Garte S J
New York University Medical Center, Institute of Environmental Medicine, New York 10016.
J Theor Biol. 1987 Nov 21;129(2):177-88. doi: 10.1016/s0022-5193(87)80011-5.
Evidence from experimental animal tumor models suggests that in many instances, the identity and mechanism of activation of cellular oncogenes is a function of both carcinogen and tissue specificity. In addition, the activation of no single oncogene has yet been found to be either sufficient or necessary for tumorigenesis in any particular experimental system. A hypothesis to account for these and other molecular and biological observations of experimental tumorigenesis has been developed. The hypothesis is based on the premise that multiple tissue specific groups or pathways of oncogenes exist in each cell, and that activation of all the oncogenes in any of these alternative pathways leads to transformation. It is assumed that each oncogene (which may be a member of one or more pathways) has a spontaneous and a carcinogen specific probability of activation. The latter value will vary from carcinogen to carcinogen. By modelling the spontaneous and carcinogen specific probabilities of activation of each gene, the number and identity of genes in each pathway, and the number of pathways in a particular cell type, it is possible to calculate the relative potency of carcinogens, the percentage of tumors containing each activated oncogene, the dose-response relationship, and other parameters. Use of this hypothetical model gives results consistent with experimental observations on oncogene activation in carcinogen-induced animal tumors.
来自实验动物肿瘤模型的证据表明，在许多情况下，细胞癌基因的身份和激活机制是致癌物和组织特异性共同作用的结果。此外，在任何特定的实验系统中，尚未发现单一癌基因的激活对于肿瘤发生是充分的或必要的。针对实验性肿瘤发生的这些以及其他分子和生物学观察结果，已经提出了一个假说。该假说基于这样一个前提：每个细胞中存在多个组织特异性的癌基因群或癌基因激活途径，并且这些替代途径中任何一个途径内所有癌基因的激活都会导致细胞转化。假定每个癌基因（可能是一个或多个途径的成员）具有自发激活概率和致癌物特异性激活概率。后者的值会因致癌物的不同而有所变化。通过对每个基因的自发激活概率和致癌物特异性激活概率、每个途径中基因的数量和身份以及特定细胞类型中途径的数量进行建模，可以计算致癌物的相对效力、含有每个激活癌基因的肿瘤百分比、剂量反应关系以及其他参数。使用这个假设模型得出的结果与致癌物诱导的动物肿瘤中癌基因激活的实验观察结果一致。
