SENSITIVITY FACTORS IN SPECIAL CARCINOGENESIS MODELS

特殊致癌模型中的敏感性因素

• 批准号: 6289097
• 负责人: Lucy M Anderson
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/6289097
• 关键词: DNA damage; DNA repair; Macaca fascicularis; alleles; cancer risk; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; dioxins; environment related neoplasm /cancer; gene induction /repression; genetic polymorphism; genetic strain; halobiphenyl /halotriphenyl compound; laboratory mouse; lung neoplasms; nasopharyngeal neoplasms; neoplasm /cancer genetics; nitrosamines; nutrition related neoplasm /cancer; receptor sensitivity; tumor promoters

Cancer is often the outcome of interaction between external exposures or lifestyle factors, and genetic susceptibilities. These processes can be studied through epidemiology, and through modeling in animals. Nasopharyngeal cancer is common only in certain geographically-delimited populations, with lifestyle factors, especially diet, implicated in causation, and genetics and infections as secondary factors. Causative chemicals in the diet may include N-nitrosamines, especially N- nitrosodimethylamine, which is activated in cells by cytochrome P450 2E1 (CYP2E1). We have found a striking correlation between incidence of nasopharyngeal cancer in Chinese and an allelic form of the CYP2E1 gene, c2c2, that may be highly expressed. However, this association was limited to nonsmokers. Among smokers, incidence of the disease was less, and was positively associated with the other allelic form of CYP2E1, c1c1. Thus a complex interplay of several exposure factors with genetic constitution determined cancer outcome. To begin to understand the role of the CYP2E1 gene in more detail, we have examined part of the structure of this gene in two species of monkey, patas and cynomolgus. The polymorphic promoter region of the gene in the patas monkeys is very similar to that of the c2c2 humans, whereas that of the cynomolgus monkeys, while still highly homologous, is much longer and has a different base sequence in the diagnostic RFLP site. The patas and human both have evolved on the savannah of Africa, whereas the cynomolgus is an arboreal species. The patas monkey has potential as a model for the susceptible c2c2 humans. We have used modeling in mice to begin to approach the question of promotion of lung tumors, suspected to occur during the long latency of human lung cancers, and a possible target for intervention strategies. Since the K-ras gene is often mutated in both murine and human lung adenocarcinomas, we have started to examine the levels and cell membrane localization of K-ras p21 in mouse lung as a function of genetics and of exposure to the tumor promoters, 2,3,7,8,-tetrachloro-dibenzo-p- dioxin (TCDD) and polychlorinated biphenyls. We discovered, for the first time, marked differences among various genetic mouse strains. Whereas the total K-ras p21 was similar in all strains, amounts in membrane were significantly greater in C57BL/6 and BALB/c mice, compared with other strains. Treatment with TCDD caused a significant increase in the p21 in lung cell membranes in some but not all mouse strains. The relevance of these changes in genetic susceptibility to tumor promotion is under study.

癌症通常是外部暴露之间相互作用的结果 或生活方式因素和遗传敏感性。这些过程可以 通过流行病学研究，并通过动物进行建模。 鼻咽癌仅在某些地理位置上很常见 人口，具有生活方式因素，尤其是饮食的人群 因果关系以及遗传学和感染作为次要因素。因果关系 饮食中的化学物质可能包括N-亚硝胺，尤其是N- 硝基二甲胺，它在细胞中被细胞色素P450 2E1激活 （CYP2E1）。我们发现发生率 鼻咽癌中文和CYP2E1基因的等位基因形式， C2C2，这可能是高度表达的。但是，这个关联是 仅限于非吸烟者。在吸烟者中，疾病的发病率较小， 并且与CYP2E1的其他等位基因形式成正相关， C1C1。因此，几种暴露因子与遗传的复杂相互作用 宪法确定了癌症的结果。 为了开始更详细地了解CYP2E1基因的作用，我们 已经检查了该基因的部分结构 猴子，Patas和Cynomolgus。多态性启动子区域 patas猴子中的基因与C2C2人类非常相似， 而cynomolgus猴子的虽然仍然高度同源 更长的时间，在诊断RFLP中具有不同的基础序列 地点。 Patas和人都在非洲的大草原上演变 而cernomolgus是树木杂志。 Patas猴子有 作为易感C2C2人类的模型的潜力。 我们已经在小鼠中使用了建模来开始处理 促进肺部肿瘤，涉嫌在长长的潜伏期中发生 人类肺癌，也是干预策略的可能目标。 由于k-ras基因在鼠和人肺中经常被突变 腺癌，我们已经开始检查水平和细胞膜 K-Ras P21在小鼠肺中的定位是遗传学和 暴露于肿瘤启动子，2,3,7,8，-tetrachloro-dibenzo-p- 二恶英（TCDD）和多氯联苯。我们发现了 第一次，各种遗传小鼠菌株之间的差异很大。 总体K-RAS P21在所有应变中相似，但 比较C57BL/6和BALB/C小鼠的膜明显更大 与其他菌株。用TCDD治疗导致显着增加 在某些但不是全部小鼠菌株中的肺细胞膜中的p21中。这 这些变化在遗传易感性对肿瘤促进性方面的相关性 正在研究。