Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug.
Cultured cell lines LL, B16, C26, and C38 established from mouse solid tumors of Lewis lung carcinoma, B16 melanoma, and colon adenocarcinomas 26 and 38, respectively, showed inherently different resistance to vincristine (VCR) in vitro. The inherent resistance to VCR of these cell lines was related to the ability of the cells to accumulate VCR. Verapamil, a calcium antagonist with coronary vasodilator activity, enhanced the cytotoxicity of VCR against these cell lines depending upon their susceptibility 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 cytotoxicity occurred. Only a 2.5-fold increase in VCR cytotoxicity was observed for B16 cells, the most sensitive cells. VCR cytotoxicity against each cell line reached almost the same level by verapamil (2.2 to 6.6 microM). Thus, the inherent resistance to VCR among the tumor lines was circumvented. Verapamil enhanced the cellular accumulation of VCR. A 3- to 4-fold increase in cellular VCR occurred in C26 cells, while approximately a 2-fold increase was observed for B16 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 transport of VCR from the cells. The most prominent inhibition was observed for C26 cells. Circumvention of inherent resistance of tumor cells to VCR by verapamil could be attained through an enhanced cellular accumulation of VCR in each of the tumor cells. The enhancement of VCR cytotoxicity and circumvention of inherent VCR resistance by verapamil could be explained by the cellular concentration of VCR, and also it might be related to the extent of VCR binding to tubulin in the cell. The chemotherapeutic effect of VCR is significantly enhanced by verapamil in colon adenocarcinoma 26-bearing mice.
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014700:Verapamil / Q000627:therapeutic use*; D014750:Vincristine / Q000627:therapeutic use*
D014750:Vincristine; D014700:Verapamil