Mizutani Y, Yoshida O, Bonavida B
Department of Urology, Faculty of Medicine, Kyoto University, Japan.
J Urol. 1998 Aug;160(2):561-70.
PURPOSE: The resistance of bladder cancer to anticancer chemotherapeutic drugs is a major problem. Several immunotherapeutic approaches have been developed to treat drug-resistant tumor cells. The Fas antigen (Fas)-Fas ligand pathway is involved in cytotoxic T lymphocyte and natural killer cell-mediated cytotoxicity. Like the Fas ligand, anti-Fas monoclonal antibody (mAb) induces apoptosis in tumor cells expressing Fas. Several anticancer drugs also mediate apoptosis and may share with Fas common intracellular pathways leading to cell killing. We reasoned that treatment of drug-resistant cancer cells with a combination of anti-Fas mAb and drugs might overcome their resistance. This study has investigated whether anticancer drugs synergize with anti-Fas mAb in cytotoxicity against bladder cancer cells. MATERIALS AND METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: Treatment of the T24 human bladder cancer cell line with anti-Fas mAb in combination with 5-fluorouracil, mitomycin C or methotrexate did not overcome resistance to these agents. However, treatment of T24 tumor cells with a combination of anti-Fas mAb and cisdiamminedichloroplatinum (II) (CDDP) resulted in a synergistic cytotoxic effect. In addition, the CDDP-resistant T24 line (T24/CDDP) was sensitive to treatment with a combination of anti-Fas mAb and CDDP. Synergy by combination of anti-Fas mAb and CDDP was also achieved in three other bladder cancer lines and four freshly derived human bladder cancer cells. The combination of anti-Fas mAb and carboplatin also resulted in a synergistic cytotoxic effect on T24 cells; however, the combination of anti-Fas mAb and trans-diamminedichloroplatinum (II) resulted in an additive cytotoxic effect. Treatment with CDDP enhanced the expression of Fas on T24 cells. The synergy achieved in cytotoxicity with anti-Fas mAb and CDDP was also achieved in apoptosis. Incubation of T24 cells with anti-Fas mAb increased the intracellular accumulation of CDDP. Treatment of freshly isolated bladder cancer cells with CDDP enhanced their susceptibility to lysis by autologous lymphocytes. CONCLUSIONS: This study demonstrates that combination treatment of bladder cancer cells with anti-Fas mAb and CDDP overcomes their resistance. Synergy was achieved with established CDDP-resistant bladder cancer cells and freshly isolated bladder cancer cells. In addition, the sensitization required low concentrations of CDDP, thus supporting the potential in vivo application of combination of CDDP and immunotherapy in the treatment of CDDP- and/or immunotherapy-resistant bladder cancer.
目的：膀胱癌对抗癌化疗药物的耐药性是一个主要问题。已经开发了几种免疫治疗方法来治疗耐药肿瘤细胞。Fas抗原（Fas）-Fas配体途径参与细胞毒性T淋巴细胞和自然杀伤细胞介导的细胞毒性。与Fas配体一样，抗Fas单克隆抗体（mAb）可诱导表达Fas的肿瘤细胞凋亡。几种抗癌药物也介导细胞凋亡，并且可能与Fas共享导致细胞杀伤的共同细胞内途径。我们推测，用抗Fas mAb和药物联合治疗耐药癌细胞可能会克服其耐药性。本研究调查了抗癌药物与抗Fas mAb联合对膀胱癌细胞的细胞毒性是否具有协同作用。 材料与方法：通过1天的微量培养四唑盐染料测定法测定细胞毒性。通过等效线图分析评估协同作用。 结果：用抗Fas mAb联合5-氟尿嘧啶、丝裂霉素C或甲氨蝶呤处理T24人膀胱癌细胞系并不能克服对这些药物的耐药性。然而，用抗Fas mAb和顺二氯二氨铂（II）（CDDP）联合处理T24肿瘤细胞产生了协同细胞毒性作用。此外，耐CDDP的T24细胞系（T24/CDDP）对用抗Fas mAb和CDDP联合处理敏感。抗Fas mAb和CDDP联合在其他三种膀胱癌细胞系和四种新鲜分离的人膀胱癌细胞中也实现了协同作用。抗Fas mAb和卡铂联合对T24细胞也产生了协同细胞毒性作用；然而，抗Fas mAb和反式二氯二氨铂（II）联合产生了相加细胞毒性作用。用CDDP处理可增强T24细胞上Fas的表达。抗Fas mAb和CDDP在细胞毒性方面实现的协同作用在细胞凋亡方面也得以实现。用抗Fas mAb孵育T24细胞可增加CDDP的细胞内蓄积。用CDDP处理新鲜分离的膀胱癌细胞可增强其对自体淋巴细胞裂解的敏感性。 结论：本研究表明，用抗Fas mAb和CDDP联合治疗膀胱癌细胞可克服其耐药性。在已建立的耐CDDP膀胱癌细胞和新鲜分离的膀胱癌细胞中实现了协同作用。此外，致敏需要低浓度的CDDP，从而支持CDDP与免疫疗法联合在体内治疗耐CDDP和/或免疫疗法的膀胱癌中的潜在应用。
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