MECHANISM BASED RADIOTHERAPY

基于机制的放射治疗

• 批准号: 6376969
• 负责人: THEODORE L DEWEESE
• 金额: $ 95.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376969
• 关键词: neoplasm /cancer radiation therapy; radiation therapy dosage

We have made important new insights into three factors that determine tumor response to radiotherapy, intrinsic mechanisms of radiosensitivity, hypoxic modulation of radiosensitivity and p21- modulated apoptosis. When taken on concert, these data suggest novel patterns of dose and dose-rate may achieve improved radiotherapy. We have measured in detail the response of genetically-defined human colorectal tumor cells to protracted and acute irradiation. These studies identify two distinct radio-response phenotypes that segregate only with p53 status. Further these data show radioresistance can be manipulated by differing patters of dose and dose rate to achieve either resistance or sensitivity. Most important we have also shown radio- resistant tumors to be susceptible to radiosensitization by factors up to 8 fold by protracted, low dose-rate irradiation. We also have demonstrated hypoxia to the dominant modulator of radioresponse in xenograft tumors for cells of similar intrinsic radiosensitivity and developed methodology to assay hypoxia distributions in tumor cells quantitatively. Further, we have demonstrated that p21-modulated apoptosis does not alter after in vitro radiosensitivity but does alter tumor response Thus these studies provide insights and methodology for improving radiotherapy through regiments that exploit the characteristics of radioresponse of cells of particular tumors, including their modulation by tumor microenvironment and apoptosis. We now propose to determine if new protocols based on our observations will improve radiotherapy. Our approach will be novel in four ways First, we will use a new cellular radiosensitivity model, termed the alpha-omega model that has fundamental differences from current models and suggest new protocols for maximum therapeutic efficiency. Second, our studies will evaluate concomitantly the contribution of three factors that are the major determinants of tumor response: i) intrinsic radiosensitivity ii) tumor microenvironment and iii) p21-modulated apoptosis. Third we will focus on protracted irradiation with or without IUdR as a potent radiosensitizer, particularly for radio-resistant tumors. Fourth, as current methodology as limited in delivering low dose-rate irradiation in adequate duration for radio-sensitizing radio- resistant tumor cells, we will also develop methodology for delivering protracted irradiation by fluid injection of immunomicrospheres containing therapeutic levels of radionuclides. Our program is composed of three projects: Cellular Mechanisms of Radiosensitivity, Microenvironmental Modulation of Radiosensitivity; and Immunomicrospheres as Radionuclide Carriers; and two Cores: Administration and Clinical Correlates, and Dosimetry, Modeling and Experimental Xenograft Therapy.

我们对确定肿瘤对放射疗法的反应，放射敏性的内在机制，放射敏感性的低氧调节和p21调节凋亡的三个因素进行了重要的新见解。当进行音乐会时，这些数据表明新型剂量和剂量率模式可能会改善放射疗法。我们已经详细介绍了遗传定义的人结直肠肿瘤细胞对长期和急性照射的响应。这些研究确定了仅在p53状态下隔离的两种不同的放射反应表型。此外，这些数据表明，可以通过不同的剂量和剂量速率模式来操纵放射线，以达到抗性或灵敏度。最重要的是，我们还显示了耐药性肿瘤易受放射敏化的敏感性，这是由于长时间的低剂量速率照射的最高8倍的因素。我们还证明了异种移植肿瘤中辐射肿瘤的主要调节剂的缺氧，用于类似的内在放射敏性细胞，并开​​发了用于定量肿瘤细胞中缺氧分布的方法。此外，我们已经证明，p21调节的凋亡在体外放射敏感性后不会改变，但确实改变了肿瘤反应，因此这些研究提供了通过利用特定肿瘤细胞的放射线特征来改善放射治疗的洞察力和方法，包括通过特定肿瘤的细胞特征，包括肿瘤微环境和凋亡的调节。现在，我们建议确定基于我们的观察结果的新方案是否会改善放射疗法。我们的方法将首先以四种方式新颖，我们将使用一种新的细胞放射敏感模型，称为α-欧米加模型，该模型与当前模型具有根本差异，并提出了新方案，以实现最大的治疗效率。其次，我们的研究将评估三个因素的贡献，这些因素是肿瘤反应的主要决定因素：i）固有放射性敏感性ii）肿瘤微环境和iii）p21 p21调节的细胞凋亡。第三，我们将专注于有或没有IUDR作为有效的放射增敏剂的长期照射，尤其是用于放射性耐药性肿瘤。第四，由于目前的方法是在适当持续时间内传递低剂量率照射的范围内，用于无线电敏化射线效果肿瘤细胞，我们还将开发方法，通过含有免疫圈的含有含辐射核酸的治疗水平的液体注射来传递延长的辐照方法。我们的计划由三个项目组成：放射敏感性的细胞机制，放射敏感性的微环境调节；作为放射性核素载体和免疫机圈；和两个核心：给药和临床相关，以及剂量法，建模和实验异种移植治疗。