Although the discovery of ICI46,474 (tamoxifen) (Figure 4), the antiestrogenic, pure trans isomer of a substituted triphenylethylene, was made by Harper, Richardson, and Walpole45-47 as part of the Fertility Control Program at ICI Pharmaceuticals (now AstraZeneca), Cheshire, UK, the study of cancer therapies was Walpole's long-term interest.48 In the late 1940s Walpole was a member of staff at ICI's Dyestuffs Division Biological Laboratory in Wilmslow, Cheshire. This establishment was the fledgling predecessor of the Pharmaceuticals Division Research Laboratories built in 1956-57 at Alderley Park near Macclesfield, Cheshire. Walpole was asked to establish animal models for the bioassay of potential alkylating agents49-54 to evaluate compounds as bladder carcinogens55 and to assess the potential health hazards for workers in the dyestuffs industry.56 Walpole made the important discovery that tris-ethyleneimino-S-triazine (M9500) was an active anticancer agent in the Walker rat carcinoma 2 5 650 and conducted extensive structure-activity relationship studies with many mono and bifunctional compounds. Although tris-ethyleneimino-S-triazine is now only of historical interest, the related compound, hexamethylmelamine (M10,567) was also found to be active by Walpole.52 Hexamethylmelamine is active in a broad spectrum of tumors including ovarian carcinoma resistant to other alkylating agents. However, Walpole's interest in alkylating agents and carcinogenesis provides only part of the background which led to his suggestion that ICI46,474 should be tested in breast cancer. Walpole was also interested in estrogens and was aware in 1963 that antiestrogens could be used for the treatment of breast cancer. The story of ICI's involvement with the hormonal treatment of breast cancer goes back to the early 1940s following the laboratory discovery by others that chlorotriphenylethylene is an orally active estrogen.57 ICI supplied the triphenylethylenes initially used by Haddow, Watkinson, and Paterson in their landmark study of the antitumor effects of synthetic estrogens in advanced breast and prostate cancer.58 These studies paved the way for the standard use of high-dose estrogen therapy to treat both breast and prostate cancer for the next two decades. In 1949, Walpole and Paterson59 studied the antitumor actions of nonsteroidal estrogen therapy on breast cancer in the hope of finding the reason why some patients responded and others did not. These early studies by Walpole were unsuccessful but the subcellular mechanism of hormonal-dependent growth was eventually discovered by Jensen with his pioneering work on the estrogen receptor.3,60
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