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Estrogen-induced Potentiation of DNA Damage and Cytotoxicity in Human Breast Cancer Cells Treated with Topoisomerase II-interactive Antitumor Drugs

MRC Unit, Department of Clinical Oncology and Radiotherapeutics, MRC Centre, Hills Rd, Cambridge CB2 2QH, United Kingdom

Hormone stimulation of responsive neoplasms is a potential strategy for improving the target selectivity of cancer chemotherapy. Using an alkaline DNA-unwinding technique to detect drug-induced DNA strand breakage, we have shown that estrogen stimulation of T-47D human breast cancer cells enhances induction of DNA cleavage by etoposide (VP-16), 4',9-acridinylaminomethanesulfon-m-anisidide (m-AMSA), mitoxantrone, and doxorubicin, drugs known to interact with the DNA-modifying enzyme topoisomerase II. No enhancement of DNA cleavage or cytotoxicity was seen in estrogen-treated cells exposed to X-rays or bleomycin. Novobiocin (an inhibitor of topoisomerase II) markedly antagonized the enhancing effect of estrogen on VP-16-induced DNA cleavage, while neutral nucleoid sedimentation detected less than 10% of such strand breaks revealed in estrogen-treated cells by alkaline unwinding. Estrogen did not affect DNA repair of lesions induced by X-rays, VP-16, or ultraviolet radiation. Enhancement of DNA cleavage was accompanied by a corresponding enhancement of cytotoxicity in cells treated with VP-16 or m-AMSA, but only minimal enhancement of cytotoxicity was seen following treatment with mitoxantrone or doxorubicin. Estrogen-treated and control cells treated with VP-16 and m-AMSA sustained similar levels of DNA cleavage for equivalent levels of cytotoxicity. These findings suggest that estrogen potentiates the cytotoxicity of VP-16 and m-AMSA by enhancing topoisomerase II-mediated DNA damage but that such "damage" does not contribute significantly to cytotoxicity induced by mitoxantrone or doxorubicin. Estrogen stimulation of receptor-positive breast cancer may prove to be a clinically relevant strategy for improving the selectivity and cytotoxicity of some, but not all, topoisomerase II-interactive drugs.

¹ Supported by The Sir Robert Menzies Memorial Trust and in part by the Royal Australasian College of Physicians. To whom requests for reprints should be addressed.

Received 5/13/87. Revised 8/25/87. Accepted 10/ 1/87.

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