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DNA Topoisomerase II Expression Is Associated with Alkylating Agent Resistance¹

Thorndike Laboratories and the Charles A. Dana Research Laboratories of the Beth Israel Hospital [J. P. E., V. T-W. C., S-W. N., N. A. R., S. Z., L. E. S.], and the Dana-Farber Cancer Institute [B. A. T.], Harvard Medical School, Boston, Massachusetts 02215

Increased expression of DNA topoisomerase II has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II into EMT6 mouse mammary carcinoma. Topoisomerase II-transfected cell lines demonstrated continued topoisomerase II mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G₀-G₁). The topoisomerase II transfectants were 5–10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G₀-G₁, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II to alkylating agent-damaged DNA.

¹ This work supported by CA01412 (to J. P. E.), POI-CA38493 (to L. E. S.), and POI-CA31303 (to B. A. T.).

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Beth Israel Hospital, 330 Brookline Avenue (DA-601), Boston, MA 02215. Phone: (617) 667-3666; Fax: (617) 667-3915.

Received 5/22/95. Accepted 10/16/95.

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