Cross-resistance to intercalating agents in an epipodophyllotoxin-resistant Chinese hamster ovary cell line: evidence for a common intracellular target.
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Several intercalating agents, as well as the epipodophyllotoxins, appear to effect DNA damage through their interaction with type II DNA topoisomerases. However, the relationship of this phenomenon to anti-tumor activity remains unproven. Our studies with an epipodophyllotoxin-resistant cell line not only provide additional evidence that the enzyme is a multidrug target but also serve to implicate it as a mediator of cytotoxic effect. When compared to wild-type cells, the epipodophyllotoxin-resistant Chinese hamster ovary cell line, VpmR-5, exhibits cross-resistance to both the cytotoxic and DNA cleavage activities of 4',9-acridinylaminomethanesulfon-m-anisidide, mitoxantrone, and Adriamycin. Steady-state concentrations of radiolabeled-4',9-acridinylaminomethanesulfon-m-anisidide and daunomycin are identical in both cell lines. Sharp plateaus in the VpmR-5 dose-response curves for Adriamycin-induced DNA strand breaks and cytotoxicity appear to be related to interference with type II topoisomerase-mediated cleavage of DNA at high concentrations of the intercalator. These data support a direct role for DNA strand scission in cell death and also suggest that multidrug resistance may be acquired by a qualitative change in type II topoisomerase that alters interaction of drug with the enzyme or enzyme-DNA complex.
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