Circumvention of resistance to anthracyclines by calcium antagonists and other membrane-perturbing agents.

Resistance to a variety of naturally occurring antitumour agents, including the anthracyclines, vinca alkaloids and actinomycin D, is associated with an outward transport system which limits intracellular drug accumulation to sublethal levels. A series of agents of unrelated structure, including calcium and calmodulin antagonists, local anaesthetics and detergents, can impair this outward transport system, and thereby promote cytotoxicity of these antitumour agents. These effects are not related to alterations in calcium fluxes, but appear to derive from membrane perturbations which also affect other transport systems. There are additional modes of drug resistance not based on transport alterations which are apparently unaffected by these second agents.