Effect of dehydroepiandrosterone and the antiestrogen EM-800 on growth of human ZR-75-1 breast cancer xenografts

Background: In the mammary gland, androgens are formed from the precursor steroid dehydroepiandrosterone (DHEA). Clinical evidence indicates that androgens have inhibitory effects on breast cancer. Estrogens, on the other hand, stimulate the development and growth of breast cancer. We studied the effect of DHEA alone or in combination with the newly described pure antiestrogen EM-800 on the growth of subcutaneous tumor xenografts formed by the human breast cancer cell line ZR-75-1 in ovariectomized nude mice. Methods: Immediately after ovariectomy, mice received daily subcutaneous injections of 0.5 mu g estrone (E-1) (an estrogenic hormone). EM-800 (15, 50, or 100 mu g) was given orally once daily. DHEA was administered percutaneously twice daily (total dose of 0.3, 1.0, or 3.0 mg) to the dorsal skin either alone or in combination with a 15-mu g daily oral dose of EM-800, Changes in tumor size in response to the treatments (in relation to measurements made on the first day of treatment) were assessed periodically, At the end of the experiments, tumors were dissected and weighed. Results: A 9.4-fold increase in tumor size in 9.5 months was observed in ovariectomized mice receiving E-1 alone. Administration of 15, 50, or 100 mu g EM-800 in E-1-supplemented mice led to inhibitions of 87.5%, 93.5%, and 94.0% in tumor size, respectively, DHEA, on the other hand, at doses of 0.3, 1.0, or 3.0 mg inhibited terminal tumor size by 50.4%, 76.8%, and 80.0%, respectively. Comparable inhibitions in tumor size were obtained with a daily 15-mu g oral dose of EM-800 with or without different doses of percutaneous DHEA. Conclusions: DHEA and EM-800 independently suppressed the growth of E-1-stimulated ZR-75-1 xenograft tumors in nude mice, Administration of DHEA at the defined doses did not alter the inhibitory effect of EM-800.