Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.
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DOI：
10.1007/s00280-015-2920-7
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发表时间：
2016-03
影响因子：
3
通讯作者：
Phillips RM
中科院分区：
文献类型：
--
作者：
Phillips RM
大多数肿瘤内存在低氧张力或缺氧区域的微环境具有深远的生物学和治疗意义。已知肿瘤缺氧促进侵袭性表型的发展，对化疗和放疗的抗性，并且与不良临床结果密切相关。有趣的是，它被认为是一个高优先级的目标和治疗策略之一，旨在消除肿瘤中的缺氧细胞是一组化合物统称为缺氧激活的前药（HAP）或生物还原药物。这些药物是无活性的前药，其需要酶促活化（通常通过1或2个电子氧化还原酶）以产生细胞毒性物质，其中对低氧细胞的选择性由（1）氧逆转或抑制活化过程的能力和（2）肿瘤中氧化还原酶表达升高的存在来确定。支撑HAP开发的概念是在40多年前建立的，多年来一直在完善，以产生新一代的HAP，这些HAP正在临床前和临床开发中。本文的目的是描述目前的进展，在HAPs的发展重点的作用机制，临床前性质和领先的例子的临床进展。
The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.