Sensitization to the cytotoxicity of adriamycin by verapamil and heat in multidrug-resistant Chinese hamster ovary cells

Development of multidrug resistance to anticancer agents is a major limitat ion for the success of cancer chemotherapy. The chemosensitizer verapamil i ncreases intracellular accumulation of drugs such as adriamycin in certain multidrug-resistant cell lines. When-combined with verapamil, hyper thermia should be able to alter membrane permeability to adriamycin and to enhance the cytotoxicity of the drug. Verapamil increased the cytotoxicity of adri amycin in multidrug-resistant Chinese hamster ovary cells (CN(R)C5) but not in drug-sensitive cells (AuxB1). Hyperthermia(42 degrees C) alone clearly increased the cytotoxicity of adriamycin in AuxB1 cells. There was also a s mall increase in CH(R)C5 cells at 42 and 43 degrees C. In drug-resistant, c ells, the cytotoxicity of adriamycin increased considerably when verapamil was combined with heat. This effect was dependent on temperature and increa sed with time of incubation. At 37 degrees C, verapamil increased the uptak e of adriamycin in CH(R)C5 cells, while drug efflux decreased. When verapam il was combined with hyperthermia, drug efflux decreased even further, Thes e results led to an overall increase in intracellular accumulation of the d rug. In drug-sensitive cells, hyperthermia Increased both the uptake and ef flux of adriamycin, but verapamil:had no effect. Verapamil plus heat increa sed the cytotoxicity of adriamycin in drug-resistant cells, and this was ac companied by altered permeability of the membrane to the drug, Hyperthermia combined with verapamil could be beneficial by increasing the effectivenes s of adriamycin in the elimination of multidrug-resistant cells in a locali zed target region. (C) 1999 by Radiation Research Society.