GENOTOXICITY OF DNA-DIRECTED ANTINEOPLASTIC AGENTS

DNA 定向抗肿瘤药物的基因毒性

• 批准号: 3180854
• 负责人: Lawrence F Povirk
• 金额: $ 8.75万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3180854
• 关键词: bacteriophage lambda; bleomycin; chemical carcinogenesis; cytotoxicity; genetic manipulation; molecular oncology; mutagen testing; neocarzinostatin; nitrogen mustard; radiotracer; transfer RNA

Many of the drugs used in the treatment of human cancers are DNA-damaging agents, and most such drugs possess mutagenic activity. It is likely that this mutagenic potential contributes to some of the adverse effects of chemotherapy, such as the onset of drug resistance and the development of second cancers in long-term survivors. The objective of the research proposed here is an understanding of the molecular mechanisms of mutagenesis by certain chemotherapeutic agents, with particular attention to identification of the important mutagenic lesions. Such an understanding would be useful in the development and selection of potentially less mutagenic and carcinogenic agents. Studies will at first center on neocarzinostatin and bleomycin, agents for which the nature of DNA damage and its sequence specificity have been well characterized. A bacterial system based on the cI gene of bacteriophage lambda will be used to test the working hypothesis that, for both these agents, modified apyrimidinic sites containing oxidized sugar moieties are important mutagenic lesions. Specific aproaches will include (1) comparison of the sequence specificity of mutagenesis with that of apyrimidinic site formation, (ii) manipulation of the occurence of apyrimidinic sites by treatment of intact lambda phage or lambda DNA under controlled conditions and (iii) examination of the effects of DNA repair defects on mutagenesis. Some initials attempts will also be made to examine mutagenesis by other chemotherapeutic agents. In particular, the nitrogen mustards are mutagenic bifunctional alkylating agents suspected of causing a high incidence of second cancers. Provided that a sufficiently strong mutagenic response can be obtained in the lambda cI gene, the spectrum of forward mutations induced will be determined, as a first step in elucidation the molecular mechanisms of mutagenesis by these agents, about which little is presently known. If the cI system is not sufficiently sensitive, an alternative system, based on a suppressor tRNA gene inserted in a bacterial plasmid, will be developed. If the tRNA gene proves to be a workable mutagenesis probe, the possibility of adapting it to studies in mammalian cells will be explored, beginning with examination of its stability in a mammalian viral vector.

许多用于治疗人类癌症的药物都是破坏dna的