 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960004497 dinutuximab Drugs 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 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 1
- 229960002074 flutamide Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 1
- 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 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960004859 glucarpidase Drugs 0.000 description 1
- 108010049491 glucarpidase Proteins 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010049611 glycogen synthase kinase 3 alpha Proteins 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960002411 imatinib Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 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 1
- 230000007794 irritation Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 1
- 229960003648 ixazomib Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 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 1
- 229960001924 melphalan Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 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
- 239000011707 mineral Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000008600 mitotic progression Effects 0.000 description 1
- 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 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011294 monotherapeutic Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 1
- 229960005163 netupitant Drugs 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 210000000633 nuclear envelope Anatomy 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
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 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 1
- 229950007318 ozogamicin Drugs 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000031877 prophase Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000003197 protein kinase B inhibitor Substances 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical compound [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- 229910001630 radium chloride Inorganic materials 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- HNMATTJJEPZZMM-BPKVFSPJSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-6-[[(2s,5z,9r,13e)-13-[2-[[4-[(2e)-2-[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazinyl]-2-methyl-4-oxobutan-2-yl]disulfanyl]ethylidene]-9-hydroxy-12-(m Chemical compound C1[C@H](OC)[C@@H](N(CC)C(C)=O)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSC(C)(C)CC(=O)N\N=C(/C)C=3C=CC(OCCCC(N)=O)=CC=3)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HNMATTJJEPZZMM-BPKVFSPJSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000031865 