This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Glisson, B. Articles by Ross, W. Search for Related Content PubMed PubMed Citation Articles by Glisson, B. Articles by Ross, W.

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.