Mizutani Y, Bonavida B, Koishihara Y, Akamatsu K, Ohsugi Y, Yoshida O
Department of Urology, Faculty of Medicine, Kyoto University, Japan.
Cancer Res. 1995 Feb 1;55(3):590-6.
Cytotoxic chemotherapy has shown little antitumor activity against renal cell carcinoma (RCC). It has been demonstrated that RCC cells secrete interleukin 6 (IL-6) and express IL-6 receptors (IL-6Rs). IL-6 inhibits apoptosis and enhances manganese superoxide dismutase expression. 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 hypothesis by examining the effect of anti-IL-6 mAb and anti-IL-6R mAb 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 cis-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 overcome their resistance to these anticancer agents. Treatment of CDDP-resistant 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 trans-diamminedichloroplatinum(II). Several experiments investigated the mechanism of the antibody-mediated sensitization of RCC cells to CDDP. Incubation 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 (gp170) 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 pi mRNA. This study demonstrates that treatment 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 down-regulation of glutathione S-transferase pi expression by anti-IL-6 mAb or anti-IL-6R mAb might play a role in the enhanced cytotoxicity obtained.(ABSTRACT TRUNCATED AT 400 WORDS)
细胞毒性化疗对肾细胞癌（RCC）几乎没有抗肿瘤活性。已证明RCC细胞分泌白细胞介素6（IL-6）并表达IL-6受体（IL-6Rs）。IL-6抑制细胞凋亡并增强锰超氧化物歧化酶的表达。几种抗癌化疗药物部分通过诱导细胞凋亡和产生自由基发挥其细胞毒性作用。因此，RCC细胞对抗癌药物的耐药性可能与IL-6表达相关。本研究通过检测抗IL-6单克隆抗体（mAb）和抗IL-6R mAb对人RCC细胞对抗癌化疗药物敏感性的影响来验证这一假设。用抗IL-6 mAb或抗IL-6R mAb联合顺二氯二氨铂（II）（CDDP）或丝裂霉素C处理Caki-1细胞克服了它们对CDDP或丝裂霉素C的耐药性。然而，用抗IL-6 mAb或抗IL-6R mAb联合阿霉素、长春碱或5-氟尿嘧啶处理Caki-1细胞并未克服它们对这些抗癌药物的耐药性。用CDDP联合抗IL-6 mAb或抗IL-6R mAb处理CDDP耐药的Caki-1细胞（Caki-1/DDP）、另外两种RCC细胞系（ACHN和A704）以及三种新鲜分离的RCC细胞逆转了所有这些肿瘤对CDDP的耐药性。然后我们研究了其他铂类衍生物的有效性。用抗IL-6 mAb或抗IL-6R mAb处理Caki-1细胞增强了它们对卡铂的敏感性，但对反式二氯二氨铂（II）不敏感。几项实验研究了抗体介导的RCC细胞对CDDP致敏的机制。用抗IL-6 mAb或抗IL-6R mAb孵育Caki-1细胞不会改变CDDP的细胞内蓄积。多药耐药表型（gp170）和c-myc癌基因的表达不受抗体介导的致敏影响。用抗IL-6 mAb或抗IL-6R mAb处理Caki-1细胞下调了谷胱甘肽S-转移酶pi mRNA的表达。本研究表明，用CDDP联合抗IL-6 mAb或抗IL-6R mAb处理RCC细胞可克服它们对CDDP的耐药性，并且抗IL-6 mAb或抗IL-6R mAb下调谷胱甘肽S-转移酶pi表达可能在增强的细胞毒性中起作用。（摘要截短至400字）
