State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Curr Drug Targets. 2019;20(6):668-678. doi: 10.2174/1389450120666181123122406.
Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia itself is a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different types of cancer are ongoing. However, none of them has been approved in clinic to date. From the studies on HAPs began, some achievements are obtained but more challenges are put forward. In this paper, we reviewed the research progress of HAPs to discuss the strategies for HAPs development. According to the research status and results of these studies, administration pattern, reductase activity, and patient selection need to be taken into consideration to further improve the efficacy of existing HAPs. As the requirement of new drug research and development, design of optimal preclinical models and clinical trials are quite important in HAPs development, while different drug delivery systems and anticancer drugs with different mechanisms can be sources of novel HAPs.
缺氧是大多数癌症病例中存在的现象，会破坏抗癌药物的疗效。幸运的是，缺氧本身是癌症治疗的一个潜在靶点。缺氧激活前药（HAPs）可以在缺氧下被还原酶选择性激活。一些有前途的 HAPs 已经被开发出来，并且许多不同类型癌症的 HAPs 临床试验正在进行中。然而，迄今为止，尚未有一种在临床上获得批准。从 HAPs 的研究开始，已经取得了一些成果，但也提出了更多的挑战。本文综述了 HAPs 的研究进展，讨论了 HAPs 开发的策略。根据这些研究的现状和结果，需要考虑给药方式、还原酶活性和患者选择，以进一步提高现有 HAPs 的疗效。作为新药研发的要求，在 HAPs 开发中，设计最佳的临床前模型和临床试验非常重要，而不同的药物传递系统和具有不同作用机制的抗癌药物可以成为新型 HAPs 的来源。
