Lown J W
Department of Chemistry, University of Alberta, Edmonton, Canada.
Pharmacol Ther. 1993 Nov;60(2):185-214. doi: 10.1016/0163-7258(93)90006-y.
The clinical treatment of neoplastic diseases relies on the complementary procedures of surgery, radiation treatment, immunotherapy and chemotherapy. The latter technique has matured from its earliest applications of mustard alkylating agents in the 1940s to an increasingly rationally based discipline, which is contributing significantly to the management of human malignancies. As the field of chemotherapy matured, several promising natural anticancer agents were identified. However, a more urgent need soon arose from the common experience of clinically limiting toxicities of most anticancer drugs, i.e. the necessity to develop less toxic clinical drug candidates. Thus, the medicinal chemist turned towards analog development involving certain anthraquinones. Hand-in-hand with this considerable synthetic effort, which uncovered several promising clinical leads, biochemical pharmacology, or study of the mechanisms of action of clinical anticancer agents, afforded deeper insight into drug metabolism and mode of action. More recently, therefore, the field of synthetic organic chemistry, which has been complemented by the methods of microbial chemistry, has been faced with new synthetic challenges, occasioned by the identification of hitherto unrecognized cellular targets for anticancer drugs, such as topoisomerases and helicases. The armementarium of the oncologist currently includes about 40-50 clinically useful chemical agents. The paradigm of cytotoxic anticancer agents is doxorubicin, an anthracycline, which is still amongst the most widely prescribed and effective of anticancer agents. The review attempts to summarize the discovery of anthracyclines and the elucidation of their several mechanisms of action and efforts towards improvement of their therapeutic efficacy.
肿瘤疾病的临床治疗依赖于手术、放射治疗、免疫疗法和化疗等互补性治疗手段。化疗技术已从20世纪40年代最早应用芥子烷化剂发展成为一门日益基于理性的学科，对人类恶性肿瘤的治疗发挥着重要作用。随着化疗领域的成熟，人们发现了几种有前景的天然抗癌药物。然而，由于大多数抗癌药物临床毒性限制这一普遍现象，很快出现了更迫切的需求，即需要开发毒性更低的临床候选药物。因此，药物化学家转向了涉及某些蒽醌的类似物开发。在这一大量合成工作（发现了几个有前景的临床先导化合物）的同时，生化药理学，即临床抗癌药物作用机制的研究，使人们对药物代谢和作用方式有了更深入的了解。因此，最近，由微生物化学方法补充的合成有机化学领域，由于发现了如拓扑异构酶和解旋酶等前所未有的抗癌药物细胞靶点，面临着新的合成挑战。肿瘤学家目前的治疗手段包括约40 - 50种临床有用的化学药物。细胞毒性抗癌药物的典范是阿霉素，一种蒽环类药物，它仍然是处方最广泛且最有效的抗癌药物之一。本综述试图总结蒽环类药物的发现、其多种作用机制的阐明以及提高其治疗效果的努力。
