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