JP6092880B2 - 抗プロゲスチン感受性腫瘍を特定および治療する方法ならびに系 - Google Patents
抗プロゲスチン感受性腫瘍を特定および治療する方法ならびに系 Download PDFInfo
- Publication number
- JP6092880B2 JP6092880B2 JP2014534716A JP2014534716A JP6092880B2 JP 6092880 B2 JP6092880 B2 JP 6092880B2 JP 2014534716 A JP2014534716 A JP 2014534716A JP 2014534716 A JP2014534716 A JP 2014534716A JP 6092880 B2 JP6092880 B2 JP 6092880B2
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- tumor
- focus
- progesterone receptor
- tissue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 136
- 239000003418 antiprogestin Substances 0.000 title claims description 98
- 230000000708 anti-progestin effect Effects 0.000 title claims description 89
- 238000000034 method Methods 0.000 title claims description 74
- 102000003998 progesterone receptors Human genes 0.000 claims description 238
- 108090000468 progesterone receptors Proteins 0.000 claims description 238
- 210000001519 tissue Anatomy 0.000 claims description 94
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 72
- 230000027455 binding Effects 0.000 claims description 65
- 238000009739 binding Methods 0.000 claims description 65
- 238000009826 distribution Methods 0.000 claims description 60
- 238000011282 treatment Methods 0.000 claims description 43
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 claims description 38
- 229950011093 onapristone Drugs 0.000 claims description 38
- 239000000186 progesterone Substances 0.000 claims description 32
- 229960003387 progesterone Drugs 0.000 claims description 32
- 238000003364 immunohistochemistry Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 210000000481 breast Anatomy 0.000 claims description 14
- 238000001574 biopsy Methods 0.000 claims description 12
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 claims description 12
- 229960003248 mifepristone Drugs 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 11
- 108020003175 receptors Proteins 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 230000003623 progesteronic effect Effects 0.000 claims description 9
- IJLXLZGJDSJGIQ-BILPMHSYSA-N (8r,9s,10r,13s,14s,16r,17s)-16-ethyl-17-(2-hydroxyacetyl)-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1C[C@@H](CC)[C@H](C(=O)CO)[C@@]1(C)CC2 IJLXLZGJDSJGIQ-BILPMHSYSA-N 0.000 claims description 8
- QSFGZNVRVZHUGV-UHFFFAOYSA-N 4-[3-cyclopropyl-5-methyl-1-(methylsulfonylmethyl)pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile Chemical compound C1CC1C1=NN(CS(C)(=O)=O)C(C)=C1OC1=CC(C)=C(C#N)C(C)=C1 QSFGZNVRVZHUGV-UHFFFAOYSA-N 0.000 claims description 8
- 230000009036 growth inhibition Effects 0.000 claims description 8
- 239000012634 fragment Substances 0.000 claims description 7
- 238000010166 immunofluorescence Methods 0.000 claims description 7
- 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 claims description 6
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 6
- 210000004696 endometrium Anatomy 0.000 claims description 6
- 201000010260 leiomyoma Diseases 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- 201000007954 uterine fibroid Diseases 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 206010027191 meningioma Diseases 0.000 claims description 5
- 210000001672 ovary Anatomy 0.000 claims description 5
- 210000002307 prostate Anatomy 0.000 claims description 5
