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: 7002181
• 负责人: Eric J Bernhard
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF OXFORD
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002181
• 关键词: SDS polyacrylamide gel electrophoresis; alkyltransferase; alleles; apoptosis; athymic mouse; biological signal transduction; confocal scanning microscopy; enzyme activity; enzyme inhibitors; gene mutation; guanine nucleotide binding protein; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; oncogenes; posttranslational modifications; protein isoforms; radiation genetics; radiation resistance; radiation sensitivity; small nuclear RNA; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Our studies to date have demonstrated that inhibiting RAS reduces the radiation survival of tumor cells in which RAS is activated by mutation or epidermal growth factor receptor (EGFR) signaling. We have used a pharmacological approach to inhibit RAS post-translational processing. This processing is required for RAS membrane binding and activity. We have shown that farnesyltransferase inhibitor (FTI) treatment radiosensitizes tumor cells with H-ras mutations without altering the radiation sensitivity of normal cells. While the effect was significant in tissue culture, animal experiments led us to examine whether FTI treatment had additional effects in vivo. Subsequent studies revealed that FTI treatment led to increased oxygenation in tumors xenografts expressing oncogenic H-ras. We propose to further explore the ability of FTIs to alter the tumor microenvironment by determining whether mutant RAS is the target for this action of FTIs. We will investigate the mechanism through which FTIs alter the oxygenation of tumors and whether it involves changes in tumor vasculature. We have also shown, using a genetic approach, that oncogenic H-, K-, and N-RAS all contribute to radiation resistance. Signaling from the three RAS isoforms to down-stream effectors has been reported to differ. This raises the question of which pathways downstream of RAS contribute to the observed radiation resistance. We propose to explore the contribution of each RAS isoform to intrinsic radiation resistance and to investigate downstream pathways using both pharmacologic inhibitors as well as novel genetic reagents. Small interfering RNA (siRNA) will be used to specifically target expression of the different RAS isoforms as well as to specifically target oncogenic RAS expression. The results of these studies could be valuable in developing new molecular targets to improve the efficacy of radiotherapy. They may also provide a rationale for the application of FTIs in the treatment of tumors with RAS activation that is due to EGFR signaling.

描述（由申请人提供）：迄今为止我们的研究表明，抑制RAS会降低肿瘤细胞的辐射存活，其中RAS通过突变或表皮生长因子受体（EGFR）信号传导激活RAS。 我们使用了药理方法来抑制RAS翻译后处理。 这种处理是RAS膜结合和活性所必需的。 我们已经表明，Farneylsylansferase抑制剂（FTI）治疗放射辐射可以通过H-RAS突变不改变正常细胞的辐射敏感性。 尽管这种作用在组织培养中很重要，但动物实验使我们检查了FTI治疗在体内是否还具有其他影响。 随后的研究表明，FTI治疗导致表达致癌H-RAS的肿瘤异种移植物中的氧合作用增加。 我们建议通过确定突变体RAS是否是FTIS的靶标，以进一步探索FTI改变肿瘤微环境的能力。 我们将研究FTI改变肿瘤氧合的机制，以及它是否涉及肿瘤脉管系统的变化。 我们还使用遗传学方法表明，致癌的H-，K-和N-RAS都有助于辐射抗性。 据报道，来自三个RAS同工型到下游效应子的信号传导有所不同。 这就提出了一个问题，即RAS下游哪种途径有助于观察到的辐射抗性。 我们建议探索每个RASOOFOR对固有辐射抗性的贡献，并使用两种药理抑制剂和新型遗传试剂研究下游途径。 小型干扰RNA（siRNA）将用于特异性靶向不同的RAS同工型的表达，并专门靶向致癌性RAS表达。 这些研究的结果对于开发新的分子靶标以提高放射疗法的功效可能很有价值。 它们还可以为FTI在用EGFR信号引起的RAS激活治疗肿瘤治疗中的应用提供基本原理。