ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物都会导致DNA损伤，并在 特定的遗传位点；然而，某些致癌物质(包括 人类致癌物质己烯雌酚、石棉、砷化合物和 苯)通常不会导致基因突变。我们已经检查了 这些化学物质诱导形态变化的活性 叙利亚人的转化、基因突变和染色体突变 仓鼠胚胎细胞在培养中。我们之前已经报道过， 己烯雌酚(DES)在缺氧条件下诱导转化 特定遗传位点的突变。此外，我们还提出了 DES的作用机制与其能力有关 诱发染色体数目的变化，即非整倍体。得克萨斯有 Colcemid样活动并破坏微管组织。 目前，正在新生儿中检测DES诱导的非整倍体。 以测试小鼠生殖道是否在体内发生这些变化 目标组织。另一个重要人类的机制 致癌物质石棉也进行了检测。石棉的能力 和其他矿物质纤维诱导细胞转化依赖于 纤维尺寸与体内间皮瘤的结果相似 归纳法。我们已经提出了石棉诱导细胞 由于它有能力引起染色体的变化而导致的转化。 我们研究了原癌基因激活在人类中的作用。 间皮瘤，与石棉接触有关。DNA 从几个间皮瘤中检出转化活性呈阳性 在NIH/3T3裸鼠致瘤性实验中。转型 基因似乎不是ras基因家族的成员，而我们是 目前正在克隆这些基因。军火库是有效的诱导剂 对细胞转化的影响。亚砷酸钠和亚砷酸钠分别是 作为基因诱变剂没有活性，但却是有效的染色体诱导剂 基因突变和基因扩增。苯诱导细胞 转化却是一种弱基因诱变剂。这种化学物质是一种非常 该系统中非整倍体的有效诱导者。这些结果 进一步支持我们的假设，即细胞转化涉及 一种染色体突变，并暗示了它在 致癌物诱导的非整倍体在癌变中的作用。

Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol, asbestos, arsenicals and benzene) usually do not induce gene mutations. We have examined the activity of these chemicals to induce morphological transformation, gene mutations and chromosome mutations in Syrian hamster embryo cells in culture. We have reported previously that diethylstilbestrol (DES) induces transformation in the absence of mutations at specific genetic loci. Furthermore, we have proposed that the mechanism of action of DES is related to its ability to induce numerical chromosome changes, i.e., aneuploidy. DES has colcemid-like activity and disrupts microtubule organization. Currently, DES-induced aneuploidy is being examined in the newborn mouse genital tract to test whether these changes occur in vivo in the target tissue. The mechanism of another important human carcinogen, asbestos, was also examined. The ability of asbestos and other mineral fibers to induce cell transformation depends on fiber dimension similar to the results in vivo for mesothelioma induction. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes. We have examined the role of proto-oncogene activation in human mesotheliomas, which are associated with asbestos exposure. DNAs from several mesotheliomas were positive for transforming activity in the NIH/3T3 nude mouse tumorigenicity assay. The transforming genes do not appear to be members of the ras gene family and we are currently cloning these genes. Arsenicals are effective inducers of cell transformation. Sodium arsenite and sodium arsenate are inactive as gene mutagens but are potent inducers of chromosome aberrations and also gene amplification. Benzene induces cell transformation but is a weak gene mutagen. This chemical is a very effective inducer of aneuploidy in this system. These results further support our hypothesis that cell transformation involves a chromosomal mutation and suggest an important role for carcinogen-induced aneuploidy in carcinogenesis.