Combination of cisplatin-procaine complex DPR with anticancer drugs increases cytotoxicity against ovarian cancer cell lines.
DPR, cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, is a newly developed water-soluble platinum compound which possess minimal cross-resistance to cisplatin and shows relatively less side effects. In an attempt to establish whether the combination of DPR with other conventional anticancer drugs would be of any benefit we assessed in vitro the cytotoxic effects of combinations of DPR with the antimetabolites 5-fluorouracil (5-FU) and methotrexate (MTX), the alkylating agents mitomycin C (MMC) and cisplatin, the antimicrotubule agent taxol (TAX), and the intercalating agent of the anthracycline group doxorubicin (DOX) on murine M5076 ovarian reticulosarcoma and human A2780 ovarian carcinoma cells. These agents were selected because of their common use in the clinic and because they represent four distinct categories of antineoplastic mechanisms. Cells were incubated for 72 h in the presence of single or combined drugs, and the cytotoxic effect was determined by the MTT assay. The analysis of combination treatment was made by the isobole method. In human A2780 cells, an overall synergy was found for DPR combined with 5-FU, DOX and cisplatin. Synergistic effects were also observed for most combinations with MTX or MMC. A DPR concentration-dependent additivity and antagonism was seen at the highest MTX concentration (1 microM), while additive effects were observed for the combined treatments of DPR and low concentrations of MMC (0.008 and 0.0016 microM). Additive effects were also observed for the association of DPR and TAX over most combinations tested. In murine M5076 cells, synergism was the prevailing result observed when DPR was combined with 5-FU, DOX, MMC or cisplatin. When administered together with MTX we observed additivity over most combinations tested. These findings suggest that DPR, when simultaneously administered with standard anticancer agents, may be advantagious for cytokilling.
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Istituto Nazionale per la Ricerca sul Cancro, Servizio di Farmacologia Tossicologica, Genova, Italy.
Pastrone
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Pellecchia
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Vannozzi
M O
MO
Cafaggi
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Esposito
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D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects; D016685:Mitomycin / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011343:Procaine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; C080075:cisplatin-procaine complex; D011343:Procaine; D016685:Mitomycin; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate