US20040185117A1 - Cephalotaxine alkaloid compositions and uses thereof - Google Patents
Cephalotaxine alkaloid compositions and uses thereof Download PDFInfo
- Publication number
- US20040185117A1 US20040185117A1 US10/769,638 US76963804A US2004185117A1 US 20040185117 A1 US20040185117 A1 US 20040185117A1 US 76963804 A US76963804 A US 76963804A US 2004185117 A1 US2004185117 A1 US 2004185117A1
- Authority
- US
- United States
- Prior art keywords
- cephalotaxine
- homoharringtonine
- antiproliferative agent
- antiproliferative
- agent
- 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.)
- Abandoned
Links
- YMNCVRSYJBNGLD-KURKYZTESA-N cephalotaxine Chemical class C([C@@]12C=C([C@H]([C@H]2C2=C3)O)OC)CCN1CCC2=CC1=C3OCO1 YMNCVRSYJBNGLD-KURKYZTESA-N 0.000 title claims abstract description 26
- 239000000203 mixture Substances 0.000 title claims description 22
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 claims abstract description 63
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 claims abstract description 60
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 claims abstract description 60
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 42
- 230000001028 anti-proliverative effect Effects 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- DSRNKUZOWRFQFO-UHFFFAOYSA-N cephalotaxine Natural products COC1=CC23CCCN2CCc4cc5OCOc5cc4C3=C1O DSRNKUZOWRFQFO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 230000001413 cellular effect Effects 0.000 claims abstract description 14
- 230000002062 proliferating effect Effects 0.000 claims abstract description 13
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 12
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 11
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 11
- 108090000790 Enzymes Proteins 0.000 claims abstract description 7
- 102000004190 Enzymes Human genes 0.000 claims abstract description 7
- 229940100198 alkylating agent Drugs 0.000 claims abstract description 4
- 239000002168 alkylating agent Substances 0.000 claims abstract description 4
- 229910052751 metal Inorganic materials 0.000 claims abstract description 4
- 239000002184 metal Substances 0.000 claims abstract description 4
- 239000000138 intercalating agent Substances 0.000 claims abstract description 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 3
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims abstract 3
- 239000002212 purine nucleoside Substances 0.000 claims abstract 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 24
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 22
- 229960004316 cisplatin Drugs 0.000 claims description 21
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 17
- 229960002949 fluorouracil Drugs 0.000 claims description 17
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 14
- 229960003048 vinblastine Drugs 0.000 claims description 14
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 14
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 13
- 229940127093 camptothecin Drugs 0.000 claims description 13
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 13
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 13
- 229960005420 etoposide Drugs 0.000 claims description 13
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 12
- 229960001338 colchicine Drugs 0.000 claims description 12
- 229960000684 cytarabine Drugs 0.000 claims description 12
- 229940045109 genistein Drugs 0.000 claims description 12
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims description 12
- 235000006539 genistein Nutrition 0.000 claims description 12
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims description 12
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 claims description 11
- 229960004701 amonafide Drugs 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000004696 coordination complex Chemical class 0.000 claims 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 claims 1
- 101710172711 Structural protein Proteins 0.000 abstract description 4
- 230000001086 cytosolic effect Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- 206010028980 Neoplasm Diseases 0.000 description 36
- 239000008215 water for injection Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 229930012538 Paclitaxel Natural products 0.000 description 11
- 229960001592 paclitaxel Drugs 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 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 10
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 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 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 6
- 231100000518 lethal Toxicity 0.000 description 6
- 230000001665 lethal effect Effects 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 5
- 238000011735 C3H mouse Methods 0.000 description 4
- 201000008808 Fibrosarcoma Diseases 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WZFZRXGNVSHCOI-UHFFFAOYSA-N acetylcephalotaxine Chemical compound C1=C2C3C(OC(C)=O)C(OC)=CC43CCCN4CCC2=CC2=C1OCO2 WZFZRXGNVSHCOI-UHFFFAOYSA-N 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000013043 chemical agent Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- -1 herringtonine Chemical class 0.000 description 3
- 229940026778 other chemotherapeutics in atc Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-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
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 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 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 190000008236 carboplatin Chemical compound 0.000 description 2
- 230000003034 chemosensitisation Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 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 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- CAOHZEUEVKYHPF-UHFFFAOYSA-N isoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)C)C(O)C(=O)OC)C4C2=CC2=C1OCO2 CAOHZEUEVKYHPF-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 241000725156 Aglaonema modestum Species 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- AQBAIEHUWUCZIE-UHFFFAOYSA-M COC(=O)CC(O)(CCCC(C)(C)O)C(=O)[O-] Chemical compound COC(=O)CC(O)(CCCC(C)(C)O)C(=O)[O-] AQBAIEHUWUCZIE-UHFFFAOYSA-M 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 241000488899 Cephalotaxus Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- WRCBXHDQHPUVHW-UHFFFAOYSA-N Deoxyharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)C)CC(=O)OC)C4C2=CC2=C1OCO2 WRCBXHDQHPUVHW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000012766 Growth delay Diseases 0.000 description 1
- HAVJATCHLFRDHY-UHFFFAOYSA-N Harringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HAVJATCHLFRDHY-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 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
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 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 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 1
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011263 bladder neck cancer Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- WRCBXHDQHPUVHW-QKBZBAIHSA-N deoxyharringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCC(C)C)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 WRCBXHDQHPUVHW-QKBZBAIHSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 229960000908 idarubicin Drugs 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
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- CAOHZEUEVKYHPF-XWHOPEMDSA-N isoharringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCC(C)C)[C@H](O)C(=O)OC)[C@H]4C2=CC2=C1OCO2 CAOHZEUEVKYHPF-XWHOPEMDSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 229960001924 melphalan Drugs 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
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002028 premature 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 150000003834 purine nucleoside derivatives Chemical class 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 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 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 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 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the technical field of the invention is the use of cephalotaxine alkaloids with antiproliferative agents to treat a host with a cellular proliferative disease.
- Conventional antiproliferative agents used in the treatment of cancer are broadly grouped as chemical compounds which (1) affect the integrity of nucleic acid polymers by binding, alkylating, inducing strand breaks, intercalating between base pairs or affecting enzymes which maintain the integrity and function of DNA and RNA; (2) chemical agents that bind to proteins to inhibit enzymatic action (e.g., antimetabolites) or the function of structural proteins necessary for cellular integrity (e.g., antitubulin agents).
- Other chemical compounds that have been identified to be useful in the treatment of some cancers include drugs which block steroid hormone action for the treatment of breast and prostate cancer, photochemically activated agents, radiation sensitizers and protectors.
- Nucleic acid polymers such as DNA and RNA are prime targets for anticancer drugs.
- Alkylating agents such as nitrogen mustards, nitrosoureas, aziridine containing compounds directly attack DNA.
- Metal coordination compounds such as cisplatin and carboplatin similarly directly attack the nucleic acid structure resulting in lesions that are difficult for the cells to repair which, in turn, can result in cell death.
- Other nucleic acid affecting compounds include anthracycline molecules such as doxorubicin, which intercalates between the nucleic acid base pairs of DNA polymers, bleomycin which causes nucleic acid strand breaks, and fraudulent nucleosides.
- Fradulent nucleosides include pyrimidine and purine nucleoside analogs which are inappropriately incorporated into nucleic polymer structures and ultimately cause premature DNA chain termination.
