Mizutani Y, Wu X X, Yoshida O, Shirasaka T, Bonavida B
Department of Urology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan.
Oncol Rep. 1999 Sep-Oct;6(5):979-82. doi: 10.3892/or.6.5.979.
Previous studies have demonstrated that cisplatin (CDDP) sensitizes bladder cancer cells to Fas-mediated cytotoxicity and that CDDP also enhances the cytotoxic effect of 5-fluorouracil (5-FU). These agents mediate apoptosis and may share common intracellular pathways leading to cell killing. We reasoned that combination treatment with CDDP, 5-FU and anti-Fas monoclonal antibody (mAb) might overcome the drug-resistance. We investigated whether CDDP, 5-FU and anti-Fas mAb synergize in cytotoxicity and apoptosis against the T24 bladder cancer line. Cytotoxicity was monitored by a one day microculture tetrazolium dye assay. Treatment of T24 cells with anti-Fas mAb in combination with CDDP or 5-FU resulted in a synergistic cytotoxic effect. In addition, combination treatment of T24 cells with CDDP, 5-FU and anti-Fas mAb further enhanced the synergistic cytotoxicity achieved by two agents. The synergy achieved in cytotoxicity with CDDP, 5-FU and anti-Fas mAb was also achieved in apoptosis. The current study demonstrates that combination treatment of bladder cancer cells with CDDP, 5-FU and anti-Fas mAb overcomes their resistance. In addition, the sensitization required low concentrations of CDDP and 5-FU, and thus supporting the potential in vivo application of combination of CDDP, 5-FU and immunotherapy in the treatment of drug-resistant bladder cancer.
先前的研究表明，顺铂（CDDP）可使膀胱癌细胞对Fas介导的细胞毒性敏感，且CDDP还可增强5-氟尿嘧啶（5-FU）的细胞毒性作用。这些药物介导细胞凋亡，可能共享导致细胞死亡的共同细胞内途径。我们推测，CDDP、5-FU与抗Fas单克隆抗体（mAb）联合治疗可能克服耐药性。我们研究了CDDP、5-FU和抗Fas mAb对T24膀胱癌细胞系的细胞毒性和凋亡是否具有协同作用。通过一日微量培养四氮唑染料法监测细胞毒性。用抗Fas mAb联合CDDP或5-FU处理T24细胞可产生协同细胞毒性作用。此外，用CDDP、5-FU和抗Fas mAb联合处理T24细胞可进一步增强两种药物联合所产生的协同细胞毒性。CDDP、5-FU和抗Fas mAb在细胞毒性方面所实现的协同作用在细胞凋亡方面也得以实现。当前研究表明，用CDDP、5-FU和抗Fas mAb联合治疗膀胱癌细胞可克服其耐药性。此外，致敏作用所需的CDDP和5-FU浓度较低，因此支持CDDP、5-FU与免疫疗法联合在体内应用于治疗耐药性膀胱癌的潜力。
