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Keywords:

  • cis-diamminedichloroplatinum (II);
  • tumor necrosis factor–alpha;
  • drug resistance;
  • mRNA

Abstract

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 cis-diamminedichloroplatinum (II) (CDDP) and tumor necrosis factor–alpha (TNF-α) used in combination on CDDP-resistant 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-α overcame the resistance of C30 cells to CDDP or TNF-α. In addition, the combination of CDDP and TNF-α 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-α showed a synergistic effect, whereas treatment with TNF-α followed by CDDP demonstrated a less cytotoxic effect. A possible mechanism of resistance to TNF-α in tumor cells is the induction of TNF-α mRNA and protein. C30 cells do not produce mRNA constitutively for TNF-α; however, treatment of C30 cells with TNF-α induces the expression of TNF-α mRNA. When CDDP was used in combination with TNF-α, the level of TNF-α mRNA induced by TNF-α was reduced significantly.

Conclusions. This study shows that the combination of CDDP and TNF-α can overcome the CDDP resistance of tumor cells and that downregulation of TNF-α mRNA by CDDP may play a role in the enhanced cytotoxicity seen with the combination of CDDP and TNF-α. 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-α and CDDP may have clinical applications in the treatment of drug-resistant tumors.