- Certain enzymes that affect the integrity and functionality of the genome can also be inhibited in cancer cells by specific chemical agents and result in cancer cell death. These include enzymes that affect ribonucleotide reductase (e.g., hydroxyurea, gemcitabine), topoisomerase I (e.g. camptothecin) and topoisomerase II (e.g., etoposide).
- cisplatin cis-diamminedichloroplatinum II, CDDP. This compound is active against several human cancers including testicular, small-cell lung, bladder, cervical and head and neck cancer.
- compositions are provided for the treatment of a host with a cellular proliferative disease, particularly a neoplasia.
- pharmaceutically acceptable cephalotaxine and an antiproliferative agent are administered in an amount sufficient to modulate the cellular proliferative disease.
- FIG. 1 depicts the general structure of a cephalotaxine analog.
- R1 and R2 represent substitution groups. Structures for R1 and R2 are shown for the cephalotaxine analog, Homoharringtonine.
- FIG. 2 depicts the structure of the cephalotaxine analog, Homoharringtonine.
- FIG. 3 shows tumor growth delay, as tumor volume on days after treatment with HHT, HHT followed by CDDP, or CDDP alone.
- a pharmaceutically acceptable cephalotaxine is administered, preferably systemically, in conjunction with an antiproliferative agent to improve the anticancer effects.
- the cephalotaxine provides a chemopotentiator effect.
- modulation of a cellular proliferative disease comprises a reduction in tumor growth.
- modulation of a disease comprises inhibition of tumor growth.
- modulation of a cellular proliferative disease comprises an increase in tumor volume quadrupling time (described below).
- modulation of a cellular proliferative disease comprises a chemopotentiator effect.
- modulation of a disease comprises a chemosensitizing effect.
- modulation of a disease comprises cytostasis.
- modulation of a disease comprises a cytotoxic effect.
- a chemical agent is a “chemopotentiator” when it enhances the effect of a known antiproliferative drug in a more than additive fashion relative to the activity of the chemopotentiator or antiproliferative agent used alone. In some cases, a chemosensitizing effect may be observed. This is defined as the effect of use of an agent that if used alone would not demonstrate significant antitumor effects but would improve the antitumor effects of an antiproliferative agent as compared to use of the antiproliferative agent by itself.
- cephalotaxine includes all members of that chemical family including alkaloid derivatives of the Chinese evergreen, Cephalotaxus fortueni and analogs thereof.
- the cephalotaxine family is defined by chemical structure as the ring structures in FIG. 1.
- a cephalotaxine analog is further defined but not limited to the structure depicted in FIG. 1, having substituent or substitute groups at R1 and R2.
- R1 and/or R2 include esters, including herringtonine, isoharringtonine, homoharringtonine, deoxyharringtonine, acetylcephalotaxine and the like. Table 1 lists structures of R1 and R2 for some of these analogs. R1 and R2 substitutions are typically employed to improve biological activity, pharmaceutical attributes such as bioavailability or stability, or decrease toxicity. In one embodiment, R1 and/or R2 include alkyl substitutions (e.g., methyl, ethyl, propyl etc.).
- R1 and/or R2 include esters (e.g., methoxy, ethoxy, butoxy, etc.).
- R1 and R2 are not limited to the above examples, however, in the scope of this invention. TABLE 1 R1 R2 isoharringtonine —OCH 3 harringtonine —OCH 3 acetylcephalotaxine —OCH 3 CH 3 CO 2 homoharringtonine —OCH 3
- a cephalotaxine analog is a further chemical refinement.
- a specific example of a cephalotaxine analog is homoharringtonine which is the butanediocate ester of cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methyl pentyl) (FIG. 2).
- antiproliferative agents are compounds which induce cytostasis or cytotoxicity. “Cytostasis” is the inhibition of cells from growing while “cytotoxicity” is defined as the killing of cells.
- Specific examples of antiproliferative agents include: antimetabolites, such as methotrexate, 5-fluorouracil, gemcitabine, cytarabine, pentostatin, 6-mercaptopurine, 6-thioguanine, L-asparaginase, hydroxyurea, N-phosphonoacetyl-L-aspartate (PALA), fludarabine, 2-chlorodeoxyadenosine, and floxuridine; structural protein agents, such as the vinca alkaloids, including vinblastine, vincristine, vindesine, vinorelbine paclitaxel, and colchicine; antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, bleomycins
- Transplantable experimental murine fibrosarcomas (2 ⁇ 10 5 RIF-1 cells) were grown intradermally in the flanks of 3 month old female C3H mice (Charles River, Holister, Calif.). When the tumors reached a volume of approximately 100 mm 3 , the mice were randomly assigned to each experimental group (4 mice per group).
- the chemopotentiator, homoharringtonine was obtained from NCI and was made to the appropriate concentration in DMSO. Cisplatin (David Bull Laboratories—Mulgrave, Australia, lot. 5201844x) was made to the appropriate concentration in water for injection. The compositions were injected systemically (i.e., intraperitoneally, i.p.), in a volume of 100 microliters. For the treatment of group 3, the chemopotentiator, homoharringtonine, was injected 30 minutes prior to the injection of cisplatin. After treatment, the growth of the tumors was monitored three times per week by caliper measurements of three perpendicular diameters of the tumor and calculation of tumor volume from the formula:
- V ⁇ / 6 ⁇ D 1 ⁇ D 2 ⁇ D 3 ,
- TVQT day zero treatment volume
- TVQT mean and as the “delay.”
- Mean TVQT is the mean days required for individual tumors to grow to four times the tumor volume at the initial treatment day.
- the “delay” is the median of days required for a tumor to grow to four times the mean size of the treated group, minus the median of days required to grow to four times the mean size of the control group.
- the data is also expressed as the ratio of the tumor volume quadrupling time of the treated tumor over the untreated control group (TVQT/CTVQT). Increasing values of this ratio indicate increased antitumor response.
- the RIF-1 murine fibrosarcoma tumor model was used to evaluate the antitumor activity of homoharringtonine, alone and in combination with various antiproliferative agents.
- the antiproliferative agents used include those that affect nucleic acid (e.g., DNA) integrity (e.g., cisplatin, cytarabine, camptothecin, etoposide, 5-fluorouracil, or amonafide), agents that affect structural proteins (e.g., paclitaxel, vinblastine, or colchicine) or cytoplasmic enzymes (e.g., genistein).
- Homoharringtonine was obtained from NCI as a powder.
- Homoharringtonine HHT-Clin
- Cisplatin for Injection, USP was obtained from David Bull Labs (Mulgrave, Australia), Lot No. 5201844x, as a lypholized powder.
- Paclitaxel was obtained from Bristol Myers Squibb Co. (Princeton, N.J.), Lot No. 9J16241, exp. September 2001, prediluted to 6 mg/mL in Cremaphor/EL.
- Cytarabine was obtained from Bedford Labs (Bedford, Ohio), Lot No. 86968A, exp. June 2002, as a lypholized powder.
- Camptothecin was obtained from Boehringer-Ingelheim, Lot No. 142088, as a powder.
- Vinblastine was obtained from Bedford Labs (Bedford, Ohio), Lot No. 112647, as a lypholized powder.
- Etoposide was obtained from Pharmacia (Kalamazoo, Mich.), Lot No. ETA013, exp. May 1999, as a liquid prediluted to 20 mg/mL.
- 5-Fluorouracil was obtained from Pharmacia (Kalamazoo, Mich.), Lot No. FFA191, exp.
- Test preparations (treatment groups) are summarized in Table 4.
- HHT-NCI was weighed into vials and dissolved in DMSO at the stated concentrations.
