Molecular mechanisms and future uses of antiestrogens - Preface

Twenty five years ago there was no tamoxifen. for the treatment of breast cancer, only ICI 46,747 an antiestrogen with potent antifertility properties in laboratory rats. Today tamoxifen is the most prescribed cancer medicine and the endocrine treatment of choice for all stages of breast cancer. The low incidence of side-effects and the fact that tamoxifen increases the survival of breast cancer patients has revolutionized the approach to the treatment of breast cancer in general practice. However, the success of tamoxifen as a cancer therapy and the finding that tamoxifen can maintain bone density and lower circulating cholesterol has provided the incentive to develop new drugs for the treatment of osteoporosis and coronary heart disease. These drugs may have the added advantage of preventing breast cancer as a beneficial side-effect. This issue describes the development of antiestrogens as clinically useful agents from the time when Dr Leonard Lerner published his pioneering paper on the first non-steroidal antiestrogen MER-25 (Lerner et al., 1958) to the present. Lerner's discovery was greeted with intense interest by the pharmaceutical industry because one of the fascinating effects of the drug was its action as a postcoital contraceptive. Regrettably MER-25 did trot achieve its promise as a clinically useful antiestrogen but a successor compound MRL-41, also described by Dr Lerner (Holtkamp et al., 1960), was successfully developed, not as a contraceptive but as an inducer of ovulation in subfertile women. MRL-41 or clomiphene became established as the therapeutic cornerstone in reproductive endocrinology, for the induction of ovulation. The reason for the intense interest in the value of antiestrogens as regulators of reproduction was because the oral contraceptive, conceived by Pincus and Chang at the Worcester Foundation for Experimental Biology (now the Worcester Foundation for Biomedical Research) in Shrewsbury, Massachusetts, had been so successful clinically. A 'morning after pill' would have been a valuable innovation but this was not to be. Nevertheless, the new antiestrogens, nafoxidine (Upjohn), CI 628 (Park-Davis), clomiphene (Merrel), and ICI 46,474 (ICI now Zeneca) were all investigated extensively in the laboratory throughout the 1960s and became standard laboratory reagents to investigate estrogen action. During the 1960s, there was only modest interest in cancer research in general and almost no interest in breast cancer therapeutics in particular. This was all to change in the 1970s with a 'declaration of war on cancer'. However, several clinical trials with antiestrogens were completed in the 1960s but toxicity and an overall lack of interest by the pharmaceutical industry retarded progress. Only by a series of fortunate circumstances did ICI 46,474 become tamoxifen and this issue is dedicated to those who helped to play the key roles in this success story. (C) 1997 Elsevier Science Ltd.