- 230000035945 sensitivity Effects 0.000 claims description 5
- 231100000588 tumorigenic Toxicity 0.000 claims description 5
- 230000000381 tumorigenic effect Effects 0.000 claims description 5
- 229960000200 ulipristal Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 3
- 229960005167 everolimus Drugs 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 229940123237 Taxane Drugs 0.000 claims description 2
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 claims description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
- 229940043275 anti-HER2 drug Drugs 0.000 claims description 2
- 229960000397 bevacizumab Drugs 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 190000008236 carboplatin Chemical compound 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- 229940046159 pegylated liposomal doxorubicin Drugs 0.000 claims description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 2
- 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 claims description 2
- 229960000575 trastuzumab Drugs 0.000 claims description 2
- 238000001262 western blot Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 claims 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 claims 1
- 229960005277 gemcitabine Drugs 0.000 claims 1
- 210000004291 uterus Anatomy 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 86
- 206010006187 Breast cancer Diseases 0.000 description 45
- 208000026310 Breast neoplasm Diseases 0.000 description 41
- 210000004940 nucleus Anatomy 0.000 description 32
- 201000011510 cancer Diseases 0.000 description 28
- 239000000523 sample Substances 0.000 description 26
- 238000010186 staining Methods 0.000 description 22
- 238000004458 analytical method Methods 0.000 description 20
- 239000000583 progesterone congener Substances 0.000 description 18
- 239000002609 medium Substances 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 108091008039 hormone receptors Proteins 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 206010014733 Endometrial cancer Diseases 0.000 description 10
- 206010014759 Endometrial neoplasm Diseases 0.000 description 10
- 238000012758 nuclear staining Methods 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 9
- 230000004913 activation Effects 0.000 description 8
- 102000015694 estrogen receptors Human genes 0.000 description 8
- 108010038795 estrogen receptors Proteins 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- -1 ronaprisan Chemical compound 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 238000004220 aggregation Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 229940011871 estrogen Drugs 0.000 description 7
- 239000000262 estrogen Substances 0.000 description 7
- 229940088597 hormone Drugs 0.000 description 7
- 239000005556 hormone Substances 0.000 description 7
- 238000001794 hormone therapy Methods 0.000 description 7
- 238000000386 microscopy Methods 0.000 description 7
- 210000002325 somatostatin-secreting cell Anatomy 0.000 description 7
- 150000003431 steroids Chemical class 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- 239000000427 antigen Substances 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 229960000074 biopharmaceutical Drugs 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 229940000406 drug candidate Drugs 0.000 description 5
