MECHANISM BASED RADIOTHERAPY

我们对决定肿瘤对放射治疗反应的三个因素，放射敏感性的内在机制，放射敏感性的缺氧调节和p21调节的细胞凋亡，有了重要的新见解。这些数据表明，采用新的剂量和剂量率模式可能会改善放射治疗。我们已经详细测量了基因定义的人结直肠肿瘤细胞对长期和急性照射的反应。这些研究确定了两种不同的放射反应表型，仅与p53状态分离。此外，这些数据表明，可以通过不同的剂量和剂量率模式来操纵辐射抗性，以实现抗性或敏感性。最重要的是，我们还表明，放射抵抗性肿瘤对放射增敏的敏感性因子高达8倍，延长，低剂量率照射。我们还证明了缺氧的主要调节剂的放射反应在异种移植肿瘤细胞相似的内在放射敏感性和开发的方法来定量测定缺氧分布在肿瘤细胞。此外，我们已经证明，p21调节的细胞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反应特征的方案来改善放射治疗的见解和方法，包括肿瘤微环境和细胞凋亡对其的调节。我们现在建议确定基于我们观察的新协议是否会改善放射治疗。我们的方法将在四个方面是新颖的首先，我们将使用一种新的细胞辐射敏感性模型，称为α-ω模型，它与当前模型有根本性的不同，并提出了新的方案，以获得最大的治疗效率。其次，我们的研究将同时评估作为肿瘤反应的主要决定因素的三个因素的贡献：i）内在放射敏感性ii）肿瘤微环境和iii）p21调节的细胞凋亡。第三，我们将集中在长期照射或不IUdR作为一个有效的放射增敏剂，特别是对放射抵抗性肿瘤。第四，由于目前的方法局限于在足够的持续时间内递送低剂量率照射以使放射敏感的放射抗性肿瘤细胞，我们还将开发通过流体注射含有治疗水平的放射性核素的免疫微球来递送延长照射的方法。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的免疫微球;和两个核心：管理和临床相关性，剂量测定，建模和实验异种移植治疗。

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.