- paclitaxel prediluted in Cremaphor/EL and dehydrated alcohol to 6 mg/mL was further diluted to 3.3 mg/mL with WFI.
- Formulations 7 and 8 were prepared by further diluting HHT-Clin to the stated concentrations with WFI.
- Formulation 9 was undiluted HHT-Clin, used as received.
- Formulation 10 was prepared by adding 1 mL of WFI to 100 mg of cytarabine as a lypholized powder.
- Formulation 11 was prepared by adding DMSO to camptothecin at a concentration of 1 mg/mL.
- Formulation 12 was made by adding 0.9% Sodium Chloride for Injection to a vial of 10 mg of vinblastine lypholized powder.
- Formulations 13-17 were prepared by diluting the appropriate amount of each test agent into saline (13-2.5 mg/mL etoposide, 14-7.5 mg/mL 5-fluorouracil, 15-7.5 mg/mL amonafide, 16-2.5 mg/mL colchicine, 17-3.75 mg/mL 5-fluorouracil).
- Formulation 18 was prepared by diluting 15 mg of genistein in 1 mL of DMSO.
- mice Female C3H mice (Charles River Laboratories, Holister, Calif.), approximately 3 months old, were used for the study. The average body weight was approximately 25 g. Animals were maintained in isolator cages on a 12-hour light-and-dark cycle. Food and water were available ad libitum.
- Tumors The RIF-1 murine fibrosarcoma cell line was maintained in in vitro culture (Waymouth medium supplemented with 20% fetal bovine serum) at 37° C. in a humidified 5% CO 2 incubator. Log-phase RIF-1 cells were trypsinized and harvested from cell culture flasks to yield a concentration of 4 ⁇ 10 6 cells/mL, then injected intradermally in a volume of 50 ⁇ L (equivalent to 2 ⁇ 10 5 cells per injection) into both flanks of each mouse. Nine days later, when tumors reached approximately 100 mm 3 in size, the animals were randomized to different treatment groups.
- Treatment Groups are summarized in Table 4. Four to five animals were assigned to each treatment group. The intraperitoneal injection volume was 100 ⁇ L. Intratumoral injections (50 ⁇ L) were made into one of the two tumors on each animal with the contralateral tumor serving as an untreated control. The oral administration volume was 100 ⁇ L. Combination treatments using two test agents were administered as two separate injections, with the second one following the first either immediately or after 30 minutes.
- Tumors were measured three times weekly for up to 22 days with Vernier calipers. Tumor volume (cubic millimeters, mm 3 ) was calculated according to the formula:
- V ⁇ / 6 ⁇ D 1 ⁇ D 2 ⁇ D 3
- D 1-3 are perpendicular diameters measured in millimeters (mm).
- Tumor volume quadrupling time defined as the time required for a tumor to grow to four times its initial volume (at the time of treatment), was used as a study endpoint.
- the TVQT was determined for each treatment group and expressed in days as the mean ⁇ standard error (SE).
- Antitumor activity or modulation of tumor growth (as measured by delayed tumor growth, i.e. increases in TVQT values) by homoharringtonine administered as a single agent or in combination with other chemotherapeutics is presented in Table 5.
- homoharringtonine had an average TVQT of 10.4 days in E026 while the untreated controls quadrupled in 7.4 days.
- homoharringtonine at 4 mg/Kg had an average TVQT of 8.5 days.
- Administration of homoharringtonine (4 mg/Kg) in combination with 5-fluorouracil (30 mg/Kg) resulted in a TVQT of 17.9 days versus 13.6 days for 5-fluorouracil, alone.
- Combination administration of homoharringtonine (4 mg/Kg) and vinblastine (2 mg/Kg) yielded a TVQT of 10.9 days versus 8.6 days for vinblastine, alone.
- intraperitoneal administration of homoharringtonine had antitumor activity, i.e. modulated tumor growth, in the RIF-1 murine fibrosarcoma tumor model.
- Intraperitoneal administration of homoharringtonine in combination with cisplatin, cytarabine, camptothecin, vinblastine, etoposide, 5-fluorouracil, amonafide, colchicine and genistein had antitumor activity levels greater than homoharringtonine alone, or the individual test agents.
- the best combinatorial activity used 5-fluorouracil, amonafide and vinblastine.
- Homoharringtonine in combination with paclitaxel had antitumor activity less than homoharringtonine alone.
- Homoharringtonine obtained from NCI and formulated in DMSO showed some lethal toxicity while homoharringtonine obtained from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China) and formulated in sterile water for use in humans did not show lethal toxicity at the doses used.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
A method of treatment of a host with a cellular proliferative disease, comprising contacting the host with a cephalotaxine and an antiproliferative agent, each in an amount sufficient to modulate said cellular proliferative disease, is described. In some embodiments, the cephalotaxine comprises homoharringtonine (cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methyl pentyl)butanediocate ester). Antiproliferative agents of the invention comprise alkylating agents, intercalating agents, metal coordination complexes, pyrimidine nucleosides, purine nucleosides, inhibitors of nucleic acid associated enzymes and proteins, and agents affecting structural proteins and cytoplasmic enzymes.
Description
- This application claims the benefit of U.S. Provisional Application No. 60/189,699, filed Mar. 15, 2000.
- The technical field of the invention is the use of cephalotaxine alkaloids with antiproliferative agents to treat a host with a cellular proliferative disease.
- There is considerable interest in modulating the efficacy of currently used antiproliferative agents to increase the rates and duration of antitumor effects associated with conventional antineoplastic agents.
- Conventional antiproliferative agents used in the treatment of cancer are broadly grouped as chemical compounds which (1) affect the integrity of nucleic acid polymers by binding, alkylating, inducing strand breaks, intercalating between base pairs or affecting enzymes which maintain the integrity and function of DNA and RNA; (2) chemical agents that bind to proteins to inhibit enzymatic action (e.g., antimetabolites) or the function of structural proteins necessary for cellular integrity (e.g., antitubulin agents). Other chemical compounds that have been identified to be useful in the treatment of some cancers include drugs which block steroid hormone action for the treatment of breast and prostate cancer, photochemically activated agents, radiation sensitizers and protectors.
- Of special interest to this invention are those compounds that directly affect the integrity of the genetic structure of the cancer cells. Nucleic acid polymers such as DNA and RNA are prime targets for anticancer drugs. Alkylating agents such as nitrogen mustards, nitrosoureas, aziridine containing compounds directly attack DNA. Metal coordination compounds such as cisplatin and carboplatin similarly directly attack the nucleic acid structure resulting in lesions that are difficult for the cells to repair which, in turn, can result in cell death. Other nucleic acid affecting compounds include anthracycline molecules such as doxorubicin, which intercalates between the nucleic acid base pairs of DNA polymers, bleomycin which causes nucleic acid strand breaks, and fraudulent nucleosides. Fradulent nucleosides include pyrimidine and purine nucleoside analogs which are inappropriately incorporated into nucleic polymer structures and ultimately cause premature DNA chain termination. Certain enzymes that affect the integrity and functionality of the genome can also be inhibited in cancer cells by specific chemical agents and result in cancer cell death. These include enzymes that affect ribonucleotide reductase (e.g., hydroxyurea, gemcitabine), topoisomerase I (e.g. camptothecin) and topoisomerase II (e.g., etoposide).
- One of the most broadly used of these DNA targeted anticancer drugs is cisplatin (cis-diamminedichloroplatinum II, CDDP). This compound is active against several human cancers including testicular, small-cell lung, bladder, cervical and head and neck cancer.