- 230000002055 immunohistochemical effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- RCOWGILQXUPXEW-FUSOFXSQSA-N (8s,11r,13s,14s,17r)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-[(z)-3-hydroxyprop-1-enyl]-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@@]2(O)\C=C/CO)[C@]2(C)C1 RCOWGILQXUPXEW-FUSOFXSQSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 102000003992 Peroxidases Human genes 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HKDLNTKNLJPAIY-WKWWZUSTSA-N Ulipristal Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)C(C)=O)[C@]2(C)C1 HKDLNTKNLJPAIY-WKWWZUSTSA-N 0.000 description 4
- 229940046836 anti-estrogen Drugs 0.000 description 4
- 230000001833 anti-estrogenic effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004624 confocal microscopy Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000328 estrogen antagonist Substances 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 229950001701 lilopristone Drugs 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 108040007629 peroxidase activity proteins Proteins 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002379 progesterone receptor modulator Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 108010077544 Chromatin Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000003886 aromatase inhibitor Substances 0.000 description 3
- GJMNAFGEUJBOCE-MEQIQULJSA-N asoprisnil Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@]([C@]3(C2)C)(COC)OC)=CC=C(\C=N\O)C=C1 GJMNAFGEUJBOCE-MEQIQULJSA-N 0.000 description 3
- 210000003855 cell nucleus Anatomy 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 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 3
- 230000012010 growth Effects 0.000 description 3
- 238000012151 immunohistochemical method Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000007634 remodeling Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- VHZPUDNSVGRVMB-RXDLHWJPSA-N (8s,11r,13s,14s,17s)-11-(4-acetylphenyl)-17-hydroxy-13-methyl-17-(1,1,2,2,2-pentafluoroethyl)-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(C(=O)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@@]2(O)C(F)(F)C(F)(F)F)[C@]2(C)C1 VHZPUDNSVGRVMB-RXDLHWJPSA-N 0.000 description 2
- 229940122815 Aromatase inhibitor Drugs 0.000 description 2
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 2
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 2
- 238000000018 DNA microarray Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 108010085012 Steroid Receptors Proteins 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
- 239000007983 Tris buffer Substances 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003388 anti-hormonal effect Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229950003620 asoprisnil Drugs 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 238000007398 colorimetric assay Methods 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 230000002254 contraceptive effect Effects 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 210000005168 endometrial cell Anatomy 0.000 description 2
- 230000002357 endometrial effect Effects 0.000 description 2
