Clinical radiosensitivity: role of DNA repair

临床放射敏感性：DNA 修复的作用

• 批准号: nhmrc : 400337
• 负责人: Dr Carl Sprung
• 金额: $ 29.69万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/clinical-radiosensitivity-role-dna-repair/99833
• 关键词: Clinical; radiosensitivity; role; DNA; repair

This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients (>95%) is restrained to assure only a small proportion risk developing severe reactions. If one could predict which individuals were more susceptible to these reactions, then their large dose could be lowered to avoid the problem, and importantly, the dose could be increased for the majority of the patients, which would lead to a higher cancer cure rate. There are over 130 genes involved in repairing DNA. We hypothesize that dysfunctional DNA repair molecules are likely candidates to cause radiosensitivity in these individuals. In fact, a few of these genes have already been found to cause radiosensitivity, but we aim to assess all of the DNA repair genes in samples from patients that have had severe reactions to radiotherapy. Here we will use biospecimens, unique to our study and obtained from clinically radiosensitive cancer patients. We will use very sensitive, state-of-the-art procedures to test RNA and protein levels in our patients' cells and the latest technology to test what happens when candidate DNA repair molecule levels are altered. Additionally, we will determine the changes in DNA repair molecule numbers in response to different doses of radiation. We anticipate that results from these experiments will lead to the development of a clinical assay to test the likelihood of an individual having a severe reaction to radiotherapy, thus allowing individualization of treatment and, reducing radiotherapy side effects ultimately increasing cancer cure rates.

这项提案将侧重于确定破坏参与修复DNA的分子对癌症放射治疗后不良反应的发展的影响。辐射对癌症是有效的，但在放射治疗期间，肿瘤附近的组织也会暴露在辐射中(这可能会破坏DNA)。大约1-5%的放射治疗患者在正常组织中会出现意想不到的严重副作用。用于治疗其余患者(95%)的放射剂量受到限制，以确保只有一小部分患者有发生严重反应的风险。如果可以预测哪些人更容易受到这些反应的影响，那么他们的大剂量就可以减少，以避免这个问题，更重要的是，大多数患者的剂量可以增加，这将导致更高的癌症治愈率。有130多个基因参与修复DNA。我们推测，功能失调的DNA修复分子可能是导致这些人辐射敏感性的候选因素。事实上，这些基因中的一些已经被发现导致辐射敏感性，但我们的目标是评估所有样本中的DNA修复基因，这些基因来自对放射治疗有严重反应的患者。在这里，我们将使用生物检验剂，这是我们研究中独有的，从临床上对放射敏感的癌症患者中获得。我们将使用非常敏感、最先进的程序来测试患者细胞中的RNA和蛋白质水平，并使用最新的技术来测试候选DNA修复分子水平改变时会发生什么。此外，我们还将确定DNA修复分子数量在不同剂量辐射下的变化。我们预计，这些实验的结果将导致开发一种临床测试，以测试个人对放射治疗发生严重反应的可能性，从而实现个体化治疗，并减少放射治疗的副作用，最终提高癌症治愈率。