CELLULAR AND ANIMAL STUDIES OF SRC INHIBITORS

SRC 抑制剂的细胞和动物研究

• 批准号: 6237173
• 负责人: GARY E GALLICK
• 金额: $ 15.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237173
• 关键词: antineoplastics; athymic mouse; colon neoplasms; cooperative study; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme inhibitors; protein tyrosine kinase; tissue /cell culture

This Program provides the biologic models for putative inhibitors using human colon adenocarcinoma cell lines and tumors derived from these cell lines. Past work from my laboratory has demonstrated that activation of pp6c-src and pp62c-yes are consistent in human colon tumors, that activated pp60c-src is important to the tumorigenicity of colon tumor cell lines in nude mice, and that well characterized human colon tumor cell lines such as HT 29 are very useful in screening putative PTK inhibitors. Thus this Program will utilize the systems we have described for screening putative PTK inhibitors developed in the first and second Programs. These screens will include determination of cytotoxicity of the compounds in normal fibroblasts as well as in colon tumor cells, growth inhibition of these cells, and effects on soft agar colony formation. Additionally, this proposal will examine the src kinase activity in inhibited cells to determine that the inhibition corresponds with the predicted mechanism. The program will also perform the tumorigenicity studies at the M.D. Anderson Cancer Center, in hind limb and in orthotopic models for colon cancer in nude mice. Specificity of inhibitors toward pp60c-src will be assessed by examining the effects of the putative PTK inhibitors in rare colon tumor cell lines without activated pp60c-src. In combination with the basic research efforts of my laboratory, this screening will test the hypothesis that a pp60c-src-specific inhibitor will reduce tumorigenicity of model colon tumor cell lines in the absence of significant toxicity. Several lead compounds rare currently at various stages of testing, so each of the various analyses will proceed simultaneously. With the studies of the other Programs in this proposal, we should determine the efficacy of src-specific inhibitors for therapeutic treatment of colon cancer, provide an understanding of the molecular profile of tumors inn which such inhibitors are likely to be affective, and further an understanding of the roles of src family PTKs in colon tumor progression.

该程序为推定抑制剂提供了使用的生物模型 源自这些细胞的人类结肠腺癌细胞系和肿瘤 线。 我实验室的过去工作表明，激活 PP6C-SRC和PP62C-YE在人类结肠肿瘤中是一致的，它激活了 PP60C-SRC对结肠肿瘤细胞系的肿瘤性很重要 裸鼠，以及良好的人类结肠肿瘤细胞系，例如 HT 29在筛选推定的PTK抑制剂方面非常有用。 因此 程序将利用我们所描述的系统进行筛选推定 PTK抑制剂在第一和第二个程序中发展。 这些屏幕 将包括确定正常化合物的细胞毒性 成纤维细胞以及结肠肿瘤细胞，这些抑制作用的生长抑制 细胞，以及对软琼脂菌落形成的影响。 另外，这个 建议将检查抑制细胞中的SRC激酶活性 确定抑制作用与预测的机制相对应。 该计划还将在医学博士上进行肿瘤性研究。 安德森癌症中心，后肢和结肠的原位模型 裸鼠的癌症。 抑制剂对PP60C-SRC的特异性将是 通过检查假定的PTK抑制剂在罕见 无活化的PP60C-SRC的结肠肿瘤细胞系。 结合 我实验室的基础研究工作，该筛查将测试 假设PP60C-SRC特异性抑制剂将降低肿瘤性 在没有明显毒性的情况下模型结肠肿瘤细胞系的。 目前在测试的各个阶段，几种铅化合物很少见，因此 在各种分析中，将同时进行。 随着研究 该提案中的其他计划，我们应该确定 SRC特异性抑制剂用于结肠癌的治疗疗法，提供 对肿瘤旅馆的分子特征的理解 抑制剂可能是情感的，进一步了解 SRC家族PTK在结肠肿瘤进展中的作用。