- 208000023965 endometrium neoplasm Diseases 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000009093 first-line therapy Methods 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 230000027758 ovulation cycle Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 150000003146 progesterones Chemical class 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 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 2
- 238000000163 radioactive labelling Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 102000005969 steroid hormone receptors Human genes 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DBLOJPKZEOYNBN-SQNIBIBYSA-N (8s,13s,14s)-13-methyl-2,6,7,8,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 DBLOJPKZEOYNBN-SQNIBIBYSA-N 0.000 description 1
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 241000501754 Astronotus ocellatus Species 0.000 description 1
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000001791 Leiomyomatosis Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 201000002132 brain angioma Diseases 0.000 description 1
- 208000013693 brain hemangioma Diseases 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- WUEMPJNONXHVNQ-UHFFFAOYSA-N heptadeca-1,6-dien-5-one Chemical compound C=CCCC(C=CCCCCCCCCCC)=O WUEMPJNONXHVNQ-UHFFFAOYSA-N 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000013388 immunohistochemistry analysis Methods 0.000 description 1
- 238000012309 immunohistochemistry technique Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 229950001947 lonaprisan Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 238000009828 non-uniform distribution Methods 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000004942 nuclear accumulation Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035752 proliferative phase Effects 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000005315 stained glass Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/025—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/743—Steroid hormones
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
- G01N2333/723—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
Description
(10S,11S,14S,15S,17R)−17−[4−(ジメチルアミノ)フェニル]−14−ヒドロキシ−15−メチル−14−(プロパ−1−イン−1−イル)テトラシクロ[8.7.0.0^{2,7}.0^{11,15}]ヘプタデカ−1,6−ジエン−5−オン
(11−ベータ,17−ベータ,17(z))−ロペニル;エストラ−4,9−ジエン−3−オン、11−(4−(ジメチルアミノ)フェニル)−17−ヒドロキシ−17−(3−ヒドロキシ−1−p;11β−[4−(ジメチルアミノ)フェニル]−17β−ヒドロキシ−17−[(Z)−3−ヒドロキシ−1−プロペニル]エストラ−4,9−ジエン−3−オン
(8R,9S,10R,13S,14S,16R,17S)−16−エチル−17−(2−ヒドロキシアセチル)−13−メチル−2,6,7,8,9,10,11,12,14,15,16,17−ドデカヒドロ−1H−シクロペンタ[a]フェナントレン−3−オン
(8S,11R,13S,14S,17S)−11−(4−アセチルフェニル)−17−ヒドロキシ−13−メチル−17−(1,1,2,2,2−ペンタフルオロエチル)−1,2,6,7,8,11,12,14,15,16−デカヒドロシクロペンタ[a]フェナントレン−3−オン
(8S,11R,13S,14S,17S)−11−[4−[(E)−ヒドロキシイミノメチル]フェニル]−17−メトキシ−17−(メトキシメチル)−13−メチル−1,2,6,7,8,11,12,14,15,16−デカヒドロシクロペンタ[a]フェナントレン−3−オン
(8S,11R,13S,14S,17R)−17−アセチル−11−[4−(ジメチルアミノ)フェニル]−17−ヒドロキシ−13−メチル−1,2,6,7,8,11,12,14,15,16−デカヒドロシクロペンタ[a]フェナントレン−3−オン
4−[3−シクロプロピル−1−(メシルメチル)−5−メチル−1H−ピラゾール−4−イル]オキシ−2,6−ジメチルベンゾニトリル
以下のセクションは、A、AD、DパターンおよびN(陰性、PR染色なし)の頻度に記載している。全ての事例は、高倍率(800倍)で分析した。2つの乳癌の事例は評価不可能であった。表4のデータは、使用する抗体(PRAまたはPRB)により分類が様々であること、およびADパターンに関して抗体間でより多く可変性が存在することを実証している。このことは、癌組織において2つのPR受容体(AおよびB)の固有の調節解除を反映する可能性が最も高い。ある特定の態様では、PRアイソフォームそれぞれで標的とされる抗体を使用して、分析の結果を解釈するためのさらなる情報を提供し得る。例えば、事例は、抗PR A抗体を用いた場合には「D」、および第2の抗PR B抗体を用いた場合には「AD」であってもよい。「AD」の後の分類に基づいて、抗プロゲスチンによる治療は、潜在的に適切である。同様に、事例は、PR Aに対する抗体を用いた場合には「A」、およびPR Bに対する抗体を用いた場合には「AD」であってもよい。これは、異常PR活性により示される悪性細胞増殖のより大きな度合いのため、種々の(より高い)用量の抗プロゲスチンを潜在的に必要とし得る。PRを決定するための従来のIHC方法は、それらがホルモン受容体(すなわち、ERおよびPR)の存在または非存在を単に示すだけであるため、この情報を提供することができない。1つの態様では、1つまたは複数の個々の抗体による分析に基づく活性化PRフォーカスパターンは、活性化PRフォーカスパターンを分析するためのさらなる情報を提供する。
