Combination chemotherapy with cisplatin and nifedipine: synergistic antitumor effects against a cisplatin-resistant subline of the B16 amelanotic melanoma

Abstract

Cisplatin has become one of the most commonly prescribed cytotoxic chemotherapeutic agents. Unfortunately, the cure rate is low due to the development or outgrowth of cisplatin-resistant cells which repopulate tumors, resulting in patient death. We reported previously that the calcium channel blocker nifedipine enhances the antitumour actions of cisplatin (cis-diamminedichloroplatinum (II] against murine tumors which are inherently cisplatin-sensitive (B16a) or inherently cisplatin-resistant (3LL). We have developed an induced cisplatin-resistant tumor variant (B16a-Pt) that is 30 times more resistant to cisplatin than its cisplatin-sensitive parent line. In short-term studies, we report that nifedipine significantly enhanced the cytotoxicity of cisplatin against primary B16a-Pt tumors and their spontaneous pulmonary metastases. In long term studies, we report that combination therapy with nifedipine and cisplatin results in significantly enhanced survival.