A novel approach to counteracting drug resistance is the development of nontoxic agents that are able to preferentially increase the sensitivity of tumor cells to the cytotoxicity of chemotherapy. The possibility that such an agent could be directed specifically against p53-defective tumor cells led us to study the new methylxanthine, Lisofylline, for its ability to sensitize ovary cancer cells to cis-diamminedichloroplatinum(II) (CDDP). In cell lines lacking functional p53 (SKOV3, SKOV3 CDDP-resistant, OVCAR3, and OVCAR432) Lisofylline (20-100 microM) enhanced the cytotoxicity of CDDP by approximately 50% as measured by the Alamar blue vital dye indicator assay. LSF had no effect on p53 wild-type cell lines: OVCAR 420, 429, and 433. Restoration of wild-type p53 phenotype by transfection of SKOV3 cells with a p53 cDNA expression vector showed reversal of sensitization by Lisofylline to CDDP cytotoxicity. While sensitization to DNA damaging agents by other methylxanthines is related to an abrogation of G2 delay, FACS data found no loss of CDDP-induced G2 block in the cell lines, demonstrating that Lisofylline enhanced sensitization. Cell death was examined by quantitative fluorescence microscopy but no increase in apoptosis attributable to Lisofylline exposure was observed. Our results show that the combination of CDDP and Lisofylline preferentially sensitizes p53-defective cancer cells to the cytotoxic effect of CDDP by a yet undetermined mechanism.