Yuspa S H, Hennings H, Saffiotti U
J Invest Dermatol. 1976 Jul;67(1):199-208. doi: 10.1111/1523-1747.ep12513040.
Skin tumors chemically induced in mice have provided an important experimental model for studying carcinogenesis and for bioassaying carcinogenic agents. The information obtained from this model suggests that the events leading to tumor formation can be divided into at least two stages, initiation and promotion. A single small dose of carinogen produces initiation which appears to be irreversible. These initiating agents may have to be metabolically activated and can interact with cellular macromolecules. The extent to which they bind to DNA correlates well with their carcinogenicity. Increased DNA replication at the time of or during the first day after these agents have been applied appears to enhance carcinogenesis. Unlike initiation, promotion appears to be reversible and the promoting agents must be applied repeatedly before tumors are formed. Promoters interact with membranes, stimulate and alter genetic expression, and increase the rate of cell proliferation. The knowledge gained from these studies in mouse skin has immeasurably helped the entire field of chemical carcinogenesis. But efforts to determine the cellular and molecular mechanisms involved in the carcinogenic process, particularly in the skin, have been hampered by the difficulties of working on whole animals and by the special problems associated with the biologic and biochemical methods required for this target organ. Such problems, however, can be solved by the use of cell cultures of mouse epidermis which can metabolize and bind carcinogens just as is done in vivo. The fact that epidermal cells in vitro proliferate synchronously should facilitate the study of the relation between the cell cycle and carcinogenesis. These cells repair chemically induced DNA damage by at least two mechanisms, excision repair and base-specific repair. When epidermal cells in vitro are exposed to promoting agents, a proliferative response analogous to that in vivo is elicited, apparently mediated through control of polyamine metabolism. Neoplastic transformation has been induced in these cultures by known skin carcinogens.
在小鼠身上化学诱导产生的皮肤肿瘤为研究致癌作用和生物测定致癌剂提供了一个重要的实验模型。从这个模型中获得的信息表明，导致肿瘤形成的事件至少可分为两个阶段，即启动阶段和促进阶段。单次小剂量致癌物可引发启动阶段，这似乎是不可逆的。这些启动剂可能必须经过代谢激活，并能与细胞大分子相互作用。它们与DNA结合的程度与其致癌性密切相关。在应用这些试剂时或应用后的第一天内DNA复制增加似乎会增强致癌作用。与启动阶段不同，促进阶段似乎是可逆的，促进剂必须在肿瘤形成之前反复应用。促进剂与细胞膜相互作用，刺激并改变基因表达，并增加细胞增殖速率。从这些小鼠皮肤研究中获得的知识对化学致癌作用的整个领域起到了不可估量的帮助。但是，确定致癌过程，特别是皮肤致癌过程中涉及的细胞和分子机制的努力，一直受到在完整动物身上进行研究的困难以及与该靶器官所需的生物学和生化方法相关的特殊问题的阻碍。然而，通过使用小鼠表皮细胞培养物可以解决这些问题，这种培养物能够像在体内一样代谢和结合致癌物。体外表皮细胞同步增殖这一事实应有助于研究细胞周期与致癌作用之间的关系。这些细胞通过至少两种机制修复化学诱导的DNA损伤，即切除修复和碱基特异性修复。当体外表皮细胞暴露于促进剂时，会引发类似于体内的增殖反应，显然是通过多胺代谢的控制介导的。已知的皮肤致癌物已在这些培养物中诱导了肿瘤转化。
