Overcoming cis-diamminedichloroplatinum (II) resistance of human ovarian tumor cells by combination treatment with cis-diamminedichloroplatinum (II) and tumor necrosis factor-alpha.

Abstract

Previous studies have demonstrated that tumor cells have different degrees of sensitivity and resistance to various cytotoxic agents. The acquisition of drug resistance is a major concern in cancer treatment. The current study investigates the cytotoxic effect of cis-diamminedichloroplatinum (II) (CDDP) and tumor necrosis factor-alpha (TNF-alpha) used in combination on CDDP-resistant human ovarian tumor cell lines. Cytotoxicity was determined by the microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. TNF-mRNA was examined by Northern blot analysis. Treatment of the CDDP-resistant C30 cells with CDDP and TNF-alpha overcame the resistance of C30 cells to CDDP or TNF-alpha. In addition, the combination of CDDP and TNF-alpha resulted in a synergistic effect on the C30-resistant line, the CDDP-sensitive parental cell line A2780, and two freshly derived ovarian carcinoma cell cultures. Treatment of C30 cells with CDDP followed by TNF-alpha showed a synergistic effect, whereas treatment with TNF-alpha followed by CDDP demonstrated a less cytotoxic effect. A possible mechanism of resistance to TNF-alpha in tumor cells is the induction of TNF-alpha mRNA and protein. C30 cells do not produce mRNA constitutively for TNF-alpha; however, treatment of C30 cells with TNF-alpha induces the expression of TNF-alpha mRNA. When CDDP was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was reduced significantly. This study shows that the combination of CDDP and TNF-alpha can overcome the CDDP resistance of tumor cells and that downregulation of TNF-alpha mRNA by CDDP may play a role in the enhanced cytotoxicity seen with the combination of CDDP and TNF-alpha. The synergistic effect obtained with established ovarian tumor cell lines and in short-term cultures of freshly isolated ovarian tumors suggests that combination treatment with TNF-alpha and CDDP may have clinical applications in the treatment of drug-resistant tumors.