MECHANISM BASED RADIOTHERAPY

基于机制的放射治疗

• 批准号: 6633321
• 负责人: THEODORE L DEWEESE
• 金额: $ 100.22万
• 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 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633321
• 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.

我们对决定肿瘤对放疗反应的三个因素、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。当综合考虑时，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辐射的反应。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模式和剂量率来操纵放射抗性，以实现抗性或敏感性。最重要的是，我们还发现，抗放射肿瘤在长期、低剂量率照射下，对放射增敏作用的敏感性高达 8 倍。我们还证明了异种移植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缺氧，并开发了定量测定肿瘤细胞中缺氧分布的方法。此外，我们还证明，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的调节）的方案来改善放射治疗提供了见解和方法。我们现在建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具有新颖性：首先，我们将使用一种新的细胞放射敏感性模型，称为α-omega模型，该模型与当前模型有根本区别，并提出新的方案以实现最大治疗效率。其次，我们的研究将同时评估肿瘤反应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，我们将重点关注使用或不使用 IUdR 的长期照射作为有效的放射增敏剂，特别是对于放射抗性肿瘤。第四，由于目前的方法仅限于在足够时间内对放射敏感的抗放射肿瘤细胞提供低剂量率照射，因此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来提供长时间照射的方法。我们的项目由三个项目组成：放射敏感性的细胞机制、放射敏感性的微环境调节；和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，以及剂量测定、建模和实验异种移植治疗。

项目成果

Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo.

肿瘤对放射治疗的反应取决于体外和体内基因型相关机制。

• DOI: 10.1186/1748-717x-5-71
• 发表时间: 2010
• 期刊: Radiation oncology (London, England)
• 作者: Williams,JerryR;Zhang,Yonggang;Zhou,Haoming;Gridley,DailaS;Koch,CameronJ;Dicello,JohnF;Slater,JamesM;Little,JohnB
• 通讯作者: Little,JohnB

Bioadhesive characterization of poly(methylidene malonate 2.12) microparticle on model extracellular matrix.

模型细胞外基质上聚（亚甲基丙二酸酯 2.12）微粒的生物粘附特性。

• DOI: 10.1016/j.biomaterials.2003.11.021
• 发表时间: 2004
• 期刊: Biomaterials.
• 作者: Chan,Vincent;Liu,Kuo-Kang;LeVisage,Catherine;Ju,Bin-Feng;Leong,KamW
• 通讯作者: Leong,KamW

Adhesion contact dynamics of primary hepatocytes on poly(ethylene terephthalate) surface.

原代肝细胞在聚对苯二甲酸乙二醇酯表面的粘附接触动力学。

• DOI: 10.1016/j.biomaterials.2004.03.041
• 发表时间: 2005
• 期刊: Biomaterials.
• 作者: Tan,WeeJin;Teo,GilbertP;Liao,Kin;Leong,KamW;Mao,Hai-Quan;Chan,Vincent
• 通讯作者: Chan,Vincent

pH responsive adhesion of phospholipid vesicle on poly(acrylic acid) cushion grafted to poly(ethylene terephthalate) surface.

• DOI: 10.1016/j.colsurfb.2004.11.002
• 发表时间: 2005-05
• 期刊: Colloids and surfaces. B, Biointerfaces
• 作者: Ning Fang;W. Tan;K. Leong;H. Mao;V. Chan

Overview of radiosensitivity of human tumor cells to low-dose-rate irradiation.

人类肿瘤细胞对低剂量率照射的放射敏感性概述。

• DOI: 10.1016/j.ijrobp.2008.06.1928
• 发表时间: 2008
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Williams,JerryR;Zhang,Yonggang;Zhou,Haoming;Gridley,DailaS;Koch,CameronJ;Slater,JamesM;Little,JohnB
• 通讯作者: Little,JohnB