Lerner L J, Jordan V C
Department of Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Cancer Res. 1990 Jul 15;50(14):4177-89.
This paper describes the laboratory discovery and clinical testing of the first nonsteroidal antiestrogen, MER-25 (ethamoxytriphetol). The compound blocks estrogen action in all species tested and has only slight but transient estrogenic effects. No other antisteroidal actions are noted. MER-25 is antiestrogenic in primates and was investigated in the clinics in a wide range of gynecological conditions, including breast and endometrial cancer. Unfortunately toxic side effects (hallucinations, etc.) precluded further investigation. A derivative of triphenylethylene, clomiphene, has some partial agonist (estrogen-like) actions in laboratory animals and following clinical evaluation is now an established agent for the induction of ovulation in subfertile women. Although clomiphene is active in advanced breast cancer, it was not developed further. In the late 1960s a related compound, tamoxifen, was evaluated to treat a number of estrogen-responsive disorders but was successfully introduced in the 1970s for the treatment of advanced breast cancer. Although there was only modest initial interest in the palliative use of tamoxifen, an enormous increase in basic and applied studies with antiestrogens resulted in a definition of the target site-specific and tumoristatic actions of tamoxifen. Close cooperation between laboratory and clinical evaluation has guided the subsequent development of tamoxifen which is now available to treat all stages of breast cancer. Long-term adjuvant tamoxifen therapy, a concept developed in the laboratory, is currently the treatment strategy of choice. The considerable success of tamoxifen has focused attention on new antiestrogens with different pharmacological properties for other potential clinical applications.
本文介绍了首个非甾体类抗雌激素药物MER-25（乙氨氧三苯乙醇）的实验室发现及临床测试情况。该化合物在所有测试物种中均能阻断雌激素作用，且仅有轻微但短暂的雌激素样效应。未观察到其他抗甾体作用。MER-25在灵长类动物中具有抗雌激素作用，并针对包括乳腺癌和子宫内膜癌在内的多种妇科疾病在临床上进行了研究。不幸的是，其毒性副作用（幻觉等）使进一步研究被迫中断。三苯乙烯衍生物克罗米芬在实验动物中具有一些部分激动剂（雌激素样）作用，经临床评估后，现已成为治疗不育女性诱导排卵的常用药物。尽管克罗米芬对晚期乳腺癌有效，但未进一步研发。20世纪60年代末，一种相关化合物他莫昔芬被评估用于治疗多种雌激素反应性疾病，并于20世纪70年代成功用于治疗晚期乳腺癌。尽管最初对他莫昔芬的姑息治疗兴趣不大，但抗雌激素药物的基础和应用研究大量增加，明确了他莫昔芬的靶点特异性和抑瘤作用。实验室与临床评估之间的密切合作指导了他莫昔芬的后续研发，目前他莫昔芬可用于治疗乳腺癌的各个阶段。实验室提出的长期辅助他莫昔芬治疗概念，目前是首选的治疗策略。他莫昔芬的显著成功使人们将注意力集中在具有不同药理特性的新型抗雌激素药物上，以用于其他潜在的临床应用。