spindle localization Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 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 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002952 tipiracil Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- LFOHPKKMDYSRLY-UHFFFAOYSA-N uridine triacetate Natural products CC(=O)OCC1OC(CN2C=CC(=O)NC2=O)C(OC(=O)C)C1OC(=O)C LFOHPKKMDYSRLY-UHFFFAOYSA-N 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 229960003498 uridine triacetate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K31/40—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
- A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- 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
- A61K31/495—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (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)
Abstract
【選択図】 図1
Description
である。
[実施例]
材料−実施例1〜5
3日目の細胞生存率および7日間にわたる増殖は、製造業者の指示に従って、Promega CellTiter 96(商標登録)AQueous One Solution Cell Proliferation Assay試薬(MTS)を用いて、9−ING−41の濃度を変化させて細胞を処理した後に測定した。処理の最後に、96ウェルプレートに20μLの試薬をウェルあたり添加し、37℃で2−4時間インキュベートした。490nm(A490)における吸光度をPowerwave XSプレートリーダー(Biotek)を用いて測定した。
EnzChekカスパーゼ3アッセイ(サーモフィッシャーサイエンティフィック)を製造者の指示に従って実施した。100,000個の細胞を12ウェルプレートにプレートし、9−ING−41の様々な濃度で24時間、二重に処理した。処理の終わりに、細胞を200rcfで5分間遠心分離し、1X PBSで1回洗浄し、キットで提供された1X溶解緩衝液50μL中で溶解した。効率的な溶解のために、細胞は1回の凍結融解サイクルを受けた。溶解した細胞は、細胞破片を除去するために再び遠心分離し、上清をアッセイに使用した。Z−DEVD−R110基質を含む2X基質作業溶液の50μLを細胞溶解液に添加し、その後室温で45分間インキュベートした。このアッセイで使用されるロダミン110由来の基質(Z−DEVD−R110)は、非蛍光ビスアミド化合物であり、細胞溶解物中の活性カスパーゼ3と多分カスパーゼ7を介して酵素的に切断されると、2段階のプロセスで蛍光モノアミドに変換され、その後、さらに蛍光R110生成物に変換される。これらの生成物の両方は、その後、対応する波長(励起496nm/発光520nm)でBiotekシナジー2蛍光プレートリーダーを使用して測定した。蛍光読取値は、標準BCAアッセイ(Pierce Thermo Fisher Scientific)を介して決定された細胞溶解液中のタンパク質量に正規化した。相対的な蛍光は、無処理対照を1とした後に計算した。
9−ING−41単独および9−ING−41とVenetoclaxまたはBAY−1143572のいずれかを組み合わせた場合のウエスタンブロットを介してKPUM−UH1細胞におけるc−MYCレベルを分析した。約10000万個の細胞を200rcfで5分間スピンダウンし、プロテアーゼおよびホスファターゼ阻害剤(Roche)を補充した50μlのMillipore Milliplex MAP溶解緩衝液で溶解する前にPBSで1回洗浄した。β−メルカプトエタノール(Bio−Rad)を補充した4Xサンプルバッファー中で変性したタンパク質をウェルあたりに装填した。Bio−RadステインフリーのCriterion 4−20%プレキャストゲルを使用した。140ボルトで90分間ゲルを走らせた後、Bio−Radゲルイメージャーを用いてステインフリー技術を活性化し、ゲル中に装填された総タンパク質レベルを可視化した。次に、ニトロセルロースターボトランスファーパックおよびシステム(Bio−Rad)を用いてタンパク質を膜にトランスファーし、トリス緩衝生理食塩水0.1%Tween 20(TBS−T)中の5%w/vドライミルクを用いて1時間膜をブロックした。その後、膜を5%TBS−T中の5%BSAで希釈した一次抗体で一晩インキュベートした。その後、膜をTBS−Tで3回(1回の15分間洗浄と2回の5分間洗浄)洗浄した後、対応するHRPと共役した二次抗体を1時間インキュベートし、前と同様にTBS−Tで洗浄した。最終洗浄後、膜をPierce SuperSignal West Pico化学発光キットを用いて現像し、Bio−Radイメージングシステムを用いて可視化した。使用した抗体は、ウサギ抗−GSK−3β(Cell Signaling,Cat.No:12456)、ウサギ抗−phospho−GSK−3β(Y216)(Abcam、Cat.No:ab75745)、Rabbit anti−c−MYC(Cell Signaling、Cat.No:5605)、ウサギ抗−c−MYC(Ser 62)(Cell Signaling、Cat.番号:13748)、ウサギ抗−c−MYC(Thr58)(Abcam、Cat.番号:ab185655)、マウス抗−β−アクチン(Sigma、Cat.番号:A5441)を1:1000希釈した。抗ウサギHRPおよび抗マウスHRP二次抗体は、Cell Signalingから購入し、1:5000希釈で使用した。必要に応じて、膜をRESTORE PLUSウエスタンブロットストリッピングバッファー(Pierce)を用いて10分間ストリッピングし、TBS−Tで数回洗浄した後、以前と同様に再ブロッキングし、再プロービングした。バンド強度の定量は、Image Jソフトウェア(NIH)を用いて行った。ダブルヒットリンパ腫細胞株KPUM−UH1におけるこれらの実験は、9−ING−41処理によりphospho−c−MYCが修飾されることを示唆する。
