Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation.
Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation.
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DOI：
10.3389/fphar.2017.00620
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发表时间：
2017
影响因子：
5.6
通讯作者：
Quirke VM
中科院分区：
文献类型：
--
作者：
Quirke VM
今天，他莫昔芬是世界上最畅销的激素乳腺癌药物之一。然而，情况并非总是如此。1962年，ICI制药实验室（现为阿斯利康公司的一部分）在一个开发避孕药的项目中合成了化合物ICI 46,474。虽然这种化合物被设计成一种抗雌激素，但它刺激而不是抑制女性的排卵。这一点，再加上它不能在其最大的潜在市场美国申请专利，意味着ICI几乎停止了这个项目。它得以挽救的部分原因是该团队的负责人亚瑟·沃波尔（Arthur Walpole）威胁要辞职，并继续推进另一个项目：开发他莫昔芬（tamoxifen），用于治疗乳腺癌。即使在那时，它的市场也显得很小，因为最初它主要被用作晚期乳腺癌的姑息治疗。他莫昔芬从孤儿药到畅销药的一个重要转折点发生在20世纪80年代，当时临床试验表明，他莫昔芬在疾病早期也可作为手术和化疗的辅助药物。后来，试验表明，它可以预防乳腺癌高风险妇女的发生或再次发生。因此，它成为第一种预防癌症的药物，有助于建立更广泛的化学预防原则，并进一步扩大了他莫昔芬和类似药物的市场。本文以他莫昔芬为例，讨论了药物设计理性方法的局限性、人类参与者的作用，以及支撑药物创新的实验室和临床之间的一系列反馈回路。这篇论文还强调了所有治疗方法都涉及的复杂的风险评估和管理，但在癌症等危及生命和充满情绪的疾病中，风险评估和管理可能更为复杂。
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.
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影响因子：
3.1
作者：
Fosket, J
通讯作者：
Fosket, J
DOI：
10.1039/jr9410000006
发表时间：
1941-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY
影响因子：
--
作者：
Carlisle, CH;Crowfoot, D
通讯作者：
Crowfoot, D
影响因子：
8.8
作者：
Cole MP;Jones CT;Todd ID
通讯作者：
Todd ID
DOI：
10.1093/jnci/90.18.1371
发表时间：
1998-09-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Fisher, B;Costantino, JP;Wolmark, N
通讯作者：
Wolmark, N
影响因子：
5.8
作者：
FRIESEN, H;GUYDA, H;HARDY, J
通讯作者：
HARDY, J