Dallas/Ft. Worth Living Legend Chair of Cancer Research, Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Endocr Relat Cancer. 2021 Jan;28(1):R11-R30. doi: 10.1530/ERC-20-0335.
Following the discovery and approval of the oral contraceptive, the pharmaceutical industry sought new opportunities for the regulation of reproduction. The discovery of the first non-steroidal anti-oestrogen MER25, with antifertility properties in laboratory animals, started a search for 'morning-after pills'. There were multiple options in the 1960s, however, one compound ICI 46,474 was investigated, but found to induce ovulation in subfertile women. A second option was to treat stage IV breast cancer. Although the patent for ICI 46,474 was awarded in the early 1960s in the UK and around the world, a patent in the USA was denied on the basis that the claims for breast cancer treatment were not supported by evidence. A trial at the Christie Hospital and Holt Radium Institute in Manchester, published in 1971, showed activity compared with alternatives: high-dose oestrogen or androgen treatment, but the US Patent Office was unswayed until 1985! The future of tamoxifen to be, was in the balance in 1972 but the project went forward as an orphan drug looking for applications and a translational research strategy was needed. Today, tamoxifen is known as the first targeted therapy in cancer with successful applications to treat all stages of breast cancer, male breast cancer, and the first medicine for the reduction of breast cancer incidence in high-risk pre- and post-menopausal women. This is the unlikely story of how an orphan medicine changed medical practice around the world, with millions of women's lives extended.
继口服避孕药被发现和批准后，制药行业寻求新的机会来调节生殖。第一种非甾体类抗雌激素 MER25 的发现，具有实验室动物的抗生育特性，开启了寻找“事后避孕药”的探索。在 20 世纪 60 年代有多种选择，但其中一种化合物 ICI 46,474 被研究，但发现它会诱导不孕妇女排卵。另一种选择是治疗 IV 期乳腺癌。尽管 ICI 46,474 的专利在 20 世纪 60 年代初在英国和世界各地获得批准，但在美国，由于缺乏乳腺癌治疗证据，专利被拒绝。曼彻斯特克里斯蒂医院和霍尔特镭研究所的一项试验于 1971 年发表，显示出与替代药物相比的活性：大剂量雌激素或雄激素治疗，但美国专利局直到 1985 年才改变立场！1972 年，他莫昔芬的未来悬而未决，但该项目作为一种孤儿药继续前进，寻找应用，并需要一种转化研究策略。如今，他莫昔芬被称为癌症的第一种靶向治疗药物，成功应用于治疗所有阶段的乳腺癌、男性乳腺癌，以及第一种用于降低高危绝经前和绝经后妇女乳腺癌发病率的药物。这是一个不太可能的故事，讲述了一种孤儿药如何改变了全世界的医疗实践，为数百万妇女延长了生命。
