MECHANISM BASED RADIOTHERAPY

我们对决定肿瘤对放疗反应的三个因素，放射敏感性的内在机制，低氧调节放射敏感性和p21调节的细胞凋亡有了重要的新见解。这些数据表明，新的剂量和剂量率模式可以改善放射治疗。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，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控制辐射抗性，以达到抗性或敏感性。最重要的是，我们还表明，放射抵抗肿瘤易受长期低剂量率辐照致敏因子的影响，致敏因子可达8倍。我们还证明了缺氧是异种移植物肿瘤中具有相似内在放射敏感性的细胞放射反应的主要调节剂，并开发了定量测定肿瘤细胞中缺氧分布的方法。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，但会改变肿瘤反应。因此，这些研究为通过利用特定肿瘤细胞的放射反应特征，包括肿瘤微环境和细胞凋亡对其的调节，提供了改进放射治疗的见解和方法。我们现在提议确定基于我们观察的新方案是否会改善放射治疗。我们的方法将在四个方面新颖：首先，我们将使用一种新的细胞放射敏感性模型，称为α - ω模型，它与目前的模型有根本区别，并提出了最大治疗效率的新方案。其次，我们的研究将同时评估三个因素的贡献，这三个因素是肿瘤反应的主要决定因素：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，我们将重点关注带或不带IUdR的长期照射作为一种有效的放射增敏剂，特别是对于放射耐药肿瘤。第四，由于目前的方法在对具有放射敏感性的肿瘤细胞进行足够时间的低剂量率照射方面存在局限性，我们还将开发一种方法，通过液体注射含有治疗水平放射性核素的免疫微球来进行长期照射。我们的计划由三个项目组成：辐射敏感性的细胞机制，辐射敏感性的微环境调制；免疫微球作为放射性核素载体；和两个核心：给药和临床相关性，剂量学，建模和实验性异种移植治疗。

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.