PR核分布の類似のパターンが、子宮内膜癌サンプルで観察される。重要なことに、正常な線維芽細胞は、生検標本サンプルで見出され、PR陽性であることが確認された。これらの正常な線維芽細胞は、D PR核分布表現型を有し、最も可能性が高いのは患者が閉経後であり、したがって生理的レベルのプロゲステロンを生じていないために、これらの正常細胞におけるPRが活性化されなかったことを示した。したがって、線維芽細胞は、内因性プロゲステロンに曝露されてはいない。対比して、癌組織は、線維芽細胞パターンにより示されるように生理的プロゲステロンの非存在下でさえ、PR(APF)の活性化形態を提示していた。
Claims (18)
- 腫瘍または疑いがある腫瘍における1以上の抗プロゲスチンによる効果を予測するインビトロの方法であって、
a)患者由来の腫瘍原性または癌性である疑いのある組織サンプルにおいてプロゲステロン受容体陽性細胞を特定すること、
b)前記組織サンプル由来のプロゲステロン陽性細胞の核内のプロゲステロン受容体のフォーカス分布度を決定すること、および
c)前記組織サンプルにおける前記フォーカス分布度が、前記プロゲステロン受容体陽性細胞の約5%よりも高いかどうかを決定すること
を含む方法。 - 前記組織を抗プロゲステロン受容体抗体に曝露することにより、前記組織サンプル由来の細胞における核内の前記フォーカス分布度を決定することをさらに含む、請求項1に記載の方法。
- 前記腫瘍または疑いがある腫瘍が、乳房、脳、髄膜腫、前立腺、卵巣、子宮内膜、子宮平滑筋腫、肺および子宮組織から成る群から選択される、請求項1に記載の方法。
- 前記抗プロゲスチンが、オナプリストン、ロナプリサン、ミフェプリストン、PF−02413873、テラプリストン、リロプリストン、ORG2058、アソプリスニルおよびウリプリスタルから成る群から選択される、請求項1に記載の方法。
- 前記フォーカス分布度が、前記組織の前記プロゲステロン陽性細胞における前記プロゲステロン受容体の結合パターンを特定することにより決定される、請求項1に記載の方法。
- 前記結合パターンが、散在性(D)、活動性(A)および活動性/散在性(AD)から成る群から選択される、請求項5に記載の方法。
- 少なくとも2つの抗体が、前記フォーカス分布度を決定するのに使用される、請求項2に記載の方法。
- 前記抗体が、抗PR−A抗体、抗PR−B抗体、および抗PR−A抗体と抗PR−B抗体との混合物、ならびにPR−AおよびPR−Bに対する二重特異的抗体から成る群から選択される、請求項2に記載の方法。
- 前記プロゲステロン受容体の前記フォーカス分布度が、免疫組織化学、免疫蛍光およびウェスタンブロットから成る群から選択される検出方法により決定される、請求項2に記載の方法。
- 1以上の抗プロゲスチンによる増殖阻害に感受性の腫瘍を治療するための医薬品の製造における抗プロゲスチンの使用であって、
前記感受性が、
a)患者由来の腫瘍原性である疑いのある組織サンプルを抗プロゲステロン受容体抗体に曝露すること、
b)前記組織サンプルにおけるプロゲステロン受容体陽性細胞を特定すること、
c)該フォーカス結合分布が、AまたはAD結合パターンを伴って、組織サンプルにおいて前記プロゲステロン受容体陽性細胞の5%よりも高い場合に、1以上の抗プロゲスチンによる増殖抑制に腫瘍が感受性であると決定されるように、前記組織由来の細胞の核内のプロゲステロン受容体のフォーカス結合分布を決定すること、ここで前記抗プロゲスチンが、1日当たり約10〜約200mgの投与量範囲である、
によって決定される
使用。 - 前記腫瘍が、乳房、脳、髄膜腫、前立腺、卵巣、子宮内膜、子宮、子宮平滑筋腫、肺および子宮組織から成る群から選択される、請求項10に記載の使用。
- 前記抗プロゲスチンが、オナプリストン、ロナプリサン、ミフェプリストン、PF−02413873、テラプリストン、リロプリストン、ORG2058、アソプリスニルおよびウリプリスタルから成る群から選択される、請求項10に記載の使用。
- 前記フォーカス分布度が、前記組織の前記細胞における前記プロゲステロン受容体の結合パターンを特定することにより決定される、請求項10に記載の使用。
- 前記結合パターンが、散在性(D)、活動性(A)および活動性/散在性(AD)から成る群から選択される、請求項13に記載の使用。
- 前記抗体が、抗PR−A抗体、抗PR−B抗体、PR−AおよびPR−Bに対する二重特異的抗体、ならびに抗PR−A抗体と抗PR−B抗体との混合物から成る群から選択される、請求項10に記載の使用。
- 患者における腫瘍を治療するための医薬品の製造におけるオナプリストンの使用であって、
前記腫瘍が、オナプリストンによる増殖阻害に感受性であり、
前記患者は、腫瘍組織生検標本において、プロゲステロン受容体陽性細胞の細胞核内のプロゲステロン受容体の約5%よりも高いフォーカス分布を示すこととして特定され、
オナプリストンが、1日当たり約10〜約200mgの量で前記患者に投与されること
を含む使用。 - 前記患者に、エベロリムス、トラスツズマブ、TM1−D、抗HER2薬、ベバシズマブ、パクリタキセル、ドセタキセル、タキサン、ドキソルビシン、リポソームドキソルビシン、ペグ化リポソームドキソルビシン、アントラサイクリン、アントラセンジオン、カルボプラチン、シスプラチン、5−FU、ゲムシタビンおよびシクロホスファミドから成る群から選択される抗腫瘍化合物を投与することをさらに含む、請求項16に記載の使用。
- 抗プロゲスチンによる治療に感受性の腫瘍を分類するための方法であって、組織サンプル、およびプロゲステロン受容体を検出できる少なくとも1つの抗体または抗体結合フラグメントを含み、該抗体または抗体結合フラグメントが、腫瘍組織検体由来の細胞のプロゲステロン受容体陽性核内のプロゲステロン受容体のフォーカス分布度を決定するのに使用され、プロゲステロン陽性細胞の細胞核内の該フォーカス分布度が約5%よりも高い場合に、該腫瘍が抗プロゲスチンによる治療に感受性である、方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161542931P | 2011-10-04 | 2011-10-04 | |
US61/542,931 | 2011-10-04 | ||
PCT/US2012/058732 WO2013052652A1 (en) | 2011-10-04 | 2012-10-04 | Methods and systems for identifying and treating anti-progestin sensitive tumors |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014530812A JP2014530812A (ja) | 2014-11-20 |
JP6092880B2 true JP6092880B2 (ja) | 2017-03-08 |
Family
ID=48044149
