Estrogen-induced potentiation of DNA damage and cytotoxicity in human breast cancer cells treated with topoisomerase II-interactive antitumor drugs.
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.
Epstein
R J
RJ
Department of Clinical Oncology and Radiotherapeutics, MRC Centre, Cambridge, United Kingdom.
Smith
P J
PJ
D000677:Amsacrine / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004967:Estrogens / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004967:Estrogens; D000677:Amsacrine; D005047:Etoposide; D004317:Doxorubicin; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II