NF−κBのシグナリング変化[MILLIPLEXMAP NF−κB Signaling Magnetic Bead Kit 6−plex Kit、EMD Millipore、分析物:c−MYC、FADD(Ser194)、IκBα(Ser32)、IKKα/β(Ser177/Ser181)、NF−κB(Ser536)、TNFR1]、DNA損傷[ミリプレックスMAP DNA損傷/遺伝毒性磁気ビーズパネル、EMDミリポア、分析対象:ATR (total)、Chk1 (Ser345)、Chk2(Thr68)、H2A.X(Ser139)、MDM2 (total)、p21(Total)、p53(Ser15)]、およびapoptotic pathways[Bio−plex pro RBM apoptosis panel 2 and 3、Bio−Rad、analytes:Bad、Bax/Bcl−2dimer、Bcl−xL、Bim、Mcl−1、active caspase 3、Bcl−xL/Bak dimer、Mcl−1/Bak dimer、survivin]は、1μM9−ING−41を48時間処理した場合に無処理対照と比較して、メーカーの指示に従って、FLEXMAP 3D装置を用いたLuminexマルチプレックス技術を用いて決定した。細胞を、プロテアーゼ阻害剤カクテル(シグマ)およびホスファターゼ阻害剤カクテル2および3(シグマ)を補充したMILLIPLEX MAP Lississバッファー中で溶解し、BCAタンパク質の定量後、15μgのタンパク質を各ウェルに添加した。すべてのサンプルを二重に実行し、9−ING−41処理した細胞と非処理対照との間のMFIまたは絶対量の変化を分析し、統計的有意性を決定するために非対数t検定を行った。
Daudi、SUDHL−4、KPUM−UH1、Karpas 422、またはTMD8細胞を、一連の濃度の9−ING−41(0μM、0.05μM、0.5μM)およびVenetoclax(0nM、0.05μM、0.5μM、5nM、5nM、50nM、500nM、5000nM)、BAY−1143572(0μM、0.005μM、0.05μM、0.5μM、5μM、50μM)、またはイデラリシブ(0μM、0.005μM、0.05μM、0.5μM、5μM、50μM)のいずれかの濃度で同時に処理した。図2を参照。MTSアッセイを用いた3日目のバイアビリティを、上述のように決定した。バックグラウンド吸光度をサンプルのA490から差し引き、ビヒクル/無処理対照のA490を1とし、残りのサンプルの相対A490を計算した。IC50は、A490が0.添加効果は、9−ING−41の0.5μMと組み合わせたときの新規薬剤のIC50の倍数変化として計算した。
このような研究は、患者からの情報提供を目的としたものではない。このリンパ腫SPORE生物試料プロトコールは、ヘルシンキ宣言に基づき、メイヨークリニック機関審査委員会によって承認された。すべての主要な患者サンプルは、脾臓またはリンパ節からの生検組織であった。新鮮な組織サンプルは、細胞懸濁液に穏やかに解離され、フィコール・パケ密度勾配遠心分離に供された。初代リンパ腫細胞は、その後、増殖アッセイに直接使用するか、またはリンパ腫診断確認後、後にウェスタン分析のために−80℃で保存した。
共通薬剤はSigma−Aldrichからのものであった。抗ヒトGSK3α(Cat#4337)、GSK3β(Cat#12456)、ホスホ−GSK3α−S21/GSK3β−S9(Cat#9327)を含む免疫ブロット用抗体は、Cell Signalingから購入した。免疫蛍光に使用したマウス抗GSK3βモノクローナル抗体(クローン7/GSK3β、Cat#610201、BD Biosciences)、抗α−チューブリン抗体(クローンMD1A、Cat#T9026)およびウサギ抗ペリセントリン抗体(Cat#ab4448)は、それぞれSigmaおよびAbcamから購入した。Alexa 488またはAlexa 565コンジュゲート二次抗体は、Life Technologies社の製品であった。
細胞を24ウェルプレートに5x105細胞/ウェルで播種し、指示された濃度の9−ING−41で48時間インキュベートした。細胞は、その後、FITC結合アネキシンV(ライフテクノロジーズ)とヨウ化プロピジウムで染色し、BD FACSカリバーフローサイトメーター上で分析に続いた。
細胞をコールドエタノールで固定および透過させ、RNaseで処理し、ヨウ化プロピジウム(Sigma)で染色した。染色した細胞を、CELLQuest PROソフトウェア(Becton Dickinson)を使用して、BD FACSカリバー上で実行した。データは、FlowJo v.Xソフトウェア(Tree Star Inc)を用いて分析した。
細胞を96ウェルプレートに1x104細胞/ウェルで播種し、指示された濃度の9−ING−41で48時間インキュベートした後、チミジン取り込みのために分析される前に、トリチウム標識チミジンで一晩パルシングした。
ウェスタン分析は、LI−COR試薬システムを使用して、LI−COR Odyssey CLXイメージャー上で、以前に記載され、開発されたように実施した。
