New antiestrogens in breast cancer: a review

A comprehensive review of the literature from 1975 to 1995 was conducted. Reports were identified using the Cancerline and Medline databases. The chemical structure, estrogen agonist and antagonist activity, and in vitro studies were reviewed and compared with those of tamoxifes. Also, the antitumor activity in cell lines and animal models was highlighted. The mechanisms of action, metabolism, route of administration, dose scheduling, antitumor activity, and side effects of each agent were reviewed and compared with those for tamoxifen, where available. Several new antiestrogens are at various stages of development. They are divided into nonsteroidal and steroidal antiestrogens. Among the nonsteroidal antiestrogens are agents like toremifene and droloxifene. Both produce response rates, and both have toxicity profiles that are comparable to tamoxifen. In addition, toremifene can chemosensitize estrogen receptor-negative tumors, reverse multidrug resistance, and affect tamoxifen-resistant tumors. The short half-life of droloxifene results in minimal serum accumulation, and therefore it may be sequentially used with other systemic therapies to maximize cell kill. ICI 182,780, a steroidal antiestrogen, is well tolerated, active in tamoxifen-resistant tumors, and has a potential role in the preoperative management of advanced breast cancer. Other potential benefits of these and other agents are discussed. Pure antiestrogens have documented antibreast cancer activity that is in some instances more potent than tamoxifen. Some have activity in estrogen receptor-negative or tamoxifen-resistant tumors. Others may help to reverse chemotherapy resistance. In addition, the potential role of these antiestrogens in radioimaging and their effect on lipid metabolism is also being recognized.