Sensitization of Human Renal Cell Carcinoma Cells to m-Dianiniiiiedi- chloroplatinum(II) by Anti-Interleukin 6 Monoclonal Antibody or Anti-Interleukin 6 Receptor Monoclonal Antibody

Cytotoxic chemotherapy has shown little antitumor activity against renal cell carcinoma (RCC). It has been demonstrated that RCC cells secrete interleukin 6 (1L-6) and express II.-6 receptors (11,-oKs). IL-6 inhibits apoptosis and enhances manganese Superoxide dismutase expres sion. Several anticancer chemotherapeutic agents exert their cytotoxic activity in part through the induction of apoptosis and the production of free radicals. Thus, the resistance of RCC cells to the anticancer agents might correlate with IL-6 expression. The present study tested this hy pothesis by examining the effect of anti-IL-6 niAh and aiili-lI ,-(>KmAb on the sensitivity of human RCC cells to anticancer chemotherapeutic agents. Treatment of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb in combination with m-diamminedichloroplatinum(II) (CDDP) or mitomycin C overcame their resistance to CDDP or mitomycin C. However, treatment of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb in combination with Adriamycin, vinblastine or 5-fluorouracil did not over come their resistance to these anticancer agents. Treatment of CDDPresistant Caki-1 cells (Caki-1/DDP), two other RCC cell lines (ACHN and A704), and three freshly derived RCC cells with CDDP in combination with anti-IL-6 mAb or anti-IL-6R mAb reversed the resistance to CDDP in all these tumors. We then studied the effectiveness of other platinum derivatives. Treatment of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb enhanced their sensitivity to carboplatin, but not to fran.v-diamminedichloroplatinum(II). Several experiments investigated the mecha nism of the antibody-mediated sensitization of RCC cells to CDDP. Incu bation of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb did not change the intracellular accumulation of CDDP. The expressions of the multidrug resistant phenotype (gplTO) and c-myc oncogene were not affected by the antibody-mediated sensitization. Treatment of Caki-1 cells with the anti-IL-6 mAb or anti-IL-6R mAb down-regulated the expression of glutathione S-transferase ITmRNA. This study demonstrates that treat ment of RCC cells with CDDP in combination with anti-IL-6 mAb or anti-IL-6R mAb can overcome their CDDP-resistance and that the downregulation of glutathione S-transferase ITexpression by anti-IL-6 mAb or ¡iiiti-ll.-6K mAb might play a role in the enhanced cytotoxicity obtained. The synergistic effect obtained with established CDDP-resistant RCC cells and freshly isolated RCC cells suggests that treatment with CDDP in combination with anti-IL-6 mAb or anti-IL-6R mAb may be applicable in the treatment of CDDP-resistant RCC.