リンパ腫細胞株からの全mRNAをRNAeasyキット(Qiagen)を用いて単離し、superscript III cDNA合成キット(Life technology)を用いてcDNAを合成した。その後、ABI 7500 Real−Time PCR Systems(Applied Biosystems)上でRT2 SYBR Green ROX qPCR Mastermix(Qiagen)を用いてqPCRを行った。
細胞の生存および増殖に対する9−ING−41のIC50をオンラインIC50計算ツール(https://www.aatbio.com/tools/ic50−calculator/)を用いて計算した。
厚さ5μmのパラフィン切片の免疫組織化学(IHC)を標準プロトコールに従って実施した。スライド上の組織切片をキシレンで脱パラフィン化し、一連のアルコールで再水和した後、クエン酸緩衝液(pH6.0)で抗原を回収し、得られたスライドを30%過酸化水素で内因性ペルオキシダーゼをクエンチした。得られたスライドは、30%過酸化水素で内因性ペルオキシダーゼをクエンチした。スライドを、抗GSK3b抗体(BD、1:150)で2時間室温でインキュベートし、トリス緩衝生理食塩水(各5分間)で3回洗浄し、ビオチン化抗マウス二次抗体(1:200)で1時間室温でインキュベートした。室温で1時間、HRP共役ABC複合体(ベクタステイン、ベクターラボラトリーズ)でスライドを処理した後、3,39−ジアミノベンジジン(DAB、ベクターラボラトリーズ)で発色を現像し、メチレンブルーでカウンターステインし、DPXでマウントし、ニコンエクリプスTi顕微鏡で検査し、イメージ化した。
セントロソームにおけるGSK3βとペリセントリンの共免疫染色(図8C−8J)のために、我々は、3%パラホルムアルデヒドを含むPBS中で室温で5分間、サイトスピンスライド上の細胞を固定することにより、不完全固定法を使用した。細胞は、その後、PBS中の0.2%トリトンX−100で10分間浸透させ、1時間PBS中の5%BSAでブロッキングに続いて、4℃で一晩マウス抗GSK3β mAbとウサギ抗ペリセントリンで免疫染色した。その後、細胞を洗浄し、フルオロクローム共役二次抗体でさらに染色した。
精製ヒト正常B・T細胞およびDLBCL、MCL、TCLリンパ腫細胞株におけるGSK3αおよびGSK3βの発現状況を調べた。RT−qPCRにより、ほとんどのリンパ腫細胞株でGSK3αおよびGSK3β mRNAの発現量が、正常リンパ球での発現量が低いのに比べて、高いが変動することがわかった(図4A)。GSK3タンパク質の発現をウエスタンブロット法で解析したところ、ほとんどのリンパ腫細胞株(Ly−19を除く)でGSK3αタンパク質が強い発現を示したのに対し、BおよびTリンパ球では弱い発現を示した(図4B、緑色)。同様に、GSK3βタンパク質もまた、すべてのリンパ腫細胞株において強く発現したが、正常リンパ球においては非常に弱く発現した(長時間の曝露後に見える;図未提示)(図4B、赤色)。これらのデータは、GSK3タンパク質がほとんどのB−およびT−リンパ腫細胞株で過剰発現することを示す。
GSK3αおよびGSK3βの両方がリンパ腫細胞において過剰発現しており、両方の酵素が細胞機能に重要な複数のシグナル伝達経路に関与することを考えると、GSK3αおよびGSK3βがリンパ腫細胞の生存および増殖を機能的に支持するかどうかを検討した。TCLおよびMCL株を低用量の9−ING−41で48時間処理したところ、アポトーシスが誘導された(図5A);DLBCL株はより高い濃度を必要とした(図5B)。対照的に、9−ING−41の10.0μMの濃度であっても、精製正常非刺激Tリンパ球または末梢血単核細胞において有意なアポトーシスは検出されなかった。各種リンパ腫細胞株の細胞生存率に対する最大効果(IC50)の半分の濃度での9−ING−41の阻害濃度を算出した(表1)。
リンパ腫細胞周期動態に対する9−ING−41の効果を調べた。9−ING−41処置後、試験したすべてのラインにおいて、処置のわずか24時間後にG2/Mでの細胞周期の遮断が見られた(図6A)ことは、GSK3活性が有糸分裂の成功した進行に必要であることを示す。このG2/M停止がGSK3β阻害に特異的に起因するかどうかをさらに決定するために、親(野生型)、GSK3A、GSK3B、およびGSK3A/BノックアウトLy−1サブクローンの細胞周期プロファイルを調べた。治療を行わなかった場合、親の野生型およびGSK3AヌルLy−1サブクローンは正常な細胞周期プロファイルを示したが、GSK3BおよびGSK3A/BノックアウトサブクローンはG2/Mでの細胞の増加を示した(図6B)。さらに、GSK3A/Bダブルノックアウトサブクローンでは、有糸分裂不全に起因すると考えられる多形(>4N)細胞の増加も認められた。GSK3B−nullおよびGSK3A/B−null Ly−1細胞のこれらの細胞周期異常は、Ly−1細胞株固有の代償メカニズムを介する可能性が高く、Ly−1子孫の生存にはほとんど影響を与えない。9−ING−41処置が、細胞周期進行に対するGSK3BシングルまたはGSK3A/B二重欠失の効果をフェノコピーすることは、GSK3Bがリンパ腫細胞周期G2/M進行に重要であること、および9−ING−41がリンパ腫細胞のための強力な細胞周期遮断剤であることを示す。
