Kelloff G J, Boone C W, Steele V E, Fay J R, Lubet R A, Crowell J A, Sigman C C
Chemoprevention Branch, Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI), Bethesda, MD 20892, USA.
J Cell Biochem Suppl. 1994;20:1-24. doi: 10.1002/jcb.240560903.
This overview of the potential mechanisms of chemopreventive activity will provide the conceptual groundwork for chemopreventive drug discovery, leading to structure-activity and mechanistic studies that identify and evaluate new agents. Possible mechanisms of chemopreventive activity with examples of promising agents include carcinogen blocking activities such as inhibition of carcinogen uptake (calcium), inhibition of formation or activation of carcinogen (arylalkyl isothiocyanates, DHEA, NSAIDs, polyphenols), deactivation or detoxification of carcinogen (oltipraz, other GSH-enhancing agents), preventing carcinogen binding to DNA (oltipraz, polyphenols), and enhancing the level or fidelity of DNA repair (NAC, protease inhibitors). Chemopreventive antioxidant activities include scavenging reactive electrophiles (GSH-enhancing agents), scavenging oxygen radicals (polyphenols, vitamin E), and inhibiting arachidonic acid metabolism (glycyrrhetinic acid, NAC, NSAIDs, polyphenols, tamoxifen). Antiproliferation/antiprogression activities include modulation of signal transduction (glycyrrhetinic acid, NSAIDs, polyphenols, retinoids, tamoxifen), modulation of hormonal and growth factor activity (NSAIDs, retinoids, tamoxifen), inhibition of aberrant oncogene activity (genistein, NSAIDs, monoterpenes), inhibition of polyamine metabolism (DFMO, retinoids, tamoxifen), induction of terminal differentiation (calcium, retinoids, vitamin D3), restoration of immune response (NSAIDs, selenium, vitamin E), enhancing intercellular communication (carotenoids, retinoids), restoration of tumor suppressor function, induction of programmed cell death (apoptosis) (butyric acid, genistein, retinoids, tamoxifen), correction of DNA methylation imbalances (folic acid), inhibition of angiogenesis (genistein, retinoids, tamoxifen), inhibition of basement membrane degradation (protease inhibitors), and activation of antimetastasis genes. A systematic drug development program for chemopreventive agents is only possible with continuing research into mechanisms of action and thoughtful application of the mechanisms to new drug design and discovery. One approach is to construct pharmacological activity profiles for promising agents. These profiles are compared among the promising agents and with untested compounds to identify similarities. Classical structure-activity studies are used to find optimal agents (high efficacy with low toxicity) based on good lead agents. Studies evaluating tissue-specific and pharmacokinetic parameters are very important. A final approach is design of mechanism-based assays and identification of mechanism-based intermediate biomarkers for evaluation of chemopreventive efficacy.
对化学预防活性潜在机制的概述将为化学预防药物的发现提供概念基础，从而开展结构活性和机制研究，以识别和评估新的药物。化学预防活性的可能机制及有前景药物的实例包括致癌物阻断活性，如抑制致癌物摄取（钙）、抑制致癌物的形成或活化（芳基烷基异硫氰酸盐、脱氢表雄酮、非甾体抗炎药、多酚）、致癌物的失活或解毒（奥替普拉、其他增强谷胱甘肽的药物）、防止致癌物与DNA结合（奥替普拉、多酚）以及提高DNA修复水平或保真度（N-乙酰半胱氨酸、蛋白酶抑制剂）。化学预防抗氧化活性包括清除活性亲电试剂（增强谷胱甘肽的药物）、清除氧自由基（多酚、维生素E）以及抑制花生四烯酸代谢（甘草次酸、N-乙酰半胱氨酸、非甾体抗炎药、多酚、他莫昔芬）。抗增殖/抗进展活性包括调节信号转导（甘草次酸、非甾体抗炎药、多酚、类视黄醇、他莫昔芬）、调节激素和生长因子活性（非甾体抗炎药、类视黄醇、他莫昔芬）、抑制异常癌基因活性（染料木黄酮、非甾体抗炎药、单萜类化合物）、抑制多胺代谢（二氟甲基鸟氨酸、类视黄醇、他莫昔芬）、诱导终末分化（钙、类视黄醇、维生素D3）、恢复免疫反应（非甾体抗炎药、硒、维生素E）、增强细胞间通讯（类胡萝卜素、类视黄醇）、恢复肿瘤抑制功能、诱导程序性细胞死亡（凋亡）（丁酸、染料木黄酮、类视黄醇、他莫昔芬）、纠正DNA甲基化失衡（叶酸）、抑制血管生成（染料木黄酮、类视黄醇、他莫昔芬）、抑制基底膜降解（蛋白酶抑制剂）以及激活抗转移基因。只有持续深入研究作用机制并将这些机制巧妙应用于新药设计和发现，才有可能制定出系统的化学预防药物研发计划。一种方法是构建有前景药物的药理活性图谱。在这些有前景的药物之间以及与未测试的化合物进行比较，以识别相似性。经典的结构活性研究用于基于优良的先导药物找到最佳药物（高效低毒）。评估组织特异性和药代动力学参数的研究非常重要。最后一种方法是设计基于机制的测定方法，并识别基于机制的中间生物标志物，以评估化学预防效果。
