COMBINATION OF CISPLATIN-PROCAINE COMPLEX DPR WITH ANTICANCER DRUGS INCREASES CYTOTOXICITY AGAINST OVARIAN-CANCER CELL-LINES

DPR, cis-diamminechloro-[2-(diethylamino)ethyl 4-aminobenzoate, N4]-ch lorideplatinum(II) monohydrochloride monohydrate, is a newly developed water-soluble platinum compound which posses minimal cross-resistance to cisplatin and shows relatively less side effects. In an attempt to establish whether the combination of DPR with other conventional anti cancer drugs would be of any benefit we assessed in vitro the cytotoxi c effects of combinations of DPR with the antimetabolites 5-fluorourac il (5-FU) and methotrexate (MTX), the alkylating agents mitomycin C (M MC) and cisplatin, the antimicrotubule agent taxol (TAX), and the inte rcalating 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 o r combined drugs, and the cytotoxic effect was determined by the MTT a ssay. The analysis of combination treatment was made by the isobole me thod. In human A2780 cells, an overall synergy was found for DPR combi ned with 5-FU, DOX and cisplatin. Synergistic effects were also observ ed for most combinations with MTX or MMC. A DPR concentration-dependen t additivity and antagonism was seen at the highest MTX concentration (1 mu M), while additive effects were observed for the combined treatm ents of DPR and low concentrations of MMC (0.008 and 0.0016 mu M). Add itive effects were also observed for the association of DPR and TAX ov er most combinations tested. In murine M5076 cells, synergism was the prevailing result observed when DPR was combined with 5-FU, DOX, MMC o r cisplatin. When administered together with MTX we observed additivit y over most combinations tested. These findings suggest that DPR, when simultaneously administered with standard anticancer agents, may be a dvantagious for cytokilling. [(C) 1998 Lippincott-Raven Publishers.].