- Although the clinical activity of currently approved antiproliferative agents against many forms of cancers can be shown, improvements in tumor response rates, duration of response and ultimately patient survival are still sought. The invention described herein demonstrates the novel use of the cephalotaxine alkaloids and analogs thereof, including homoharringtonine (HHT) which can potentiate the antitumor effects of chemotherapeutic drugs, in particular, agents affecting the integrity of nucleic polymers such as DNA.
- Methods and compositions are provided for the treatment of a host with a cellular proliferative disease, particularly a neoplasia. In the subject methods, pharmaceutically acceptable cephalotaxine and an antiproliferative agent are administered in an amount sufficient to modulate the cellular proliferative disease.
- FIG. 1 depicts the general structure of a cephalotaxine analog. R1 and R2 represent substitution groups. Structures for R1 and R2 are shown for the cephalotaxine analog, Homoharringtonine.
- FIG. 2 depicts the structure of the cephalotaxine analog, Homoharringtonine.
- FIG. 3 shows tumor growth delay, as tumor volume on days after treatment with HHT, HHT followed by CDDP, or CDDP alone.
- Methods and compositions are provided for the treatment of a host with a cellular proliferative disease, particularly a neoplasia. In the subject methods, a pharmaceutically acceptable cephalotaxine is administered, preferably systemically, in conjunction with an antiproliferative agent to improve the anticancer effects. In a preferred embodiment, the cephalotaxine provides a chemopotentiator effect.
- The agents are provided in amounts sufficient to modulate a cellular proliferative disease. In one embodiment, modulation of a cellular proliferative disease comprises a reduction in tumor growth. In another embodiment, modulation of a disease comprises inhibition of tumor growth. In another embodiment, modulation of a cellular proliferative disease comprises an increase in tumor volume quadrupling time (described below). In another embodiment, modulation of a cellular proliferative disease comprises a chemopotentiator effect. In another embodiment, modulation of a disease comprises a chemosensitizing effect. In other embodiments, modulation of a disease comprises cytostasis. In still other embodiments, modulation of a disease comprises a cytotoxic effect.
- A chemical agent is a “chemopotentiator” when it enhances the effect of a known antiproliferative drug in a more than additive fashion relative to the activity of the chemopotentiator or antiproliferative agent used alone. In some cases, a chemosensitizing effect may be observed. This is defined as the effect of use of an agent that if used alone would not demonstrate significant antitumor effects but would improve the antitumor effects of an antiproliferative agent as compared to use of the antiproliferative agent by itself.
- As used herein, the term “cephalotaxine” includes all members of that chemical family including alkaloid derivatives of the Chinese evergreen,Cephalotaxus fortueni and analogs thereof. The cephalotaxine family is defined by chemical structure as the ring structures in FIG. 1.
- A cephalotaxine analog is further defined but not limited to the structure depicted in FIG. 1, having substituent or substitute groups at R1 and R2. Examples of R1 and/or R2 include esters, including herringtonine, isoharringtonine, homoharringtonine, deoxyharringtonine, acetylcephalotaxine and the like. Table 1 lists structures of R1 and R2 for some of these analogs. R1 and R2 substitutions are typically employed to improve biological activity, pharmaceutical attributes such as bioavailability or stability, or decrease toxicity. In one embodiment, R1 and/or R2 include alkyl substitutions (e.g., methyl, ethyl, propyl etc.). In another embodiment, R1 and/or R2 include esters (e.g., methoxy, ethoxy, butoxy, etc.). R1 and R2 are not limited to the above examples, however, in the scope of this invention.
TABLE 1 R1 R2 isoharringtonine —OCH3 harringtonine —OCH3 acetylcephalotaxine —OCH3 CH3CO2 homoharringtonine —OCH3 - A cephalotaxine analog is a further chemical refinement. A specific example of a cephalotaxine analog is homoharringtonine which is the butanediocate ester of cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methyl pentyl) (FIG. 2).
- As used herein, antiproliferative agents are compounds which induce cytostasis or cytotoxicity. “Cytostasis” is the inhibition of cells from growing while “cytotoxicity” is defined as the killing of cells. Specific examples of antiproliferative agents include: antimetabolites, such as methotrexate, 5-fluorouracil, gemcitabine, cytarabine, pentostatin, 6-mercaptopurine, 6-thioguanine, L-asparaginase, hydroxyurea, N-phosphonoacetyl-L-aspartate (PALA), fludarabine, 2-chlorodeoxyadenosine, and floxuridine; structural protein agents, such as the vinca alkaloids, including vinblastine, vincristine, vindesine, vinorelbine paclitaxel, and colchicine; antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, bleomycins, plicamycin, and mitomycin; hormone antagonists, such as tamoxifen and luteinizing hormone releasing hormone (LHRH) analogs; nucleic acid damaging agents such as the alkylating agents mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, dacarbazine, methylnitrosourea, semustine (methyl-CCNU), chlorozotocin, busulfan, procarbazine, melphalan, carmustine (BCNU), lomustine (CCNU), and thiotepa, the intercalating agents doxorubicin, dactinomycin, daurorubicin and mitoxantrone, the topoisomerase inhibitors etoposide, camptothecin and teniposide, and the metal coordination complexes cisplatin and carboplatin.
- The following examples are offered by way of illustration and not by way of limitation.
- Chemopotentiation of Cisplatin (CDDP) by Homoharringtonine (HHT)
- Transplantable experimental murine fibrosarcomas (2×105 RIF-1 cells) were grown intradermally in the flanks of 3 month old female C3H mice (Charles River, Holister, Calif.). When the tumors reached a volume of approximately 100 mm3, the mice were randomly assigned to each experimental group (4 mice per group).
- The experimental compositions were prepared as described in Table 2.
TABLE 2 Agent Dose Solvent Supplier Homoharringtonine 2 mg/kg DMSO NCI Cisplatin 4 mg/kg Water for injection David Bull Labs - The chemopotentiator, homoharringtonine, was obtained from NCI and was made to the appropriate concentration in DMSO. Cisplatin (David Bull Laboratories—Mulgrave, Australia, lot. 5201844x) was made to the appropriate concentration in water for injection. The compositions were injected systemically (i.e., intraperitoneally, i.p.), in a volume of 100 microliters. For the treatment of group 3, the chemopotentiator, homoharringtonine, was injected 30 minutes prior to the injection of cisplatin. After treatment, the growth of the tumors was monitored three times per week by caliper measurements of three perpendicular diameters of the tumor and calculation of tumor volume from the formula:
- V=π/6×D 1 ×D 2 ×D 3,
- where D1-3 is in mm.
- The tumors were followed until they reached a size of four times their day zero treatment volume (TVQT), or up to 30 days after treatment, whichever came first. The data is expressed as the “tumor volume quadrupling time” (TVQT) mean and as the “delay.” Mean TVQT is the mean days required for individual tumors to grow to four times the tumor volume at the initial treatment day. The “delay” is the median of days required for a tumor to grow to four times the mean size of the treated group, minus the median of days required to grow to four times the mean size of the control group. The data is also expressed as the ratio of the tumor volume quadrupling time of the treated tumor over the untreated control group (TVQT/CTVQT). Increasing values of this ratio indicate increased antitumor response.
- The data is presented in Table 3 below and in FIG. 3.
TABLE 3 Dose TVQT/ Median Delay Group Treatment (mg/kg) Mean TVQT ± S.E. CTVQT (TVQT) (Days) 1 Untreated Control — 8.3 ± 0.4 1.0 8.6 0.00 2 Homoharringtonine 2 10.1 ± 0.4 1.2 9.8 1.20 3 Homoharringtonine → 2 → 4 14.9 ± 0.8 1.8 14.8 6.17 Cisplatin 4 Cisplatin 4 12.9 ± 1.1 1.5 12.5 3.83 - The results of Table 3 indicate that the antiproliferative activity of cisplatin is enhanced by the use of the chemopotentiator, homoharringtonine in that a more than additive effect was observed when both compounds were used to treat the tumor bearing mice (group 3) in comparison to the use of cisplatin alone (group 4) or homoharringtonine alone (group 2).
- Effect of Homoharringtonine, Alone and in Combination with Other Chemotherapeutics on RIF-1 Tumor Growth in C3H Mice
- The RIF-1 murine fibrosarcoma tumor model was used to evaluate the antitumor activity of homoharringtonine, alone and in combination with various antiproliferative agents. The antiproliferative agents used include those that affect nucleic acid (e.g., DNA) integrity (e.g., cisplatin, cytarabine, camptothecin, etoposide, 5-fluorouracil, or amonafide), agents that affect structural proteins (e.g., paclitaxel, vinblastine, or colchicine) or cytoplasmic enzymes (e.g., genistein).
- Homoharringtonine (HHT-NCI) was obtained from NCI as a powder. Homoharringtonine (HHT-Clin) was obtained from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China), in 1 mL vials, prediluted with water to 1 mg/mL. Cisplatin for Injection, USP, was obtained from David Bull Labs (Mulgrave, Australia), Lot No. 5201844x, as a lypholized powder. Paclitaxel was obtained from Bristol Myers Squibb Co. (Princeton, N.J.), Lot No. 9J16241, exp. September 2001, prediluted to 6 mg/mL in Cremaphor/EL. Cytarabine was obtained from Bedford Labs (Bedford, Ohio), Lot No. 86968A, exp. June 2002, as a lypholized powder. Camptothecin was obtained from Boehringer-Ingelheim, Lot No. 142088, as a powder. Vinblastine was obtained from Bedford Labs (Bedford, Ohio), Lot No. 112647, as a lypholized powder. Etoposide was obtained from Pharmacia (Kalamazoo, Mich.), Lot No. ETA013, exp. May 1999, as a liquid prediluted to 20 mg/mL. 5-Fluorouracil was obtained from Pharmacia (Kalamazoo, Mich.), Lot No. FFA191, exp. July 2000, as a liquid prediluted to 50 mg/mL. Amonafide was obtained from Penta Biotech (Union City, Calif.), Lot No. 039-01, as a powder. Colchicine was obtained from Sigma (St. Louis, Mo.), Lot No. 55H0685, as a powder. Genistein was obtained from ChemCon GmbH (Freburg i. Br.), Lot No. CC-6700-26, as a powder. DMSO was obtained from Sigma (St. Louis, Mo.), Lot No. 80K3695 0.9% Sodium Chloride for Injection, USP (saline) was manufactured by Abbott Laboratories (Lot No. 55-199-DK). Sterile Water for Injection, USP (WFI) was manufactured by Lyphomed, Inc. (Lot No. 390849).
- Formulations: Test preparations (treatment groups) are summarized in Table 4.
- For preparation of formulations 1-4, HHT-NCI was weighed into vials and dissolved in DMSO at the stated concentrations.
- For
formulation 5, the contents of a 10-mg vial of lyophilized CDDP (Cisplatin for Injection) was resuspended with 10 mL WFI to produce a 1 mg/mL CDDP suspension. - For formulation 6, paclitaxel, prediluted in Cremaphor/EL and dehydrated alcohol to 6 mg/mL was further diluted to 3.3 mg/mL with WFI.
- Formulations 7 and 8 were prepared by further diluting HHT-Clin to the stated concentrations with WFI. Formulation 9 was undiluted HHT-Clin, used as received.
-
Formulation 10 was prepared by adding 1 mL of WFI to 100 mg of cytarabine as a lypholized powder. - Formulation 11 was prepared by adding DMSO to camptothecin at a concentration of 1 mg/mL.
-
Formulation 12 was made by adding 0.9% Sodium Chloride for Injection to a vial of 10 mg of vinblastine lypholized powder. - Formulations 13-17 were prepared by diluting the appropriate amount of each test agent into saline (13-2.5 mg/mL etoposide, 14-7.5 mg/mL 5-fluorouracil, 15-7.5 mg/mL amonafide, 16-2.5 mg/mL colchicine, 17-3.75 mg/mL 5-fluorouracil).
- Formulation 18 was prepared by diluting 15 mg of genistein in 1 mL of DMSO.
- Animals: Female C3H mice (Charles River Laboratories, Holister, Calif.), approximately 3 months old, were used for the study. The average body weight was approximately 25 g. Animals were maintained in isolator cages on a 12-hour light-and-dark cycle. Food and water were available ad libitum.
- Tumors: The RIF-1 murine fibrosarcoma cell line was maintained in in vitro culture (Waymouth medium supplemented with 20% fetal bovine serum) at 37° C. in a humidified 5% CO2 incubator. Log-phase RIF-1 cells were trypsinized and harvested from cell culture flasks to yield a concentration of 4×106 cells/mL, then injected intradermally in a volume of 50 μL (equivalent to 2×105 cells per injection) into both flanks of each mouse. Nine days later, when tumors reached approximately 100 mm3 in size, the animals were randomized to different treatment groups.
- Treatment Groups: Treatment groups are summarized in Table 4. Four to five animals were assigned to each treatment group. The intraperitoneal injection volume was 100 μL. Intratumoral injections (50 μL) were made into one of the two tumors on each animal with the contralateral tumor serving as an untreated control. The oral administration volume was 100 μL. Combination treatments using two test agents were administered as two separate injections, with the second one following the first either immediately or after 30 minutes.
- Evaluation of Tumor Volume Quadrupling Time: Tumors were measured three times weekly for up to 22 days with Vernier calipers. Tumor volume (cubic millimeters, mm3) was calculated according to the formula:
- V=π/6×D 1 ×D 2 ×D 3
- in which D1-3 are perpendicular diameters measured in millimeters (mm). Tumor volume quadrupling time (TVQT), defined as the time required for a tumor to grow to four times its initial volume (at the time of treatment), was used as a study endpoint. The TVQT was determined for each treatment group and expressed in days as the mean±standard error (SE).
- Antitumor activity or modulation of tumor growth (as measured by delayed tumor growth, i.e. increases in TVQT values) by homoharringtonine administered as a single agent or in combination with other chemotherapeutics is presented in Table 5.
- Results from eight separate experiments are included in this study. In experiment E010, tumors in untreated control animals quadrupled in size in an average of 7.2 days. Intraperitoneal administration of homoharringtonine from NCI at 5 mg/Kg had a TVQT of 14.5 days and intratumoral administration of homoharringtonine at that dose resulted in a TVQT of 15.6 days.
- In experiment E011, untreated control animals quadrupled in size an average of 8.3 days while intraperitoneal administration of homoharringtonine from NCI at 2 mg/Kg extended the mean TVQT to 10.1 days, and the additional intraperitoneal administration of CDDP further extended the mean TVQT to 14.9 days. While paclitaxel (10 mg/Kg), alone, demonstrated a TVQT of 8.8 days, the addition of homoharringtonine (2 mg/kg) did not change the TVQT, making paclitaxel the only agent with combinatorial activity less than that of homoharringtonine, alone.
