Elsevier

Steroids

Volume 72, Issue 1, January 2007, Pages 7-25
Steroids

Review
Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

https://doi.org/10.1016/j.steroids.2006.10.009Get rights and content

Abstract

This article describes the origins and evolution of “antiestrogenic” medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer.

However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.

Section snippets

V. Craig Jordan: ICI 46,474 to tamoxifen

In 1967 Arthur Walpole and Mike Harper at the Imperial Chemical Industries (ICI) Pharmaceutical Division in Alderley Park, Cheshire reported the antiestrogenic and antifertility properties of a substituted triphenylethylene ICI 46,464 [6], [7]. The Alderley Park team had been tasked during the 1960s to discover compounds to modulate fertility. Although Walpole also had an interest in anticancer chemotherapy, [8] as head of the fertility control program, he did not conduct any laboratory

Angela M.H. Brodie—aromatase inhibitors: developing 4-hydroxyandrostenedione

I had received my PhD degree from Manchester University and was awarded an NIH Postdoctoral Training Fellowship, which brought me to the Worcester Foundation in 1962. The exciting atmosphere of cutting edge research enticed me to remain there after my fellowship. By the early 1970s, I had married a fellow scientist, Harry Brodie, and joined his lab working on the biochemistry of aromatase, the key enzyme in the biosynthesis of estrogens. Harry, an organic chemist, had begun developing

Non-steroidal aromatase inhibitors

Non-steroidal aromatase inhibitors contain a heteroatom (e.g., N, S, O) possessing a free electron pair for coordination with the heme iron (Fe3+) and a substituent for interaction with other regions of the enzyme (Fig. 5). This type of binding is reflected in Soret band changes (usually bathochromic with respect to Type I inhibitors). Compounds that carry a nitrogen heteroatom have been the most studied and their binding with cytochrome P-450 enzymes give rise to a Type II difference spectrum

Aromatase inhibitors as chemopreventive agents

Aromatase inhibitors have potential for chemoprevention in women with increased risk of developing breast cancer for many of the same reasons as tamoxifen. Thus, reducing the number of proliferative events by inhibiting the stimulatory effects of estrogen will reduce the number of mutations that would otherwise occur. Evidence to support the value of aromatase inhibitors in the prevention setting comes from the adjuvant clinical trials that compare and contrast tamoxifen with an aromatase

Acknowledgements

Dr. Jordan is supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer CA 89018, R01 GM067156, FCCC Core Grant NIH P30 CA006927, the Avon Foundation and the Weg Fund of Fox Chase Cancer Center. Dr. Angela Brodie is supported by NIH R01CA-62483, NIH R01CA-27440, and DOD Centers of Excellence “Center for

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