CELLULAR AND ANIMAL STUDIES OF SRC INHIBITORS

SRC 抑制剂的细胞和动物研究

• 批准号: 6203193
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203193
• 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.

该程序为可能的抑制剂提供生物模型，使用 人结肠腺癌细胞系及其衍生的肿瘤 台词。我实验室过去的工作表明，激活 Pp6c-src和pp62c-yes在激活的人结肠肿瘤中是一致的 Pp60c-src对结肠癌细胞系的致瘤性具有重要意义 裸鼠，这很好地表征了人类结肠癌细胞系，如 HT29在筛选可能的PTK抑制剂方面非常有用。因此，这就是 计划将利用我们所描述的系统来筛选假定的 在第一个和第二个计划中开发了PTK抑制剂。这些屏幕 将包括测定这些化合物在正常情况下的细胞毒性 成纤维细胞以及结肠肿瘤细胞中，这些细胞的生长抑制 细胞，以及对软琼脂集落形成的影响。此外，这一点 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一致。 该计划还将在M.D.进行致瘤性研究。 安德森癌症中心，在后肢和结肠原位模型中 裸鼠体内的癌症。抑制剂对pp60c-src的特异性将是 通过检查假定的PTK抑制剂对REARE患者的影响进行评估 未激活pp60c-src的结肠癌细胞株。结合使用 我的实验室的基础研究努力，这次筛选将考验 假设pp60c-src特异性抑制剂将降低肿瘤致瘤性 模型结肠肿瘤细胞株在没有明显毒性的情况下。 几种目前处于不同测试阶段的稀有先导化合物，因此每一种 不同的分析将同时进行。随着对…的研究 在这项提案中的其他方案，我们应该确定其有效性 用于结肠癌治疗的SRC特异性抑制剂，提供 对肿瘤的分子图谱的了解 抑制剂很可能是情绪性的，并进一步了解 Src家族蛋白酪氨酸激酶在结肠癌进展中的作用。