G2/Mで停止した細胞は、フローサイトメトリーのヒストグラム(図6A)上では単一のDNA含有量(4N)のピークとして現れるが、実際には、成功した細胞分裂に重要なG2/Mには少なくとも5つの連続したステップ(M1−M5)が存在する。これらには、前相(M1、染色体の凝縮、分裂紡錘体形成開始)、前メタフェース(M2、核膜破壊、セントロソーム分極)、メタフェース(M3、染色体対が中間平面に整列)、アナフェース(M4、娘染色体の分離)、テロフェーズ(M5、娘核の再形成)、および最終的なサイトキネシス(2つの娘細胞の分離)が含まれる。これらの離散的な工程のそれぞれは、ライト染色された細胞上でユニークな識別可能な核の形態を持つ(図7Aに描かれる)。どの段階で逮捕されるようになるかを決定するために、未処理および9−ING−41処理されたジェコ細胞の形態を調べた。図7B(左パネル)に示されているように、すべてのM1−M5分裂段階は未処理のジェコ細胞で容易に同定されたが、9−ING−41処理された細胞(右パネル)では、大部分の細胞が、凝縮した染色体の形態と、M2−M5形態を持つ同定可能な細胞を伴わずに、プロトフェイズ(M1)細胞に類似した細胞質染色の減少を示した。100個の有糸分裂細胞の差動計数によって、有糸分裂細胞のすべての段階(M1−M5)は、未処理の細胞で容易に識別可能であることが見出された;9−ING−41処理の有糸分裂細胞では、原相(M1)細胞のみが説明された(図7C)。同様の結果は、DHL−6、Ly−3、Mino、Karpas299を含む他のリンパ腫株でも観察された。これらの観察は、GSK3活性が有糸分裂期の進行に必要であるという結論を支持する。
2つの重要な前相イベント、セントロソーム分極および有糸分裂紡錘体形成におけるGSK3βの関与を調べた。間期のJeko細胞またはLy−1細胞におけるGSK3βタンパク質の細胞内局在を免疫蛍光染色で調べた。間期の間期において、GSK3βは、ジェコ(Jeko)細胞では核内に顕著に局在し、細胞質ではセントロソーム様ペアドットに局在した(図8A−B)。さらに、これらの細胞質のペアドットが実際にセントロソームであることを示すために、不完全固定プロトコルを用いて、まず、wt Ly−1細胞をGSK3βタンパク質とセントロソームマーカーであるペリセントリンのために染色したところ、細胞質のGSK3βドットはペリセントリンと完全にコロケーションすることが判明した(図8D−8F)。さらに、抗GSK3β抗体染色は、GSK3BヌルLy1細胞においてGSK3βタンパク質に特異的であることが示された(図8G−J)。このことから、GSK3βは間期細胞のセントロソームと核に局在していると結論づけた。
MCL、高悪性度B細胞リンパ腫、濾胞性リンパ腫グレード3B、DLBCL、または血管性免疫芽球性TCLを有する患者から新鮮に分離された一次リンパ腫細胞におけるGSK3αおよびGSK3βタンパク質の発現を調べた。5つのサンプルはすべて、正常血液B細胞コントロールと比較し、GSK3αおよびGSK3βタンパク質の発現が強かった(図9A)。これらの患者細胞は、9−ING−41の抗増殖効果にも同様に反応した(図9B)。様々なタイプのリンパ腫を有する別のコホートの患者からのパラフィンサンプルを、GSK3βタンパク質の発現についてIHCでプローブした。図9Cに示すように、すべてのサンプルにおいて、GSK3βの過剰発現が変動する強度で認められた。Gene Expression Profile Interactive Analysis(http://gepia.cancerpku.cn)の公開データベースから得られた一次DLBCL患者サンプルのRNA−Seq解析もまた、正常リンパ球よりもリンパ腫においてGSK3αおよびGSK3βの発現が増加することを示した。
ホタルルシフェラーゼレポーター遺伝子Flucを発現するジェコ細胞を有するNGSマウスを皮下注射することにより、MCL異種移植マウスモデルを樹立した。
びまん性大細胞型B細胞リンパ腫のヒトに9−ING−41を1日1mg/kg投与し、21日サイクルで6回投与した。治療後、そのヒトのDLBCLは寛解する。
T細胞リンパ腫(非ホジキン)に苦しむヒトに、9−ING−41を1日2mg/kg、21日サイクルで6回投与する。処置後、このヒトのT細胞リンパ腫は寛解する。
Claims (29)
- その治療を必要とする患者に悪性リンパ増殖性障害を治療する方法であって、前記患者に有効量のGSK−3β阻害剤を投与する工程を含む方法。
- 請求項1記載の方法において、前記悪性リンパ増殖性障害は、悪性B細胞リンパ増殖性障害である、方法。
- 請求項2記載の方法において、前記悪性B細胞リンパ増殖性障害は、びまん性大細胞型B細胞リンパ腫、急性リンパ性白血病、リンパ球芽球期慢性骨髄性白血病、慢性リンパ性白血病/小リンパ球性リンパ腫、管外縁帯B細胞リンパ腫、粘膜関連リンパ組織リンパ腫、濾胞性リンパ腫、マントル細胞リンパ腫、結節性辺縁帯B細胞リンパ腫、バーキットリンパ腫、毛細血管白血病、原発性中枢神経系リンパ腫、脾臓辺縁帯B細胞リンパ腫、ウォルデンストロームマクログロブリン血症/リンパ形成不全リンパ腫、多発性骨髄腫、血漿細胞異形成症、血漿細胞新生物、原発性縦隔B細胞リンパ腫、ホジキン病、またはカステルマン病である、方法。
- 請求項3記載の方法において、前記悪性B細胞リンパ増殖性障害は、びまん性大細胞型B細胞リンパ腫である、方法。
- 請求項4記載の方法において、前記びまん性大細胞型B細胞リンパ腫は、ダブルヒットリンパ腫である、方法。
- 請求項1記載の方法において、前記悪性リンパ増殖性障害は、悪性T細胞リンパ増殖性障害である、方法。
- 請求項6記載の方法において、前記悪性T細胞リンパ増殖性障害は、T細胞白血病/リンパ腫、管外ナチュラルキラー/T細胞リンパ腫、皮膚T細胞リンパ腫、腸管症型T細胞リンパ腫、血管免疫芽球性T細胞リンパ腫、未分化大T/ヌル細胞リンパ腫、皮下パンニクル炎様T細胞リンパ腫、T細胞性急性リンパ性白血病、T細胞性大粒径リンパ球白血病、リンパ球芽球期慢性骨髄性白血病、移植後リンパ増殖症候群、ヒトT細胞白血病ウイルス1型陽性(HTLV−1+)成人T細胞白血病・リンパ腫(ATL)、T細胞前リンパ球性白血病(T−PLL)、または非特定型T細胞リンパ腫である、方法。
- 請求項1〜7のいずれか1項記載の方法において、前記悪性リンパ増殖性障害は、化学療法抵抗性である、方法。
- 請求項1〜8のいずれか1項記載の方法において、前記GSK−3β阻害剤は、9−ING−41、チデグルシブ、LY2090314、CHIR−99021、CHIR−98014、SB216763、SB415286、AR−A011418、CG701338、またはCG202796である、方法。
- 請求項9記載の方法において、前記GSK−3β阻害剤は、9−ING−41、チデグルシブ、またはLY2090314である、方法。