- Homoharringtonine from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China), formulated in sterile water at either 2 mg/Kg or 4 mg/Kg was used for the remainder of the combination studies.
- At 2 mg/Kg, homoharringtonine had an average TVQT of 10.4 days in E026 while the untreated controls quadrupled in 7.4 days. Combination administration of cisplatin (4 mg/Kg) with homoharringtonine (2 mg/Kg) yielded a TVQT of 11.1 days, which was greater than homoharringtonine (TVQT=10.4 days) or cisplatin (TVQT=9.4 days), alone.
- In experiment E030, where untreated controls quadrupled in 6.7 days, homoharringtonine treatment (2 mg/Kg) yielded a TVQT of 7.9 days and camptothecin or cytarabine gave TVQT's of 9.4 or 7.6 days, respectively. Combination administration of homoharringtonine (2 mg/Kg) with camptothecin (6 mg/Kg) or cytarabine (400 mg/Kg) increased the TVQT's to 10.1 and 8.6 days, resepectively.
- In E032, where untreated controls quadrupled in 6.5 days, homoharringtonine at 4 mg/Kg had an average TVQT of 8.5 days. Administration of homoharringtonine (4 mg/Kg) in combination with 5-fluorouracil (30 mg/Kg) resulted in a TVQT of 17.9 days versus 13.6 days for 5-fluorouracil, alone. Combination administration of homoharringtonine (4 mg/Kg) and vinblastine (2 mg/Kg) yielded a TVQT of 10.9 days versus 8.6 days for vinblastine, alone. Combination administration of homoharringtonine (4 mg/Kg) and cisplatin (4 mg/Kg) or amonafide (30 mg/Kg) yielded TVQT's of 10.4 and 10.2 days, respectively, versus 9.9 and 7.6 days for those agents, alone. Homoharringtonine in combination with etoposide (10 mg/Kg) gave a TVQT of 8.7 days while etoposide, alone, was 8.5 days.
- Orally administered colchicine (10 mg/Kg), in E033, yielded a TVQT of 6.3 days, while untreated contols and homoharringtonine (4 mg/Kg) gave TVQT's of 7.8 and 8.3 days. Homoharringtonine in combination with colchicine at these doses increased the TVQT to 9.4 days.
- In E036, genistein (60 mg/Kg) in combination with homoharringtonine (4 mg/Kg) had a TVQT of 9.2 days, which was greater than that of genistein, alone (7.1 days).
- There were animal deaths in some groups that were recorded as follows. Three of four mice died after treatment of homoharringtonine obtained from NCI and formulated in DMSO at 1.25 mg/mL. Two of five mice died after receiving this formulation intratumorally. Four of four mice died after treatment of this same homoharringtonine formulated to 2.5 mg/mL in DMSO. The combination of homoharringtonine (0.5 mg/mL) in DMSO with paclitaxel (2.5 mg/mL) was lethal to two of four mice, and the combination of homoharringtonine (0.5 mg/mL) in DMSO with cisplatin (1 mg/mL) was lethal to one of four mice. The combination of homoharringtonine (1 mg/mL) in vinblastine (0.5 mg/mL) was lethal to one of four mice given that treatment, and the combination of homoharringtonine (1 mg/mL) and genistein (15 mg/mL) was lethal to two of five mice.
- In summary, intraperitoneal administration of homoharringtonine had antitumor activity, i.e. modulated tumor growth, in the RIF-1 murine fibrosarcoma tumor model. Intraperitoneal administration of homoharringtonine in combination with cisplatin, cytarabine, camptothecin, vinblastine, etoposide, 5-fluorouracil, amonafide, colchicine and genistein had antitumor activity levels greater than homoharringtonine alone, or the individual test agents. The best combinatorial activity used 5-fluorouracil, amonafide and vinblastine. Homoharringtonine in combination with paclitaxel had antitumor activity less than homoharringtonine alone. Homoharringtonine obtained from NCI and formulated in DMSO showed some lethal toxicity while homoharringtonine obtained from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China) and formulated in sterile water for use in humans did not show lethal toxicity at the doses used.
TABLE 4 Summary of Treatment Groups Concen- Route Injection Formu- tration of Volume lation Treatment (mg/mL) Administration (μL) 1 HHT-NCI in DMSO 1.25 IP 100 2 HHT-NCI in DMSO 2.5 IP 100 3 HHT-NCI in DMSO 2.5 IT 50 4 HHT-NCI in DMSO 0.5 IP 100 5 CDDP in WFI 1 IP 100 6 Paclitaxel in WFI 2.5 IP 100 7 HHT-Clin in WFI 0.5 IP 100 8 HHT-Clin in WFI 0.25 IP 100 9 HHT-Clin in WFI 1 IP 100 10 Cytarabine in WFI 100 IP 100 11 Camptothecin in 2.5 IP 100 DMSO 12 Vinblastine in saline 0.5 IP 100 13 Etoposide in saline 2.5 IP 100 14 5-Fluorouracil in 7.5 IP 100 saline 15 Amonafide in saline 7.5 IP 100 16 Colchicine in saline 2.5 PO 100 17 5-Fluorouracil in 3.75 IP 100 saline 18 Genistein in DMSO 15 IP 100 -
TABLE 5 Effect of Homoharringtonine and Homoharringtonine in Combination with Other Chemotherapeutics on RIF-1 Tumor Growth in C3H Mice Formu- # of TVQT (days) Exp. # lation Treatment Tumors (Mean ± SE) E010 — Untreated control 8 7.2 ± 0.1 E010 1 HHT-NCI (5 mg/Kg) 2* 14.5 ± 0.9 E010 2 HHT-NCI (10 mg/Kg) 0* All Died E010 3 HHT-NCI (5 mg/Kg) 3* 15.6 ± 1.8 E011 Untreated control 8 8.3 ± 0.4 E011 4 HHT-NCI (2 mg/Kg) 8 10.1 ± 0.4 E011 5 CDDP (4 mg/Kg) 8 12.9 ± 1.1 E011 4, 5 HHT-NCI -30′- CDDP 6* 14.9 ± 0.8 E011 6 Paclitaxel (10 mg/Kg) 8 8.8 ± 0.4 E011 4, 6 HHT -30′- Paclitaxel 4* 8.8 ± 0.4 E026 — Untreated control 8 7.4 ± 0.3 E026 7 HHT-Clin (2 mg/Kg) 8 10.4 ± 1.0 E026 5 CDDP (4 mg/Kg) 8 9.4 ± 0.5 E026 7, 5 HHT-Clin + CDDP 8 11.1 ± 0.4 E026 7, 5 HHT-Clin -30′- CDDP 8 10.1 ± 0.4 E028 — Untreated control 8 8.7 ± 0.5 E028 8 HHT-Clin (1 mg/Kg) 8 9.2 ± 0.7 E028 9 HHT-Clin (4 mg/Kg) 8 10.1 ± 0.4 E030 — Untreated control 8 6.7 ± 0.4 E030 7 HHT-Clin (2 mg/Kg) 8 7.9 ± 0.3 E030 10 Cytarabine (400 mg/Kg) 8 7.6 ± 0.2 E030 7, 10 HHT-Clin + Cytarabine 8 8.6 ± 0.4 E030 11 Camptothecin (6 mg/Kg) 8 9.4 ± 0.4 E030 7, 11 HHT-Clin + Camptothecin 8 10.1 ± 0.6 E032 — Untreated control 8 6.5 ± 0.6 E032 9 HHT-Clin (4 mg/Kg) 8 8.5 ± 0.5 E032 5 CDDP (4 mg/Kg) 8 9.9 ± 0.6 E032 9, 5 HHT-Clin + CDDP 8 10.4 ± 0.4 E032 12 Vinblastine (2 mg/Kg) 8 8.6 ± 0.4 E032 9, 12 HHT-Clin + Vinblastine 6* 10.9 ± 0.4 E032 13 Etoposide (10 mg/Kg) 8 8.5 ± 1.0 E032 9, 13 HHT-Clin + Etoposide 8 8.7 ± 0.5 E032 14 5-Fluorouracil (30 mg/Kg) 8 13.6 ± 1.9 E032 9, 14 HHT-Clin + 5-Fluorouracil 8 17.9 ± 0.7 E032 15 Amonafide (30 mg/Kg) 8 7.6 ± 0.4 E032 9, 15 HHT-Clin + Amonafide 8 10.2 ± 0.5 E033 — Untreated control 8 7.8 ± 0.6 E033 9 HHT-Clin (4 mg/Kg) 8 8.3 ± 0.4 E033 16 Colchicine (10 mg/Kg) 8 6.3 ± 0.3 E033 9, 16 HHT-Clin + Colchicine 8 9.4 ± 0.5 E033 17 5-Fluorouracil (15 mg/Kg) 8 6.7 ± 0.4 E033 9, 17 HHT-Clin + 5 Fluorouracil 8 8.6 ± 0.3 E036 — Untreated control 8 6.8 ± 0.4 E036 18 Genistein (60 mg/Kg) 8 7.1 ± 0.4 E036 9, 18 HHT-Clin + Genistein 6* 9.2 ± 0.5
Claims (14)
1. A method of treatment of a host with a cellular proliferative disease, comprising contacting said host with a cephalotaxine and an antiproliferative agent, each in an amount sufficient to modulate said cellular proliferative disease.
