Promotion of daunorubicin uptake and toxicity by the calcium antagonist tiapamil and its analogs

Abstract

Studies were performed with the anthracycline-responsive P388 murine leukemia cell line, and with P388/ADR, a subline selected for doxorubicin resistance. In the P388/ADR cell line, the observed 100-fold daunorubicin resistance is associated with an outward drug transport system which can be inhibited by several calcium antagonists, eg, verapamil and nifedipine. An examination of compounds related to tiapamil, a verapamil analog, has identified a structure which is tenfold more effective than verapamil at potentiating anthracycline accumulation and responsiveness in P388/ADR cells. At no nontoxic level of any calcium antagonist examined was it possible to wholly reverse the degree of daunorubicin resistance found in the P388/ADR cell line.