Calcium Channel Blockers and Cisplatin: Synergistic Antimetastatic Effects

Abstract

Recurrent cancers (Devita, 1983; Goldie and Coldman, 1984) and metasta-tic disease (Fidler, 1978; Tanigawa et al, 1984) often result from the outgrowth of tumor cells that are resistant to chemotherapeutic agents. Initial attempts to enhance the antitumor actions of these agents against drug-resistant cancers were focused on variations in drug protocols such as dosage, scheduling, mode of administration and duration of therapy (Wittes et al., 1979; Ozols et al., 1982). Other approaches focused on the use of combination chemotherapy whereby cytotoxic agents with toxicities against different normal host tissues were administered in combination. Although this type of combination therapy has improved the cure rate for many cancers, the ultimate failure of this strategy due to drug-resistant recurrent disease and/or metastatic disease is well documented (Ling et al., 1983; Citrin and Hogan, 1982). A new approach to the chemotherapy of drug-resistant tumors is the combined use of a non-cytotoxic agent which enhances the antitumor effects of one or more of the commonly used cytotoxic organic or natural product chemotherapeutic agents (e.g. anthracycline antibiotics, vinca alkaloids). Tsuruo et al. (1981) first reported that the combination of the calcium channel blocker, verapamil, and the cytotoxic chemotherapeutic agent, vincristine, overcomes the resistance of P388 (a murine leukemia) to vincristine both in vitro and in vivo. Subsequent reports by Tsuruo et al.