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014534716A Expired - Fee Related JP6092880B2 (ja) | 2011-10-04 | 2012-10-04 | 抗プロゲスチン感受性腫瘍を特定および治療する方法ならびに系 |
Country Status (14)
Country | Link |
---|---|
US (2) | US9046534B2 (ja) |
EP (1) | EP2763680A4 (ja) |
JP (1) | JP6092880B2 (ja) |
KR (1) | KR102009007B1 (ja) |
CN (1) | CN103957920B (ja) |
AU (1) | AU2012318618B2 (ja) |
BR (1) | BR112014008203A2 (ja) |
CA (1) | CA2849335A1 (ja) |
HK (1) | HK1200104A1 (ja) |
IL (1) | IL231683B (ja) |
MX (1) | MX369028B (ja) |
RU (1) | RU2672874C2 (ja) |
WO (1) | WO2013052652A1 (ja) |
ZA (1) | ZA201401965B (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9833431B2 (en) * | 2013-11-01 | 2017-12-05 | Pitney Pharmaceuticals Pty Limited | Pharmaceutical combinations for the treatment of cancer |
KR20170023771A (ko) * | 2014-04-08 | 2017-03-06 | 아르노 테라퓨틱스 인코포레이티드 | 프로게스테론 수용체 서브타입을 확인하기 위한 시스템 및 방법 |
SG11201607918TA (en) * | 2014-04-24 | 2016-11-29 | Pfizer | Cancer treatment |
CA2966753A1 (en) | 2014-11-17 | 2016-05-26 | Arno Therapeutics, Inc. | Onapristone extended-release compositions and methods |
WO2017053793A1 (en) | 2015-09-25 | 2017-03-30 | Arno Therapeutics, Inc. | Methods of making onapristone intermediates |
US10548905B2 (en) | 2015-12-15 | 2020-02-04 | Context Biopharma Inc. | Amorphous onapristone compositions and methods of making the same |
SG11201807421TA (en) * | 2016-03-01 | 2018-09-27 | Corcept Therapeutics Inc | The use of glucocorticoid receptor modulators to potentiate checkpoint inhibitors |
US20180148471A1 (en) | 2016-11-30 | 2018-05-31 | Arno Therapeutics, Inc. | Methods for onapristone synthesis dehydration and deprotection |
WO2020132046A1 (en) | 2018-12-19 | 2020-06-25 | Corcept Therapeutics Incorporated | Methods of treating cancer comprising administration of a glucocorticoid receptor modulator and a cancer chemotherapy agent |
US11234971B2 (en) | 2018-12-19 | 2022-02-01 | Corcept Therapeutics Incorporated | Methods of treating cancer comprising administration of a glucocorticoid receptor modulator and a cancer chemotherapy agent |
KR102072944B1 (ko) | 2019-07-23 | 2020-02-03 | (주)스타원코퍼레이션 | 펜을 이용한 학습 장치 |
RU2766662C1 (ru) * | 2021-05-18 | 2022-03-15 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии имени Н.Н. Петрова" Министерства здравоохранения Российской Федерации | Способ определения лекарственной чувствительности немелкоклеточного рака легкого in vitro |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4742000A (en) | 1986-05-02 | 1988-05-03 | University Of Chicago | Antibody to human progesterone receptor and diagnostic materials and methods |
US5283190A (en) | 1989-07-31 | 1994-02-01 | Traish Adbulmaged M | Specific monoclonal antibodies against a defined epitope of progesterone receptor and methods for their use |
EA010593B1 (ru) * | 2000-10-18 | 2008-10-30 | Шеринг Акциенгезельшафт | Применение антипрогестинов для индукции апоптоза клетки |
UY26966A1 (es) * | 2000-10-18 | 2002-06-20 | Schering Ag | Uso de antiprogestinas para la inducción de apoptosis en una célula |
US20040121304A1 (en) * | 2001-12-21 | 2004-06-24 | Ulrike Fuhrmann | Method for screening for progesterone receptor isoform-specific ligands and for tissue-selective progesterone receptor ligands |
US20100160275A1 (en) * | 2006-09-26 | 2010-06-24 | Lee Eva Y H P | Methods and compositions for cancer prevention and treatment |
