TUMOR RADIOSENSITIZATION BY PRENYLTRANSFERASE INHIBITORS

异戊二烯基转移酶抑制剂对肿瘤放射增敏

• 批准号: 2467975
• 负责人: Eric J Bernhard
• 金额: $ 21.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-12 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467975
• 关键词: SDS polyacrylamide gel electrophoresis; alkyltransferase; alleles; apoptosis; athymic mouse; biological signal transduction; cell transformation; enzyme activity; enzyme inhibitors; fibroblasts; gene mutation; isoprenoid; laboratory rat; neoplasm /cancer genetics; neoplastic cell; neoplastic growth; oncogenes; posttranslational modifications; radiation genetics; radiation related neoplasm /cancer; radiation sensitivity; tissue /cell culture; western blottings

DESCRIPTION: One obstacle to successful radiotherapy is the elevated resistance to ionizing radiation that many tumors display relative to adjacent normal tissues. Thus the radiosensitivity of normal tissue limits the radiation dose that can be delivered to a tumor. The combined effect of tumor resistance and normal tissue sensitivity can result in incomplete elimination of tumor cells and local recurrence. This grant address this problem by developing a method to specifically sensitize tumor cells to radiation using an approach based on the contribution of ras oncogenes to radiation resistance. Ras oncogenes are frequently mutated in human tumors treated with radiation therapy. These include pancreatic, colon, ovarian, and thyroid carcinomas sarcomas and late stage cervical carcinomas. Ras mutations have furthermore been shown to cause increase radiation resistance in experimental tumor systems. Thus, inhibition of the activity of oncogenic ras might be hypothesized to lead to radiation sensitization of the tumor cells. Since normal cells do not contain oncogenic ras, such an approach should not affect these cells. Farnesyltransferase and geranylgeranyltransferase inhibitors are compounds that specifically inhibit the post-translational prenylation of ras which is required for membrane association and signal transduction activity. The action of farnesyltransferase inhibitors (FTI) appears to be greatest against activated H-ras oncogenes, and consequently little or no effect is seen in normal cells as doses that significantly alter the morphology, growth and radiation-resistance of H-ras transformed cells. Geranylgeranyltransferase inhibitors (GGTI) show selective activity against K-ras prenylation. Both inhibitors have been shown to impede tumor growth, and are thus ideal candidates for combined modality therapy with radiation. The goal of this study is to determine whether the specificity of these inhibitors for the activated ras in tumor cells can be exploited such that these agents can be used as tumor cell radiosensitizers during radiation therapy.

描述：成功放疗的一个障碍是升高 对电离辐射的抗性，许多肿瘤相对于 邻近的正常组织。 因此，正常组织极限的放射敏性 可以输送到肿瘤的辐射剂量。 的综合效果 肿瘤耐药性和正常组织敏感性可能导致不完整 消除肿瘤细胞和局部复发。 这笔赠款解决这个问题 通过开发一种将肿瘤细胞特异性敏感的方法来解决的问题 使用基于Ras Oncogenes对的方法进行辐射 辐射阻力。 RAS癌基因在人类肿瘤中经常突变 通过放射治疗治疗。 其中包括胰腺，结肠，卵巢， 甲状腺癌肉瘤和后期宫颈癌。 拉斯 此外，突变已被证明会增加辐射电阻 在实验性肿瘤系统中。 因此，抑制活性 可能假设致癌性RA会导致辐射敏化 肿瘤细胞。 由于正常细胞不含致癌性RA，因此 方法不应影响这些细胞。 Farnesylsylansferase和geranylgeranylylansylysferass抑制剂是化合物 特别抑制了RAS的翻译后原始化 膜关联和信号转导活性所需。 这 Farnesylsylansfer酶抑制剂（FTI）的作用似乎是最大的 反对激活的H-Ras Oncogenes，因此很少或没有影响 在正常细胞中被视为显着改变形态的剂量， H-RAS转化细胞的生长和辐射抗性。 黄烷基凝血酶转移酶抑制剂（GGTI）显示出针对针对的选择性活性 K-RAS原始化。 两种抑制剂均已证明会阻碍肿瘤的生长， 因此，是将模态疗法与辐射结合疗法的理想候选者。 这项研究的目的是确定这些的特异性是否 可以利用肿瘤细胞中激活RAS的抑制剂 这些药物可以在辐射过程中用作肿瘤细胞放射增敏剂 治疗。