Chemically induced cell proliferation in carcinogenesis.
Chemically induced cell proliferation in carcinogenesis.
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致癌过程中化学诱导的细胞增殖。
DOI：
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发表时间：
1992
期刊：
影响因子：
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通讯作者：
T. Goldsworthy
中科院分区：
文献类型：
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作者：
B. E. Butterworth;J. Popp;R. Conolly;T. Goldsworthy
癌变可以通过多种途径进行，包括正常细胞生长控制基因的顺序突变和所产生的癌前或癌细胞的克隆扩增。化学致癌物可能通过诱导突变和/或改变细胞生长控制来起作用。一类化学致癌物是遗传毒物。这些化合物或其代谢物是DNA反应性的，并直接诱导突变或致染色体断裂变化。大多数诱变剂也具有致癌性的观察结果是目前许多预测分析和风险评估模型的基础;然而，有不同类别的非遗传毒性致癌物不与DNA相互作用。有丝分裂原直接诱导靶组织中的细胞增殖;细胞毒素产生细胞死亡，随后是再生细胞增殖。由有丝分裂原和细胞毒素诱导的不同毒性和/或生长刺激可以为自发或化学诱导的癌前或癌细胞提供优先生长优势。诱变剂是更有效的致癌物，其剂量也诱导细胞增殖，并且突变活性可能作为继发于细胞增殖的事件发生。因此，化学诱导的细胞增殖是遗传毒性和非遗传毒性致癌物的重要机制考虑。许多实验室正在研究化学诱导的细胞增殖和致癌活性之间复杂的定量关系。在确定癌症生物测定的剂量、对化学致癌物进行分类和提供更切合实际的风险评估方法时，应考虑到这些资料。在将啮齿动物模型的癌症风险外推至人类时，特别值得关注的是那些仅在靶器官中产生细胞致死性和再生细胞增殖的剂量下才表现出致癌活性的非遗传毒性物质。
Carcinogenesis can proceed by a variety of pathways involving the sequential mutation of normal cellular growth control genes and the clonal expansion of the resulting precancerous or cancerous cells. Chemical carcinogens may act by inducing mutations and/or altering cellular growth control. One class of chemical carcinogens are the genotoxicants. These compounds or their metabolites are DNA reactive and directly induce mutations or clastogenic changes. The observation that most mutagens are also carcinogenic is the basis for many current predictive assays and risk assessment models; however, there are different classes of nongenotoxic carcinogens that do not interact with DNA. Mitogens directly induce cell proliferation in the target tissue; cytotoxicants produce cell death followed by regenerative cell proliferation. Differential toxicity and/or growth stimulation induced by mitogens and cytotoxicants may provide a preferential growth advantage to spontaneous or chemically induced precancerous or cancerous cells. Mutagens are much more effective carcinogens at doses that also induce cell proliferation, and mutational activity may occur as an event secondary to cell proliferation. Thus, chemically induced cell proliferation is an important mechanistic consideration for both genotoxic and nongenotoxic carcinogens. The complex quantitative relationships between chemically induced cell proliferation and carcinogenic activity are under study in many laboratories. Such information should be considered in setting doses for cancer bioassays, for classifying chemical carcinogens and in providing more realistic approaches to risk assessment. Of particular concern in extrapolating cancer risk from rodent models to humans are those nongenotoxic agents that exhibit carcinogenic activity only at doses that also produce cytolethality and regenerative cell proliferation in the target organ.