PATHOLOGY OF CHEMICAL CARCINOGENISIS

化学介导的恶性转化的潜在机制是 有待探索。将使用的模型系统包括体内暴露 啮齿动物对硫代乙酰胺、乙硫氨酸、烷基亚硝胺和氨基偶氮的敏感性 染料。在体外，肝细胞培养物暴露于这些相同的介质将 也会被雇佣。此前的数据显示，对核限制的修改 暴露在致癌物下的肝细胞中的RNA物种，潜在地 代表启动或促进事件，或两者兼而有之。主要领域 要研究的内容包括：(1)对无细胞模型的分析 核糖核酸运输决定高能键的作用 作为一种驱动力，并分析选择 分泌和反向扩散到细胞核的RNA物种；(2) 两阶段模型的体内限制性分析 了解“核泄漏”是否与肝癌的发生有关 启动或促进；(3)体外系统的保真度 接受了调查。信使类(α1-糖蛋白)的特异性cDNAs探针 和AlphaMu球蛋白)将用于测量体内信使释放和 将这些数据与松节油和雄激素的体外释放进行比较 对雄性大鼠的刺激。此外，这些cdna探针将用于 分离体内和体外的信使以比较剪接， 加工，体内、体外释放后的聚腺苷酸化； 4)将尝试提纯和表征核基质和 核膜核糖核酸酶并确定其在运输中的作用。这个 这些也代表了由ATP驱动的核酸内切酶的可能性将是 测试过。这一点似乎与遗传基因的表观频率有关 与癌基因表达相关的信息重新定位。这些 实验将被用来检验恶性的假说 转化涉及转录和加工过程中的改变 RNA，至少作为癌症表型表达的基础。

The mechanisms underlying chemically-mediated malignant transformation are to be explored. Model systems to be used include in vivo exposure of rodents to thioacetamide, ethionine, alkylnitrosamines, and amino azo dyes. In vitro exposure of hepatocyte cultures to these same agents will also be employed. Previous data show a modification of nuclear restriction of RNA species in liver cells exposed to carcinogens, potentially representing an initiating or a promoting event, or both. The major areas to be investigated include: (1) an analysis of the cell-free model of nuclear RNA transport to determine the role of high-energy bond hydrolysis as a driving force, and to assay for the significance of both selection of RNA species for secretion and for back-diffusion to the nucleus; (2) an analysis of in vivo restriction in the two-stage model of hepatocarcinogenesis to learn whether "nuclear leakage" is related to initiation or to promotion; (3) the fidelity of the in vitro system will be surveyed. Specific cDNA probes for messenger species (Alpha1-glycoprotein and AlphaMu-globulin) will be used to measure messenger release in vivo and compare these data to in vitro release following turpentine and androgenic stimulation of male rats. Additionally, these cDNA probes will be used to isolate the messengers in vivo and in vitro to compare splicing, processing, and polyadenylation following the release in vivo and in vitro; 4) an attempt wil be made to purify and characterize the nuclear matrix and nuclear envelope NTase and to define their role in transport. The potential that these also represent an ATP driven endonuclease will be tested. This point seems relevant to the apparent frequency of genetic information relocation associated with oncogene expression. These experiments will be used to test the hypothesis that malignant transformation involves alterations in the transcription and processing of RNA, at least as a basis for the phenotypic expression of cancer.