Antiestrogens: the Past and the Future

Introduction

The breast is the leading site for cancer incidence and the second most common site for cancer death among U.S. women [1]. Antitumor action and chemoprevention have been the focus of laboratory work and clinical trials for many years. As new agents are discovered, they will continue to be tested against tamoxifen, the current standard for the treatment and prevention of breast cancer. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. The Study of Tamoxifen and Raloxifene (STAR) trial and prior prevention studies will be discussed in an attempt understand the bridge from the laboratory to the clinic.

In 1936, Professor Antoine Lacassagne suggested that if breast cancer was caused by a special hereditary sensitivity to estrogen, then the disease could be prevented by developing a therapeutic antagonist to estrogen action in the breast [2]. Forty years ago there was little interest in treating breast cancer with new hormonal drugs, and most of the endocrinology research was focused on understanding reproduction. The first nonsteroidal antiestrogen, MER25, was developed as a contraceptive and described by Lerner and co-workers in 1958 [3]. This drug failed in clinical trial because the large doses caused neurotoxicity [4]. Drug discovery switched to triphenylethylene-based compounds that resulted first in clomiphene and then tamoxifen [5] (Fig. [1]). A research focus on cancer therapy in the 1970's facilitated tamoxifen's development as a breast cancer treatment.

Fig. 1 Molecular structure of tamoxifen, and clomiphene.

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