MECHANISM BASED RADIOTHERAPY

我们在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、低氧对放射敏感性的调节和p21调节的细胞凋亡方面取得了重要的新见解。综合起来看，这些数据表明，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类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，这两种表型仅与P53状态相分离。此外，这些数据表明，辐射抵抗可以通过不同的剂量和剂量率模式来操纵，以实现抵抗或敏感性。最重要的是，我们还表明，通过长时间、低剂量率的照射，耐辐射肿瘤对放射增敏的敏感性最高可达8倍。我们还证明了对于具有相似内在放射敏感性的细胞，低氧是异种移植瘤中辐射反应的主要调节因子，并开发了定量测定肿瘤细胞中低氧分布的方法。此外，我们已经证明，p21调控的细胞凋亡在体外放射敏感性后不会改变，但确实会改变肿瘤的反应。因此，这些研究为通过利用特定肿瘤细胞的放射反应特性(包括肿瘤微环境和细胞凋亡的调节)来改善放射治疗提供了见解和方法。我们现在建议根据我们的观察结果确定新的方案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-omega模型，该模型与现有模型有根本的不同，并提出了新的方案，以实现最大的治疗效率。其次，我们的研究将同时评估作为肿瘤反应主要决定因素的三个因素的贡献：i)固有的放射敏感性，ii)肿瘤微环境和iii)p21调节的细胞凋亡。第三，我们将重点放在使用或不使用IUdR作为一种有效的放射增敏剂的长期照射上，特别是对放射耐药的肿瘤。第四，由于目前的方法对放射增敏的肿瘤细胞在足够的时间内提供低剂量率照射是有限的，我们还将开发通过液体注射含有治疗水平的放射性核素的免疫微球进行长期照射的方法。我们的计划由三个项目组成：放射敏感性的细胞机制、辐射敏感性的微环境调节、免疫微球作为放射性核素载体；以及两个核心：给药和临床相关以及剂量学、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.