CYTOTOXICITY, ACCUMULATION, AND EFFLUX OF CISPLATIN AND ITS METABOLITES IN HUMAN OVARIAN-CARCINOMA CELLS

Cisplatin (CP) is one of the most useful antineoplastic drugs. When CP is dissolved in human plasma, different metabolites are formed. Using the OV 2008 human ovarian cancer cell line, we examined the relative cytotoxicities of CP and its metabolites (aquated CP [AP], monomethion ine CP [MP], bismethionine CP [BP], and a mixture of CP metabolites in ultrafiltrated human plasma [UP]) in vitro. By clonogenic assay, cell survival (percent of mean +/- SE) of OV 2008 cells exposed for 1 hr t o 6.7 mu M of CP was 9.8 +/- 0.7 and for its equal platinum contents o f AP, MP, BP, and UP solutions were 3.3 +/- 0.7, 9.8 +/- 0.9, 15.9 +/- 1.1, 76.8 +/- 2.1, and 13.1 +/- 0.7, respectively. AP was the most cy totoxic species, and BP was the least cytotoxic species. Cellular plat inum uptake (ng/10(6) cells) after addition of 0.33, 1.6, and 2.5 mM o f each species for 1 hr was measured and a strong correlation was foun d between cytotoxicity of each CP metabolite and its corresponding cel lular platinum (Pt) uptake (r = 0.997). There was a strong correlation between cytotoxicity of the CP metabolites and their DNA binding. Wit h fractionation of these cells into DNA, nucleoplasm and cytoplasm, th e highest platinum content was found on DNA. The most important factor that seems to be responsible for the cytotoxicities of the different CP metabolites is the amount of their associated intracellular accumul ation, and particularly the degree of their binding to DNA. (C) 1996 A cademic Press, Inc.