Tumor-activated prodrugs - A new approach to cancer therapy
Tumor-activated prodrugs - A new approach to cancer therapy
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DOI：
10.1081/cnv-200027148
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发表时间：
2004-01-01
影响因子：
2.4
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Denny, WA
全身性细胞毒性(抗增殖)抗癌药物主要依赖于它们对癌细胞和正常细胞之间的细胞动力学差异的治疗效果。一种旨在提高此类化合物杀灭肿瘤细胞的选择性的方法是使用毒性较低的前药形式，可以在肿瘤组织中选择性地激活(肿瘤激活的前药；TAP)。有几种可能被利用的机制可用于选择性激活TAP。有些利用肿瘤生理学的独特方面，如选择性酶表达或缺氧。其他的是基于肿瘤特异性递送技术，包括通过单抗(ADEPT)传递到肿瘤细胞的外源性酶激活前药物，或者通过包含相应基因的DNA构建体在肿瘤细胞中产生前药物(GDEPT)。无论使用哪种激活机制，只有一小部分肿瘤细胞可能有能力激活前药。因此，TAP需要充分利用这些“激活”细胞，通过“旁观者效应”杀死不能激活的细胞。人们已经探索了多种化学方法来选择性地激活TAP。给出了最重要的例子--内源性酶或辐射还原苯醌、N-氧化物和硝基芳香族化合物；内源性多肽酶裂解酰胺；以及各种外源性酶，包括磷酸酶、激动酶、酰胺酶和糖苷酶的水解性代谢。
Systemic cytotoxic (antiproliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumor cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumor tissue (tumor-activated prodrugs; TAP). There are several mechanisms potentially exploitable for the selective activation of TAP. Some utilize unique aspects of tumor physiology such as selective enzyme expression or hypoxia. Others are based on tumor-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumor cells via monoclonal antibodies (ADEPT) or generated in tumor cells from DNA constructs containing the corresponding gene (GDEPT). Whichever activating mechanism is used, only a small proportion of the tumor cells are likely to be competent to activate the prodrug. Therefore, TAP need to fully exploit these "activator" cells by being capable of killing activation-incompetent cells as well via a "bystander effect." A wide variety of chemistries have been explored for the selective activation of TAP. Examples are given of the most important-the reduction of quinones, N-oxides, and nitroaromatics by endogenous enzymes or radiation; the cleavage of amides by endogenous peptidases; and hydrolytic metabolism by a variety of exogenous enzymes, including phosphatases, kinases, amidases, and glycosidases.