- 請求項10記載の方法において、前記GSK−3β阻害剤は、9−ING−41である、方法。
- 請求項10記載の方法において、前記GSK−3β阻害剤は、チデグルシブである、方法。
- 請求項10記載の方法において、前記GSK−3β阻害剤は、LY2090314である、方法。
- 請求項1〜13のいずれか1項記載の方法において、前記GSK−3β阻害剤は、第2の治療剤と組み合わせて投与される、方法。
- 請求項14記載の方法において、前記第二の治療剤は、サブ治療量で投与される、方法。
- 請求項14または15記載の方法において、前記第二の治療剤は、抗癌剤である、方法。
- 請求項16記載の方法において、前記抗癌剤は、アポトーシスモジュレーター、CDKモジュレーター、またはmTOR/AKT/PI3Kのモジュレーターである、方法。
- 請求項17記載の方法において、前記抗癌剤は、アポトーシスモジュレーターである、方法。
- 請求項18記載の方法において、前記アポトーシスモジュレーターは、Bcl−2阻害剤である、方法。
- 請求項19記載の方法において、前記Bcl−2阻害剤は、ベネトクラックス、ABT−737、またはナビトクラックスである、方法。
- 請求項20の方法であって、前記Bcl−2インヒビターは、ベネトグラックスである、方法。
- 請求項17記載の方法において、前記抗癌剤は、CDKモジュレーターである、方法。
- 請求項22記載の方法において、前記CDKモジュレーターは、CDK9阻害剤である、方法。
- 請求項23記載の方法において、前記CDK9阻害剤は、BAY−1143572、LDC000067、ダイナシクリブ(SCH727965)、SNS−032(BMS−387032)、AT7519、P276−00、AZD5438、PHA−767491、またはPHA−793887である、方法。
- 請求項24記載の方法において、前記CDK9阻害剤は、BAY−1143572である、方法。
- 請求項17記載の方法において、前記抗癌剤は、mTOR/AKT/PI3K経路のモジュレーターである、方法。
- 請求項26の方法であって、前記mTOR/AKT/PI3K経路のモジュレーターは、PI3Kインヒビターである、方法。
- 請求項27記載の方法において、前記PI3K阻害剤は、コパンリシブまたはイデラリシブである、方法。
- 請求項28記載の方法において、前記PI3K阻害剤は、イデラリシブである、方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862680739P | 2018-06-05 | 2018-06-05 | |
US62/680,739 | 2018-06-05 | ||
PCT/US2019/035576 WO2019236703A1 (en) | 2018-06-05 | 2019-06-05 | Methods of treating malignant lymphoproliferative disorders |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024056596A Division JP2024096738A (ja) | 2018-06-05 | 2024-03-29 | 悪性リンパ腫性障害の治療法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021527039A true JP2021527039A (ja) | 2021-10-11 |
JPWO2019236703A5 JPWO2019236703A5 (ja) | 2022-06-13 |
Family
ID=68769443
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020567578A Pending JP2021527039A (ja) | 2018-06-05 | 2019-06-05 | 悪性リンパ腫性障害の治療法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US11510904B2 (ja) |
EP (1) | EP3801768A4 (ja) |
JP (1) | JP2021527039A (ja) |
KR (1) | KR20210045364A (ja) |
CN (2) | CN112351819B (ja) |
AU (1) | AU2019280693A1 (ja) |
BR (1) | BR112020024931A2 (ja) |
CA (1) | CA3102555A1 (ja) |
IL (1) | IL279155A (ja) |
MX (1) | MX2020013163A (ja) |
WO (1) | WO2019236703A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021527039A (ja) * | 2018-06-05 | 2021-10-11 | アクチュエイト セラピューティクス、インク. | 悪性リンパ腫性障害の治療法 |
EP4081213A1 (en) * | 2019-12-26 | 2022-11-02 | Actuate Therapeutics Inc. | Compounds for the treatment of myelofibrosis |
US20240009170A1 (en) * | 2020-11-17 | 2024-01-11 | Brown University | Inhibition of glycogen synthase kinase-3 (gsk-3) |
CN113684180B (zh) * | 2021-08-31 | 2023-05-26 | 山东大学第二医院 | 一种提高骨髓瘤杀伤活性的nk细胞制备方法 |
WO2023172629A2 (en) * | 2022-03-08 | 2023-09-14 | Brown University | Anticancer maleimide derivatives for use with immune checkpoint blockade |
