Laboratory studies to develop general principles for the adjuvant treatment of breast cancer with antiestrogens: problems and potential for future clinical applications.

The general pharmacology of tamoxifen in animals and man is reviewed with particular reference to the long-term adjuvant therapy of node-positive breast cancer. Rats with dimethylbenzanthracene (DMBA)-induced mammary carcinomata have been used extensively as a laboratory model to study hormone-dependent cancer. The administration of a 30-day course of tamoxifen (50 micrograms daily) starting 5, 15, 30, or 50 days after DMBA caused a delay in tumor appearance and decrease in the cumulative number of tumors that were induced by 200 days. Similarly, the administration of increasing doses of tamoxifen (0.2, 3, 50, and 800 micrograms daily) between 30 and 60 days after DMBA produced a dose-related delay in tumor appearance and a decrease in the cumulative number of tumors at 200 days. Since the tumors that were induced after tamoxifen still responded to ovariectomy, tamoxifen appears to act as an inhibitor of the tumor cell cycle rather than as a tumoricidal agent in this model. This principle was exemplified by comparing a short course (30 day) with a continuous course (170 day) of tamoxifen initiated 30 days after DMBA. The short course of therapy only delayed tumor appearance whereas continuous therapy maintained 90% of the animals in a tumor-free state. These data strongly support the use of long-term (up to five-year) adjuvant therapy with tamoxifen in patients as a suppressive therapy for hormone-sensitive metastases.