CELLULAR AND ANIMAL STUDIES OF SRC INHIBITORS

SRC 抑制剂的细胞和动物研究

• 批准号: 6102660
• 负责人: GARY E GALLICK
• 金额: $ 14.64万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102660
• 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.

该计划使用以下方法提供推定抑制剂的生物模型 人结肠腺癌细胞系和源自这些细胞的肿瘤 线。 我实验室过去的工作表明，激活 pp6c-src 和 pp62c-yes 在人类结肠肿瘤中是一致的，激活 pp60c-src 对结肠肿瘤细胞系的致瘤性很重要 裸鼠，以及充分表征的人类结肠肿瘤细胞系，例如 HT 29 对于筛选假定的 PTK 抑制剂非常有用。 因此这个 计划将利用我们描述的系统来筛选假定的 第一期和第二期开发的PTK抑制剂。 这些屏幕 将包括正常情况下化合物的细胞毒性测定 成纤维细胞以及结肠肿瘤细胞，这些细胞的生长抑制 细胞，以及对软琼脂集落形成的影响。 另外，这 该提案将检查受抑制细胞中的 src 激酶活性，以 确定抑制与预测的机制相对应。 该项目还将在医学博士中心进行致瘤性研究。 安德森癌症中心，后肢和结肠原位模型 裸鼠患癌症。 抑制剂对 pp60c-src 的特异性为 通过检查假定的 PTK 抑制剂在罕见疾病中的作用来评估 未激活 pp60c-src 的结肠肿瘤细胞系。 结合 我实验室的基础研究工作，这次筛选将测试 假设 pp60c-src 特异性抑制剂会降低致瘤性 在没有显着毒性的情况下模型结肠肿瘤细胞系的研究。 几种先导化合物目前处于不同的测试阶段，因此每种化合物都很罕见 各种分析将同时进行。 随着研究 对于本提案中的其他计划，我们应该确定其功效 用于治疗结肠癌的 src 特异性抑制剂，提供 了解肿瘤的分子谱 抑制剂可能是情感性的，并进一步了解 src 家族 PTK 在结肠肿瘤进展中的作用。