MECHANISM(S) OF TUMOR PROGRESSION AND METASTASIS

肿瘤进展和转移的机制

• 批准号: 3179223
• 负责人: PHILIP FROST
• 金额: $ 11.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-08-01 至 1989-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3179223
• 关键词: DNA methylation; azacitidine; carcinogenesis; clone cells; disease /disorder model; drug resistance; host neoplasm interaction; immunogenetics; isozymes; molecular genetics; mouse leukemia; mutant; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplasm /cancer transplantation; neoplastic growth; radiotracer; suppressor T lymphocyte; tissue /cell culture; tumor antigens; tumor promoters

The primary goal of this proposal is to define (at least in part) the mechanism(s) of tumor progression. To achieve this, we plan to further analyse the role of DNA hypomethylation in the progression of tumors from the benign to the malignant state. Because it is possible that hypomethylation in itself may be insufficient to achieve this transition (i.e., secondary agents likely play a role), the central focus of this proposal is to study the role of genomic destabilization in tumor progression. We believe that agents such as 5-aza-d-Cyd and DFMO, which respectively cause DNA hypomethylation and polyamine depletion, can broadly destabilize DNA and result in augmented genomic injury induced by secondary agents. The agents which we have chosen to provide 'secondary' injury are MNNG (a monofunctional alkylating agent) and m-AMSA, an intercalating agent. The key factor in these studies is that the effects of each of these agents, 5-aza-d-Cyd, DFMO, MNNG and m-AMSA, can be quantitated biochemically. In addition, we have chosen to study tumor cell lines with known characteristics so that specific phenotypic changes induced by each agent alone or in defined combinations can be readily assessed. Four phenotypic characteristics will be analyzed including the generation of drug resistant mutants, metastatic variants, immunogenic variants, and changes in isozymes. Chromosomal rearrangements will also be assessed. These protocols will therefore allow for a systematic analysis (using the parameters outlined) of the role of genomic instability in the generation of phenotypic diversity. A secondary goal of these studies is to address the role of DNA hypomethylation in carcinogenesis. Both an in vivo and in vitro model for potential murine lymphoma/leukemia generation are outlined.

本提案的主要目标是（至少部分）定义 肿瘤进展的机制。 为了实现这一目标，我们计划 进一步分析DNA低甲基化在 肿瘤从良性发展到恶性。 因为低甲基化本身可能是 不足以实现这种转变（即，二级代理可能 发挥作用），本建议的中心重点是研究 基因组不稳定性在肿瘤进展中的作用。 我们认为 例如5-aza-d-Cyd和DFMO的试剂，其分别引起 DNA低甲基化和多胺缺失，可以广泛地 使DNA不稳定并导致诱导的增强的基因组损伤 二级代理人。 我们选择提供的代理商 “继发性”损伤是MNNG（单官能烷化剂） 和嵌入剂m-AMSA。 其中的关键因素 研究表明，这些试剂中的每一种，5-aza-d-Cyd， DFMO、MNNG和m-AMSA可生化定量。 此外，我们还选择了研究已知的肿瘤细胞系， 特征，从而使特定的表型变化诱导 单独的或以限定的组合形式的每种试剂可以容易地 评估。 将分析四个表型特征 包括产生耐药突变体、转移性 变体、免疫原性变体和同工酶的变化。 还将评估染色体重排。 这些 因此，协议将允许系统分析（使用 参数概述）的作用，基因组的不稳定性， 表型多样性的产生。 这些研究的第二个目标是解决DNA的作用， 低甲基化在癌发生中的作用。 体内和体外 潜在的鼠淋巴瘤/白血病生成模型是 概述。