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化学预防剂开发计划，以确定和开发能够预防、延缓或逆转癌变过程的药物。为了评估试验性新药的安全性，必须对其毒理学潜力进行评估。毒性筛选包括遗传毒性研究，包括体外和体内试验，以检测直接或间接引起遗传损伤的化合物。目前接受的一系列遗传毒性测试，如FDA规定的，包括细菌基因突变、哺乳动物细胞染色体损伤和用啮齿动物骨髓造血细胞评估体内染色体损伤的测定。这些要求可以通过沙门氏菌组氨酸逆转诱变（Ames）实验（包含大肠杆菌色氨酸逆转实验）、中国仓鼠卵巢（CHO）细胞的体外染色体畸变和小鼠骨髓微核实验来满足。该研究的化合物选择将从快速获取预防干预发展（Rapid）计划中进行。该研究应符合支持NDA申请的毒理学研究的当前行业标准，并应在AAALAC认可的、NIH/OPRR和USDA注册的实验室（活跃的机构动物护理和使用委员会（IACUC））中按照FDA良好实验室规范（GLP）规定进行。

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).