ROLE OF MUTAGENESIS IN CARCINOGENESIS

诱变在致癌过程中的作用

• 批准号: 3965229
• 负责人: J C BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3965229
• 关键词: DNA repair; aneuploidy; arsenic; asbestos; benzene; carcinogen testing; cellular oncology; chemical carcinogen; chemical carcinogenesis; chromosome aberrations; diethylstilbestrol; dosage; embryo /fetus tissue /cell culture; environment related neoplasm /cancer; epithelium; gene mutation; molecular oncology; mutagens; mutant; neoplasm /cancer genetics; preneoplastic state; tissue /cell culture; toxicant interaction; trachea neoplasm; tumor promoters

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, proposed as carcinogenic but not mutagenic, 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. We have now shown that DES has colcemid-like activity in that it disrupts microtubule organization. Inhibition of polymerization of spindle microtubules is therefore a possible mechanism for DES-induced aneuploidy and possibly cell transformation according to our hypothesis. This hypothesis is further supported by our observations that colcemid and vincristine sulfate, two well-known inducers of aneuploidy, are also inducers of morphological transformation. The mechanism of another important human carcinogen, asbestos, was also examined. The ability of asbestos and other mineral fibers to induce cell transformation was observed to depend on fiber dimension similar to the results found in vivo in studies on mesothelioma induction. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes in the treated cells. We recently found that asbestos fibers induce anaphase abnormalities indicating that a direct physical interaction of the fibers with chromosomes occurs during mitosis. In the asbestos-induced cell lines a nonrandom chromosome change, trisomy of chromosome 11, was found. These results further support our hypothesis that the mechanism of asbestos-induced transformation is due to a chromosomal mutation. Thus, our results suggest an important role for carcinogen-induced aneuploidy in carcinogenesis.

大多数化学致癌物会诱导DNA损伤，并且在特定的 遗传基因座；但是，某些致癌物（包括人类致癌物 二乙基的贝特罗，石棉，砷和苯）通常不会诱导 基因突变。 我们研究了这些化学物质的活性，提出 作为致癌而不是诱变，以诱导形态转化， 叙利亚仓鼠胚胎细胞中的基因突变和染色体突变 文化。 我们先前报道了二乙基stilbestrol（des）诱导 在没有特定遗传基因座突变的情况下转变。 此外，我们建议DES的作用机理是 与诱导数字染色体变化的能力有关，即 非整倍性。 现在，我们已经表明DES具有类似colcemid的活性 它破坏了微管组织。 抑制聚合 因此，纺锤微管是DES诱导的可能机制 根据我们的假设，非整倍性和可能的​​细胞转化。 我们的观察结果进一步支持了这一假设 硫酸盐硫酸盐，两个众所周知的非整倍性诱导剂，也是 形态转化的诱导者。 另一个机制 还检查了重要的人类致癌石棉。 能力 石棉和其他以诱导细胞转化的矿物纤维是 观察到依赖于纤维尺寸，类似于体内发现的结果 在间皮瘤诱导的研究中。 我们提出了石棉 由于其能够诱导染色体的能力，诱导细胞转化 处理的细胞的变化。 我们最近发现石棉纤维 诱导后期异常，表明直接物理互动 有丝分裂期间发生染色体的纤维。 在 石棉诱导的细胞系非随机染色体变化，三体 发现11号染色体。 这些结果进一步支持我们的假设 石棉引起的转化的机制是由于 染色体突变。 因此，我们的结果表明了重要的作用 致癌物诱导的癌变中的非整倍性。