Today, tamoxifen is one of the world's best-selling hormonal breast cancer drugs. However, it was not always so. Compound ICI 46,474 (as it was first known) was synthesized in 1962 within a project to develop a contraceptive pill in the pharmaceutical laboratories of ICI (now part of AstraZeneca). Although designed to act as an anti-estrogen, the compound stimulated, rather than suppressed ovulation in women. This, and the fact that it could not be patented in the USA, its largest potential market, meant that ICI nearly stopped the project. It was saved partly because the team's leader, Arthur Walpole, threatened to resign, and pressed on with another project: to develop tamoxifen as a treatment for breast cancer. Even then, its market appeared small, because at first it was mainly used as a palliative treatment for advanced breast cancer. An important turning point in tamoxifen's journey from orphan drug to best-selling medicine occurred in the 1980s, when clinical trials showed that it was also useful as an adjuvant to surgery and chemotherapy in the early stages of the disease. Later, trials demonstrated that it could prevent its occurrence or re-occurrence in women at high risk of breast cancer. Thus, it became the first preventive for any cancer, helping to establish the broader principles of chemoprevention, and extending the market for tamoxifen and similar drugs further still. Using tamoxifen as a case study, this paper discusses the limits of the rational approach to drug design, the role of human actors, and the series of feedback loops between bench and bedside that underpins pharmaceutical innovation. The paper also highlights the complex evaluation and management of risk that are involved in all therapies, but more especially perhaps in life-threatening and emotion-laden diseases like cancer.
The concept of drug receptors has played a significant role in the biomedical sciences and in pharmaceutical innovation in the second half of the twentieth century. Although the concept dates back to the work of the German bacteriologist and immunologist Paul Ehrlich and of the British physiologist John Newport Langley at the end of the nineteenth and the beginning of the twentieth century, its acceptance was delayed because of conflicting ideas about drug action, and because of uncertainties and hesitations about the concept itself.
The relationship between medicine and the study of life is as old as medicine itself. Nevertheless, historians have highlighted the great transformation that took place in the nineteenth century when first physiology and then bacteriology became important resources for the classification, diagnosis, and treatment of human diseases.1 In that period, significant links developed between the sites specializing in biological experimentation (i.e. laboratories) on the one hand, and the places of healing (i.e. hospitals, dispensaries) and public health offices on the other. Together, they helped to fashion modern, professional medicine.2 However, many historical studies have also argued that this mobilization of biological knowledge exerted a limited impact on medical practice in general, and clinical practice in particular.
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