Endocrine pharmacology of antiestrogens as antitumor agents

In 1958, Lerner and co-workers (1) described the biological properties of the first nonsteroidal antiestrogen MER25 (see Fig. 1). The discovery of this new class of drugs opened up a variety of clinical possibilities (2, 3), but early studies were terminated because of toxic side effects. Another member of this new class of drugs, clomiphene (then known as chloramiphene or MRL41), held the promise of being a potential antifertility agent (4); however, clinical studies demonstrated that ovulation was induced (5). The drug is now available as a profertility agent in subfertile women (6). During the 1960s a range of antiestrogens was synthesized by the pharmaceutical industry for potential applications in gynecology (7, 8). In the main though, these agents were used only to study reproductive endocrinology in the laboratory. However the focus of clinical application slowly changed from the broad market of contraception to the relatively small market of advanced breast cancer therapy.