GENETOXICITY STUDIES OF CHEMOPREDVENTIVE AGENTS - TASK A

美国国家癌症研究所癌症预防部化学预防剂开发研究小组指导了一项研究性化学预防剂开发计划，以确定和开发预防，延迟或逆转致癌过程的药物。 为了评估研究性新药的安全性，必须对其毒理学潜力进行评价。 毒性筛选包括遗传毒性研究，包括体外和体内试验，以检测直接或间接诱导遗传损伤的化合物。 根据FDA的规定，目前公认的遗传毒性试验组合包括细菌基因突变试验、哺乳动物细胞染色体损伤试验和使用啮齿动物骨髓造血细胞评价的体内染色体损伤试验。 通过沙门氏菌组氨酸回复突变（艾姆斯）试验（包括大肠杆菌色氨酸回复突变试验）、中国仓鼠卵巢（CHO）细胞体外染色体畸变试验和小鼠骨髓微核试验可满足这些要求。 该研究的化合物选择将从快速获得预防干预开发（RAPID）计划中进行。 这些研究应符合支持NDA申请的毒理学研究的现行行业标准，并应根据FDA药物非临床研究质量管理规范（GLP）法规在AAALAC认证的、NIH/OPRR和USDA注册的实验室（具有活跃的机构动物护理和使用委员会（IACUC））中进行。

The National Cancer Institute, Division of Cancer Prevention, Chemopreventive Agent Development Research Group directs an investigational chemopreventive agent development program to identify and develop drugs that will prevent, delay, or reverse the process of carcinogenesis. In order to assess safety of investigational new agents, they must be evaluated for their toxicological potential. Toxicity screening includes genetoxicity studies consisting of in vitro and in vivo tests to detect compounds that directly or indirectly induce genetic damage. The currently accepted battery of genetic toxicity tests, as specified by FDA, consists of assays for gene mutation in bacteria, chromosomal damage in mammalian cells, and in vivo chromosomal damage evaluated using rodent bone marrow hematopoetic cells. These requirements can be satisfied by Salmonella histidine reversion mutagenesis (Ames) assay with inclusion of an Escherichia coli tryptophan reversion assay, in vitro chromosomal aberration in Chinese hamster ovary (CHO) cells, and the mouse bone marrow micronucleus assay. Compound selection for the study will be made from the Rapid Access to Preventive Intervention Development (RAPID) Program. The studies shall fulfill current industry standards for toxicology studies supporting NDA application and shall be conducted under FDA Good Laboratory Practice (GLP) regulations in AAALAC accredited, NIH/OPRR & USDA registered laboratories with active Institutional Animal Care and Use Committee (IACUC).