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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Prodrug strategies in cancer therapy.
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Prodrug strategies in cancer therapy.

机译：癌症治疗中的前药策略。

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摘要

Systemic cytotoxic (anti-proliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumour cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumour tissue (tumour-activated prodrugs; TAP). There are several mechanisms potentially exploitable for selective activation. Some utilise unique aspects of tumour physiology such as selective enzyme expression, hypoxia, and low extracellular pH. Others are based on tumour-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumour cells via monoclonal antibodies (ADEPT), or generated in tumour cells from DNA constructs containing the corresponding gene (GDEPT). Because only a small proportion of the tumour cells may be competent to activate the prodrug, whichever activating mechanism is used, TAP need to be capable of killing activation-incompetent cells as well via a "bystander effect", in order to fully exploit these "activator" cells. A wide variety of chemistries have been explored for the selective activation of TAP. These include reduction of quinones, N-oxides, nitroaromatics and metal complexes by endogenous enzymes or radiation, amide cleavage by endogenous peptidases, and metabolism by a variety of exogenous enzymes, including phosphatases, kinases, amidases and glycosidases.
机译：全身细胞毒性（抗增殖）抗癌药主要依靠其对癌症细胞与正常细胞之间细胞动力学差异的治疗作用。旨在通过此类化合物杀死肿瘤细胞的选择性的一种方法是使用毒性较小的前药形式，该形式可以在肿瘤组织中选择性激活（肿瘤激活的前药; TAP）。有几种机制可用于选择性激活。一些利用肿瘤生理学的独特方面，例如选择性酶表达，缺氧和低细胞外pH。其他的则基于肿瘤特异性递送技术，包括通过经由单克隆抗体（ADEPT）递送至肿瘤细胞的外源酶激活前药，或在肿瘤细胞中由含有相应基因的DNA构建体产生的前药（GDEPT）。由于只有一小部分肿瘤细胞可能具有激活前药的能力，无论使用哪种激活机制，TAP都需要能够通过“旁观者效应”杀死不能激活激活的细胞，以便充分利用这些“活化剂”细胞。为了选择性激活TAP，已经探索了多种化学方法。这些包括通过内源性酶或辐射还原醌，N-氧化物，硝基芳族化合物和金属络合物，通过内源性肽酶裂解酰胺，以及通过各种外源性酶代谢，包括磷酸酶，激酶，酰胺酶和糖苷酶。

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