WO2024006750A1 (en) * | 2022-06-27 | 2024-01-04 | Actuate Therapeutics, Inc. | Oral dosage forms of elraglusib |
WO2024028433A1 (en) * | 2022-08-04 | 2024-02-08 | Institut National de la Santé et de la Recherche Médicale | Methods for the treatment of lymphoproliferative disorders |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016060741A (ja) * | 2014-09-12 | 2016-04-25 | 国立大学法人 鹿児島大学 | 成人t細胞白血病治療薬 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008077138A1 (en) | 2006-12-19 | 2008-06-26 | The Board Of Trustees Of The University Of Illinois | 3-benzofuranyl-4-indolyl maleimides as potent gsk3 inhibitors for neurogenerative disorders |
KR20140130124A (ko) * | 2012-02-21 | 2014-11-07 | 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 | 글리코겐 합성효소 키나아제 3 베타 억제제로서 1h-인다졸-3-카복사미드 화합물 |
US20160375006A1 (en) | 2012-10-12 | 2016-12-29 | The Broad Institute, Inc. | Uses of paralog-selective inhibitors of gsk3 kinases |
PT2909204T (pt) | 2012-10-12 | 2019-03-21 | Dana Farber Cancer Inst Inc | Inibidores de gsk3 e métodos de utilização dos mesmos |
WO2014165851A1 (en) | 2013-04-05 | 2014-10-09 | The Children's Hospital Of Philadelphia | Transient up-regulation of myc in b-cell lymphomas |
WO2015155738A2 (en) * | 2014-04-09 | 2015-10-15 | Christopher Rudd | Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity |
JP2021527039A (ja) * | 2018-06-05 | 2021-10-11 | アクチュエイト セラピューティクス、インク. | 悪性リンパ腫性障害の治療法 |
-
2019
- 2019-06-05 JP JP2020567578A patent/JP2021527039A/ja active Pending
- 2019-06-05 KR KR1020207037918A patent/KR20210045364A/ko unknown
- 2019-06-05 WO PCT/US2019/035576 patent/WO2019236703A1/en unknown
- 2019-06-05 US US15/734,699 patent/US11510904B2/en active Active
- 2019-06-05 EP EP19815715.8A patent/EP3801768A4/en active Pending
- 2019-06-05 BR BR112020024931-9A patent/BR112020024931A2/pt unknown
- 2019-06-05 CA CA3102555A patent/CA3102555A1/en active Pending
- 2019-06-05 CN CN201980037210.9A patent/CN112351819B/zh active Active
- 2019-06-05 AU AU2019280693A patent/AU2019280693A1/en active Pending
- 2019-06-05 CN CN202311356900.5A patent/CN117883438A/zh active Pending
- 2019-06-05 MX MX2020013163A patent/MX2020013163A/es unknown
-
2020
- 2020-12-02 IL IL279155A patent/IL279155A/en unknown
-
2022
- 2022-11-03 US US18/052,369 patent/US11980607B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016060741A (ja) * | 2014-09-12 | 2016-04-25 | 国立大学法人 鹿児島大学 | 成人t細胞白血病治療薬 |
Non-Patent Citations (4)
Title |
---|
KARMALI R. ET AL., ONCOTARGET, vol. 8, no. 70, JPN6023021209, 2017, pages 114924 - 114934, ISSN: 0005070897 * |
