Yamasaki H, Mesnil M, Nakazawa H
Unit of Multistage Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Toxicol Lett. 1992 Dec;64-65 Spec No:597-604. doi: 10.1016/0378-4274(92)90237-e.
Multistage carcinogenesis involves genotoxic as well as non-genotoxic mechanisms. The importance of genotoxic events in human carcinogenesis is apparent from the analysis of tumours: for example, five to six genetic alterations can be found in most malignant colorectal tumours. While such measurable "footprints" (e.g. ras, p53 mutations) can be left in tumours by genotoxic events, non-genotoxic events cannot directly generate them. Thus, the lack of specific indicators of non-genotoxic events in carcinogenesis makes the identification of non-genotoxic carcinogens difficult. It is also important to emphasize that apparent "genotoxic" endpoints (mutations, chromosome aberrations) could be induced by "non-genotoxic" agents through indirect mechanisms (e.g. induced cell proliferation and/or genomic instability, oxidative damage, deamination of 5-methyl cytosine). This emphasizes the need for differentiating "events" from the actual "activities" of chemicals and the difficulty of classification of carcinogens into genotoxic and non-genotoxic. One of the best models for the study of interaction of genotoxic and non-genotoxic mechanisms during carcinogenesis is a two-stage carcinogenesis system using mouse skin, rat liver or cultured cells. Molecular analysis of tumours produced on mouse skin by the classical initiation-promotion protocol indicates that the mutation spectra of oncogenes, e.g. Ha-ras, are determined by initiating (genotoxic) and not by promoting (non-genotoxic) agents. However, since usually no tumours appear without the application of tumour-promoting agents, the manifestation of genotoxic events (Ha-ras mutation) is dependent on the action of non-genotoxic agents. Using a BALB c 3T3 two-stage cell transformation system, we have now succeeded in confirming this and have quantitated the initiation and promotion events. These studies may help us not only in understanding mechanisms of carcinogenesis but also in developing molecular quantitative risk assessment in terms of multistage carcinogenesis.
多阶段致癌作用涉及遗传毒性以及非遗传毒性机制。从肿瘤分析中可以明显看出遗传毒性事件在人类致癌作用中的重要性：例如，在大多数恶性结直肠癌肿瘤中可发现五到六种基因改变。虽然遗传毒性事件可在肿瘤中留下此类可测量的“印记”（如ras、p53突变），但非遗传毒性事件无法直接产生这些印记。因此，致癌作用中缺乏非遗传毒性事件的特异性指标使得鉴定非遗传毒性致癌物变得困难。同样重要的是要强调，明显的“遗传毒性”终点（突变、染色体畸变）可能由“非遗传毒性”剂通过间接机制（如诱导细胞增殖和/或基因组不稳定、氧化损伤、5-甲基胞嘧啶脱氨基）诱导产生。这强调了区分化学物质的“事件”与实际“活性”的必要性，以及将致癌物分为遗传毒性和非遗传毒性的困难。研究致癌过程中遗传毒性和非遗传毒性机制相互作用的最佳模型之一是使用小鼠皮肤、大鼠肝脏或培养细胞的两阶段致癌系统。通过经典启动-促进方案在小鼠皮肤上产生的肿瘤的分子分析表明，癌基因（如Ha-ras）的突变谱由启动（遗传毒性）剂而非促进（非遗传毒性）剂决定。然而，由于通常不应用肿瘤促进剂就不会出现肿瘤，遗传毒性事件（Ha-ras突变）的表现依赖于非遗传毒性剂的作用。使用BALB c 3T3两阶段细胞转化系统，我们现在已成功证实了这一点，并对启动和促进事件进行了定量。这些研究不仅可能有助于我们理解致癌机制，还可能有助于在多阶段致癌作用方面开展分子定量风险评估。
