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Cross-Resistance to Intercalating Agents in an Epipodophyllotoxin-resistant Chinese Hamster Ovary Cell Line: Evidence for a Common Intracellular Target¹

Departments of Pharmacology and Medicine, University of Florida College and Medicine, Gainesville, Florida 32610 [B. G., P. H., W. R.], and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada [R. G.]

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 epipodophyllotoxinresistant 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, Vpm^R-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 Vpm^R-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.

¹ This work was supported by American Cancer Society Grant CH-261 and NIH Grant CA-24586.

² Pharmaceutical Manufacturer's Association Clinical Pharmacology Fellow. Present address: Division of Medicine, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Drive, Houston, TX 77030.

³ To whom requests for reprints should be addressed, at Box J-267, JHMHC, University of Florida, Gainesville, FL 32610.

Received 8/ 6/85. Revised 11/26/85. Accepted 12/11/85.