Background. 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 cisdiamminedichloroplatinum (11) (CDDP) and tumor necrosis factor-alpha (TNF-a) used in combination on CDDPresistant human ovarian tumor cell lines.
Methods. Cytotoxicity was determined by the microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. TNF-mRNA was examined by Northern blot analysis.
Results. Treatment of the CDDP-resistant C30 cells with CDDP and TNF-a overcame the resistance of C30 cells to CDDP or TNF-a. In addition, the combination of CDDP and TNF-a 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-a showed a synergistic effect, whereas treatment with TNF-a followed by CDDP demonstrated a less cytotoxic effect. A possible mechanism of resistance to TNF-a in tumor cells is the induction of TNF-a mRNA and protein. C30 cells do not produce mRNA constitutively for TNF-a; however, treatment of C30 cells with TNF-a induces the expression of TNF-a mRNA. When CDDP