This paper describes the laboratory discovery and clinical testing of the first nonsteroidal
antiestrogen,
MER-25 (
ethamoxytriphetol). The compound blocks
estrogen action in all species tested and has only slight but transient
estrogenic effects. No other antisteroidal actions are noted.
MER-25 is antiestrogenic in primates and was investigated in the clinics in a wide range of gynecological conditions, including breast and
endometrial cancer. Unfortunately toxic side effects (
hallucinations, etc.) precluded further investigation. A derivative of
triphenylethylene,
clomiphene, has some partial agonist (
estrogen-like) actions in laboratory animals and following clinical evaluation is now an established agent for the induction of ovulation in subfertile women. Although
clomiphene is active in advanced
breast cancer, it was not developed further. In the late 1960s a related compound,
tamoxifen, was evaluated to treat a number of
estrogen-responsive disorders but was successfully introduced in the 1970s for the treatment of advanced
breast cancer. Although there was only modest initial interest in the palliative use of
tamoxifen, an enormous increase in basic and applied studies with
antiestrogens resulted in a definition of the target site-specific and tumoristatic actions of
tamoxifen. Close cooperation between laboratory and clinical evaluation has guided the subsequent development of
tamoxifen which is now available to treat all stages of
breast cancer. Long-term adjuvant
tamoxifen therapy, a concept developed in the laboratory, is currently the treatment strategy of choice. The considerable success of
tamoxifen has focused attention on new
antiestrogens with different pharmacological properties for other potential clinical applications.