KITAGAWA Y. ET AL.: "Glycogen Synthase Kinase-3 (GSK-3) Inhibition Induces Cytotoxicity in Adult T-Cell Leukemia/Lymphoma", AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 25, no. 11, JPN6023021207, 2009, pages 70, ISSN: 0005070899 * |
OUGOLKOV A. ET AL., BLOOD, vol. 110, no. 2, JPN6023021206, 2007, pages 735 - 742, ISSN: 0005070900 * |
SONG E. ET AL., EXPERIMENTAL HEMATOLOGY, vol. 38, JPN6023021208, 2010, pages 908 - 921, ISSN: 0005070898 * |
Also Published As
Publication number | Publication date |
---|---|
WO2019236703A1 (en) | 2019-12-12 |
AU2019280693A1 (en) | 2020-12-03 |
EP3801768A1 (en) | 2021-04-14 |
MX2020013163A (es) | 2021-02-18 |
CA3102555A1 (en) | 2019-12-12 |
CN117883438A (zh) | 2024-04-16 |
BR112020024931A2 (pt) | 2021-03-09 |
CN112351819B (zh) | 2023-11-10 |
US11510904B2 (en) | 2022-11-29 |
US20230126700A1 (en) | 2023-04-27 |
IL279155A (en) | 2021-01-31 |
CN112351819A (zh) | 2021-02-09 |
KR20210045364A (ko) | 2021-04-26 |
US20210228546A1 (en) | 2021-07-29 |
EP3801768A4 (en) | 2022-04-20 |
US11980607B2 (en) | 2024-05-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2021527039A (ja) | 悪性リンパ腫性障害の治療法 | |
US9526915B2 (en) | Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase | |
US20100029683A1 (en) | Methods for regulating cell mitosis by inhibiting serine/threonine phosphateses | |
Busch et al. | Similar cisplatin sensitivity of HPV-positive and-negative HNSCC cell lines | |
JP2023533485A (ja) | 重症型の肺高血圧症の治療方法 | |
CA3058276A1 (en) | Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer | |
US20190055563A1 (en) | Polymerase q as a target in hr-deficient cancers | |
US20220072003A1 (en) | Organic compounds | |
CN116327954A (zh) | 血液癌症的组合治疗 | |
TW202021961A (zh) | 用於治療胰臟癌的方法 | |
AU2022355108A1 (en) | Methods of treating solid tumor using heteroaromatic macrocyclic ether compounds | |
JP2020516612A (ja) | 癌の治療のための化合物、組成物およびその使用 | |
JP2024096738A (ja) | 悪性リンパ腫性障害の治療法 | |
CA3146792A1 (en) | Combination therapy for cancer treatment | |
JP6352952B2 (ja) | グリアジンペプチドを用いた癌の治療のためのキットおよび方法 | |
WO2022063134A1 (zh) | Csf1r激酶抑制剂及其用途 | |
JP6969778B2 (ja) | 誤りがちdna修復経路の抑制によるがんの治療 | |
US20150258139A1 (en) | Methods for treatment of cancer using lipoplatin | |
JP2022145629A (ja) | スラミンを含む組成物 | |
JP2023136704A (ja) | 癌の予防及び/又は治療薬 | |
TW202421147A (zh) | 用於治療套細胞淋巴瘤(MCL)之阿貝西尼(Abemaciclib)及維奈托克(Venetoclax)的組合 | |
JP2008291017A (ja) | Wip1発現増強剤及び癌治療増感剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220603 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220603 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230530 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230829 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20231205 |