TWI539953B (zh) * | 2008-04-28 | 2016-07-01 | 瑞波若斯治療學公司 | 用於治療乳癌之組成物和方法 |
-
2012
- 2012-10-04 JP JP2014534716A patent/JP6092880B2/ja not_active Expired - Fee Related
- 2012-10-04 KR KR1020147010316A patent/KR102009007B1/ko active IP Right Grant
- 2012-10-04 RU RU2014110504A patent/RU2672874C2/ru not_active IP Right Cessation
- 2012-10-04 WO PCT/US2012/058732 patent/WO2013052652A1/en active Application Filing
- 2012-10-04 BR BR112014008203A patent/BR112014008203A2/pt not_active IP Right Cessation
- 2012-10-04 EP EP12837954.2A patent/EP2763680A4/en not_active Withdrawn
- 2012-10-04 CN CN201280048864.XA patent/CN103957920B/zh not_active Expired - Fee Related
- 2012-10-04 MX MX2014003690A patent/MX369028B/es active IP Right Grant
- 2012-10-04 US US13/644,872 patent/US9046534B2/en not_active Expired - Fee Related
- 2012-10-04 AU AU2012318618A patent/AU2012318618B2/en not_active Ceased
- 2012-10-04 CA CA2849335A patent/CA2849335A1/en not_active Abandoned
-
2014
- 2014-03-18 ZA ZA2014/01965A patent/ZA201401965B/en unknown
- 2014-03-24 IL IL231683A patent/IL231683B/en not_active IP Right Cessation
-
2015
- 2015-01-19 HK HK15100581.8A patent/HK1200104A1/xx unknown
- 2015-04-28 US US14/698,100 patent/US20190145979A9/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU2012318618A1 (en) | 2014-04-17 |
EP2763680A1 (en) | 2014-08-13 |
CN103957920A (zh) | 2014-07-30 |
JP2014530812A (ja) | 2014-11-20 |
MX2014003690A (es) | 2015-01-12 |
HK1200104A1 (en) | 2015-07-31 |
KR102009007B1 (ko) | 2019-08-08 |
RU2014110504A (ru) | 2015-11-10 |
IL231683A0 (en) | 2014-05-28 |
US9046534B2 (en) | 2015-06-02 |
CN103957920B (zh) | 2018-04-20 |
RU2672874C2 (ru) | 2018-11-20 |
MX369028B (es) | 2019-10-25 |
KR20140093663A (ko) | 2014-07-28 |
BR112014008203A2 (pt) | 2017-04-18 |
CA2849335A1 (en) | 2013-04-11 |
NZ717890A (en) | 2017-10-27 |
AU2012318618B2 (en) | 2017-01-12 |
IL231683B (en) | 2019-02-28 |
US20130095170A1 (en) | 2013-04-18 |
WO2013052652A1 (en) | 2013-04-11 |
NZ623140A (en) | 2016-06-24 |
ZA201401965B (en) | 2019-03-27 |
US20190145979A9 (en) | 2019-05-16 |
US20150241435A1 (en) | 2015-08-27 |
EP2763680A4 (en) | 2015-05-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6092880B2 (ja) | 抗プロゲスチン感受性腫瘍を特定および治療する方法ならびに系 | |
US20170102388A1 (en) | Breast cancer diagnostics using rankl and opg | |
Slattery et al. | Estrogen and progesterone receptors in colon tumors | |
US20070031902A1 (en) | Predictive Methods For Cancer Chemotherapy | |
US20150285803A1 (en) | Systems and methods for identifying progesterone receptor subtypes | |
AU2012332481B2 (en) | Assay for predictive biomarkers of anti-estrogen efficacy | |
NZ623140B2 (en) | Methods and systems for identifying and treating anti-progestin sensitive tumors | |
NZ717890B2 (en) | Methods and Systems for Identifying and Treating Anti-Progestin Sensitive Tumors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150925 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160628 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160926 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20170110 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170209 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6092880 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |