Kelloff G J, Boone C W, Steele V E, Crowell J A, Lubet R A, Greenwald P, Hawk E T, Fay J R, Sigman C C
Chemoprevention Branch, National Cancer Institute, Bethesda, MD, USA.
IARC Sci Publ. 1996(139):203-19.
Possible chemopreventive mechanisms include carcinogen-blocking activities, antioxidant/anti-inflammatory activities and antiproliferation/antiprogression activities. Carcinogen-blocking activities encompass inhibition of carcinogen uptake, inhibition of carcinogen formation or activation, deactivation or detoxification of carcinogens, prevention of carcinogen binding to DNA, and enhancement of the level or fidelity of DNA repair. Antioxidant/anti-inflammatory activities include scavenging of reactive electrophiles and oxygen radicals, and inhibition of arachidonic acid metabolism. Antiproliferation/antiprogression activities comprise modulation of signal transduction, modulation of hormonal and growth factor activity, inhibition of aberrant oncogene activity, inhibition of polyamine metabolism, induction of terminal differentiation, restoration of immune responses, enhancement of intercellular communication, restoration of tumour suppressor function, induction of apoptosis, telomerase inhibition, correction of DNA methylation imbalances, inhibition of angiogenesis, inhibition of basement membrane degradation, and activation of antimetastasis genes. In evaluating the potential efficacy of chemopreventive agents several mechanistic parameters are weighed: (1) the number of chemoprevention-related pharmacological activities, (2) the impact of the agent on likely carcinogenesis pathways to the targeted cancer, (3) pharmacodynamics, and (4) specificity for chemopreventive activity compared with interference with normal cellular function. Mechanistic data are important throughout the development process for chemopreventive drugs, and they are particularly important in the earlier phases of identifying promising candidate agents and characterizing efficacy. In vitro mechanistic assays are a first step in evaluating chemopreventive potential. Mechanistic considerations are also useful in defining animal efficacy models and in interpreting the results of assays in these models. Mechanistic data are also applied in designing short-term Phase II clinical chemoprevention trials that use reductions in intermediate biomarkers of cancer rather than cancer incidence as end points. The basis for identifying and evaluating these biomarkers is in understanding carcinogenesis and chemopreventive mechanisms.
可能的化学预防机制包括致癌物阻断活性、抗氧化/抗炎活性和抗增殖/抗进展活性。致癌物阻断活性包括抑制致癌物摄取、抑制致癌物形成或活化、使致癌物失活或解毒、防止致癌物与DNA结合以及提高DNA修复水平或保真度。抗氧化/抗炎活性包括清除活性亲电试剂和氧自由基以及抑制花生四烯酸代谢。抗增殖/抗进展活性包括调节信号转导、调节激素和生长因子活性、抑制异常癌基因活性、抑制多胺代谢、诱导终末分化、恢复免疫反应、增强细胞间通讯、恢复肿瘤抑制功能、诱导细胞凋亡、抑制端粒酶、纠正DNA甲基化失衡、抑制血管生成、抑制基底膜降解以及激活抗转移基因。在评估化学预防剂的潜在疗效时，会权衡几个机制参数：（1）与化学预防相关的药理活性数量；（2）该试剂对靶向癌症可能的致癌途径的影响；（3）药效学；（4）与干扰正常细胞功能相比，化学预防活性的特异性。机制数据在化学预防药物的整个开发过程中都很重要，在识别有前景的候选药物和表征疗效的早期阶段尤其重要。体外机制测定是评估化学预防潜力的第一步。机制考量在定义动物疗效模型和解释这些模型中的测定结果时也很有用。机制数据还应用于设计短期II期临床化学预防试验，这些试验以癌症中间生物标志物的降低而非癌症发病率作为终点。识别和评估这些生物标志物的基础在于理解致癌作用和化学预防机制。
