Mechanisms for Cisplatin-FUra Synergism and Cisplatin Resistance in Human Ovarian Carcinoma Cells both in vitro and in vivo

Abstract

Cisplatin and FUra act synergisticly in human carcinomas. An increase in the availability of reduced folates necessary for tight binding of FdUMP to thymidylate synthase (TS) contributes to the enhanced cytotoxicity of this drug combination. The human ovarian A2780 cell line made three-fold resistant to cisplatin has been shown to have a three-fold elevation of m-RNA for dihydrofolate reductase (DHFR) and TS. However, this increase did not result from an amplification of the genes for these two enzymes. In contrast, ovarian carcinoma cells from patients who failed treatment with cisplatin and FUra have been shown to have both enhanced gene expression and increased gene copy number for DHFR and TS.