2. The method according to claim 1 , wherein said cephalotaxine comprises the butanediocate ester cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methyl pentyl).
3. The method according to claim 1 , wherein said cephalotaxine comprises a homoharringtonine analog.
4. The method according to claim 1 wherein said antiproliferative agent comprises an agent that interacts with nucleic acids.
5. The method according to claim 1 wherein said antiproliferative agent comprises an alkylating agent, an intercalating agent, a metal coordination complex, a pyrimidine nucleoside, a purine nucleoside, an inhibitor of nucleic acid associated enzymes, or an inhibitor of nucleic acid associated proteins.
6. The method according to claim 1 wherein said antiproliferative comprises cisplatin, cytarabine, camptothecin, vinblastine, etoposide, 5-fluorouracil, amonafide, colchicine, or genistein.
7. A method according to claim 1 wherein said cephalotaxine is administered before the administration of said antiproliferative agent.
8. A method according to claim 1 wherein said cephalotaxine is administered during the administration of said antiproliferative agent.
9. A method according to claim 1 wherein said cephalotaxine is administered after the administration of said antiproliferative agent.
10. The method of claim 1 wherein the modulation on said disease with said composition is greater than that for said antiproliferative agent alone.
11. A composition comprising a cephalotaxine and an antiproliferative agent.
12. The composition of claim 11 wherein said cephalotaxine comprises homoharringtonine.
13. The composition of claim 11 wherein said antiproliferative agent comprises cisplatin, cytarabine, camptothecin, vinblastine, etoposide, 5-fluorouracil, amonafide, colchicine, or genistein.
14. Use of a cephalotaxine and an antiproliferative agent in the formulation of a medicament for the treatment of a cellular proliferative disease.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/769,638 US20040185117A1 (en) | 2000-03-15 | 2004-01-30 | Cephalotaxine alkaloid compositions and uses thereof |
US12/761,251 US20110008307A1 (en) | 2000-03-15 | 2010-04-15 | Cephalotaxine Alkaloid Compositions and Uses Thereof |
US13/336,917 US20120207855A1 (en) | 2000-03-15 | 2011-12-23 | Cephalotaxine alkaloid compositions and uses thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18969900P | 2000-03-15 | 2000-03-15 | |
US09/810,527 US6734178B2 (en) | 2000-03-15 | 2001-03-15 | Cephalotaxine alkaloid compositions and uses thereof |
US10/769,638 US20040185117A1 (en) | 2000-03-15 | 2004-01-30 | Cephalotaxine alkaloid compositions and uses thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/810,527 Division US6734178B2 (en) | 2000-03-15 | 2001-03-15 | Cephalotaxine alkaloid compositions and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/761,251 Continuation US20110008307A1 (en) | 2000-03-15 | 2010-04-15 | Cephalotaxine Alkaloid Compositions and Uses Thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040185117A1 true US20040185117A1 (en) | 2004-09-23 |
Family
ID=22698410
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/810,527 Expired - Lifetime US6734178B2 (en) | 2000-03-15 | 2001-03-15 | Cephalotaxine alkaloid compositions and uses thereof |
US10/769,638 Abandoned US20040185117A1 (en) | 2000-03-15 | 2004-01-30 | Cephalotaxine alkaloid compositions and uses thereof |
US12/761,251 Abandoned US20110008307A1 (en) | 2000-03-15 | 2010-04-15 | Cephalotaxine Alkaloid Compositions and Uses Thereof |
US13/336,917 Abandoned US20120207855A1 (en) | 2000-03-15 | 2011-12-23 | Cephalotaxine alkaloid compositions and uses thereof |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/810,527 Expired - Lifetime US6734178B2 (en) | 2000-03-15 | 2001-03-15 | Cephalotaxine alkaloid compositions and uses thereof |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/761,251 Abandoned US20110008307A1 (en) | 2000-03-15 | 2010-04-15 | Cephalotaxine Alkaloid Compositions and Uses Thereof |
US13/336,917 Abandoned US20120207855A1 (en) | 2000-03-15 | 2011-12-23 | Cephalotaxine alkaloid compositions and uses thereof |
Country Status (12)
Country | Link |
---|---|
US (4) | US6734178B2 (en) |
EP (1) | EP1263440B1 (en) |
JP (1) | JP4929436B2 (en) |
AT (1) | ATE330611T1 (en) |
AU (2) | AU4580301A (en) |
CA (1) | CA2402710A1 (en) |
DE (1) | DE60120928T2 (en) |
DK (1) | DK1263440T3 (en) |
ES (1) | ES2267741T3 (en) |
HK (1) | HK1052138A1 (en) |
PT (1) | PT1263440E (en) |
WO (1) | WO2001068098A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050142214A1 (en) * | 2000-04-12 | 2005-06-30 | Chemgenex Therapeutics, Inc. | Naphthalimide compositions and uses thereof |
US20050288310A1 (en) * | 2004-06-04 | 2005-12-29 | Chemgenex Pharmaceuticals, Inc. | Methods of treating cellular proliferative disease using naphthalimide and PARP-1 inhibitors |
US20060211648A1 (en) * | 2000-04-12 | 2006-09-21 | Chemgenex Pharmaceuticals, Inc. | Naphthalimide compositions and uses thereof |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4580301A (en) * | 2000-03-15 | 2001-09-24 | Chemgenex Therapeutics Inc | Cephalotaxine alkaloid compositions and uses thereof |
EP1274458B1 (en) | 2000-04-12 | 2005-09-28 | ChemGenex Pharmaceuticals, Inc. | Compositions containing a naphthalmide and an antiproliferative agent |
US20020123469A1 (en) * | 2000-10-31 | 2002-09-05 | Brown Dennis M. | Antiproliferative colchicine compositions and uses thereof |
US20050170015A1 (en) * | 2000-10-31 | 2005-08-04 | Brown Dennis M. | Antiproliferative colchicine compositions and uses thereof |
WO2003075943A2 (en) * | 2002-03-06 | 2003-09-18 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising wogonin, isoliquiritigenin and/or coumestrol |
EP1534295A4 (en) * | 2002-07-17 | 2009-08-05 | Chemgenex Pharmaceuticals Inc | Formulations and methods of administration of cephalotaxines, including homoharringtonine |
