Promotion by Verapamil of Vincristine Respons iveness in Tumor Cell

Cultured cell lines LL, B1 6, C26, and C38 establ ished from mouse solid tumors of Lewis lung carcinoma, B1 6 melanoma, and colon adenocarc inomas 26 and 38, respectively, showed inherent ly dif ferent resistance to vincrist ine (VCR) in vitro. The inherent resistance to VCR of these cell lines was related to the abil ity of the cells to accumulate VCR. Verapamil , a calcium antagonist with coronary vasodi lator activity, enhanced the cytotox ic i ty of VCR against these cell lines depending upon their susceptibi l i ty to VCR. C26 cells, the most resistant, became the most susceptible to VCR with a nontoxic dose of verapamil. A 12-fold increase in VCR cytotoxic i ty occurred. Only a 2.5-fold increase in VCR cytotox ic i ty was observed for B16 cells, the most sensitive cells. VCR cytotoxic i ty against each cell line reached almost the same level by verapamil (2.2 to 6.6 /~M). Thus, the inherent resistance to VCR among the tumor lines was circumvented. Verapamil enhanced the cellular accumulat ion of VCR. A 3to 4-fold increase in cel lular VCR occurred in C26 cells, while approx imate ly a 2-fold increase was observed for B1 6 and LL cells. A similar rate of enhancement was observed for both bound and free VCR, indicating that verapamil does not enhance the affinity of VCR to tubulin. Verapamil inhibited the outward t ransport of VCR from the cells. The most prominent inhibition was observed for C26 cells. Circumvent ion of inherent resistance of tumor cells to VCR by verapamil could be attained through an enhanced cel lular accumulat ion of VCR in each of the tumor cells. The enhancement of VCR cytotoxic i ty and ci rcumvent ion of inherent VCR resistance by verapamil could be explained by the cel lular concentrat ion of VCR, and also it might be related to the extent of VCR binding to tubulin in the cell. The chemotherapeut ic effect of VCR is signif icant ly enhanced by verapamil in colon adenocarc inoma 26-bear ing mice.