WO2004009030A2 (en) * | 2002-07-22 | 2004-01-29 | Chemgenex Pharmaceuticals Limited | Angiogenesis inhibition by cephalotaxine alkaloids, derivatives, compositions and uses thereof |
CN100396286C (en) * | 2002-12-30 | 2008-06-25 | 北京大学第一医院 | Use of homoharringtonine and harringtonine in inhibiting vascularization |
AU2006213915A1 (en) * | 2005-02-10 | 2006-08-17 | Chemgenex Pharmaceuticals, Inc. | Medical devices |
US20090068236A1 (en) * | 2007-04-13 | 2009-03-12 | Chemgenex Pharmaceuticals, Inc. | Oral Cephalotaxine Dosage Forms |
WO2009148654A2 (en) | 2008-03-03 | 2009-12-10 | Sloan-Kettering Institute For Cancer Research | Cephalotaxus esters, methods of synthesis, and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4399282A (en) * | 1979-07-10 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives |
US5525731A (en) * | 1992-07-23 | 1996-06-11 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues and methods of preparation thereof |
US6630173B2 (en) * | 2000-04-12 | 2003-10-07 | Chemgenex Therapeutics, Inc. | Naphthalimide compositions and uses thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4675318A (en) * | 1985-05-28 | 1987-06-23 | Yaguang Liu | Safe antileukemia drug, SAL |
AU4580301A (en) * | 2000-03-15 | 2001-09-24 | Chemgenex Therapeutics Inc | Cephalotaxine alkaloid compositions and uses thereof |
-
2001
- 2001-03-15 AU AU4580301A patent/AU4580301A/en active Pending
- 2001-03-15 PT PT01918763T patent/PT1263440E/en unknown
- 2001-03-15 ES ES01918763T patent/ES2267741T3/en not_active Expired - Lifetime
- 2001-03-15 CA CA002402710A patent/CA2402710A1/en not_active Abandoned
- 2001-03-15 DE DE60120928T patent/DE60120928T2/en not_active Expired - Lifetime
- 2001-03-15 EP EP01918763A patent/EP1263440B1/en not_active Expired - Lifetime
- 2001-03-15 DK DK01918763T patent/DK1263440T3/en active
- 2001-03-15 JP JP2001566662A patent/JP4929436B2/en not_active Expired - Fee Related
- 2001-03-15 AU AU2001245803A patent/AU2001245803B8/en not_active Ceased
- 2001-03-15 US US09/810,527 patent/US6734178B2/en not_active Expired - Lifetime
- 2001-03-15 AT AT01918763T patent/ATE330611T1/en active
- 2001-03-15 WO PCT/US2001/008480 patent/WO2001068098A2/en active IP Right Grant
-
2003
- 2003-06-11 HK HK03104183A patent/HK1052138A1/en not_active IP Right Cessation
-
2004
- 2004-01-30 US US10/769,638 patent/US20040185117A1/en not_active Abandoned
-
2010
- 2010-04-15 US US12/761,251 patent/US20110008307A1/en not_active Abandoned
-
2011
- 2011-12-23 US US13/336,917 patent/US20120207855A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4399282A (en) * | 1979-07-10 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives |
US5525731A (en) * | 1992-07-23 | 1996-06-11 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues and methods of preparation thereof |
US6630173B2 (en) * | 2000-04-12 | 2003-10-07 | Chemgenex Therapeutics, Inc. | Naphthalimide compositions and uses thereof |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050142214A1 (en) * | 2000-04-12 | 2005-06-30 | Chemgenex Therapeutics, Inc. | Naphthalimide compositions and uses thereof |
US20060211648A1 (en) * | 2000-04-12 | 2006-09-21 | Chemgenex Pharmaceuticals, Inc. | Naphthalimide compositions and uses thereof |
US7135481B2 (en) | 2000-04-12 | 2006-11-14 | Chemgenex Pharmaceuticals, Inc. | Naphthalimide compositions and uses thereof |
US20050288310A1 (en) * | 2004-06-04 | 2005-12-29 | Chemgenex Pharmaceuticals, Inc. | Methods of treating cellular proliferative disease using naphthalimide and PARP-1 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
WO2001068098A3 (en) | 2002-06-06 |
AU2001245803B8 (en) | 2006-02-02 |
DE60120928T2 (en) | 2007-02-08 |
EP1263440A2 (en) | 2002-12-11 |
US20120207855A1 (en) | 2012-08-16 |
WO2001068098A2 (en) | 2001-09-20 |
AU4580301A (en) | 2001-09-24 |
DE60120928D1 (en) | 2006-08-03 |
CA2402710A1 (en) | 2001-09-20 |
HK1052138A1 (en) | 2003-09-05 |
JP2003526667A (en) | 2003-09-09 |
JP4929436B2 (en) | 2012-05-09 |
DK1263440T3 (en) | 2006-10-23 |
EP1263440B1 (en) | 2006-06-21 |
ATE330611T1 (en) | 2006-07-15 |
AU2001245803B2 (en) | 2005-12-15 |
US20020032190A1 (en) | 2002-03-14 |
ES2267741T3 (en) | 2007-03-16 |
US20110008307A1 (en) | 2011-01-13 |
US6734178B2 (en) | 2004-05-11 |
PT1263440E (en) | 2006-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110008307A1 (en) | Cephalotaxine Alkaloid Compositions and Uses Thereof | |
US6630173B2 (en) | Naphthalimide compositions and uses thereof | |
AU2001245803A1 (en) | Cephalotaxine alkaloid compositions and uses thereof | |
AU2022203774A1 (en) | Glycolipids and pharmaceutical compositions thereof for use in therapy | |
US20020037328A1 (en) | Hexitol compositions and uses thereof | |
US7135481B2 (en) | Naphthalimide compositions and uses thereof | |
US20020040011A1 (en) | Naphthoquinone compositions and uses thereof | |
US20050170015A1 (en) | Antiproliferative colchicine compositions and uses thereof | |
AU2006202650B2 (en) | Compositions containing a naphthalimide and an antiproliferative agent | |
US20020123469A1 (en) | Antiproliferative colchicine compositions and uses thereof | |
AU2001253483B2 (en) | Compositions containing a naphthalimide and an antiproliferative agent | |
AU2001253483A1 (en) | Compositions containing a naphthalimide and an antiproliferative agent | |
US20020022652A1 (en) | Methylnogarol compositions and uses thereof | |
US20060211648A1 (en) | Naphthalimide compositions and uses thereof | |
US11717505B2 (en) | Dianhydrogalactitol for the treatment of diffuse intrinsic pontine gliomas |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CHEMGENEX PHARMACEUTICALS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BROWN, DENNIS M.;REEL/FRAME:016799/0635 Effective date: 20051107 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |