HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY WITH VASCULAR TARGETING

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。最近，人们对高剂量单分割或少分割(低分割)放射治疗脑外肿瘤的新用途产生了浓厚的兴趣。一旦被归入脑内病变，放射外科治疗颅外肿瘤因其放射生物学优势以及重要的是实施了安全输送的适当技术而越来越受欢迎。关于它在治疗原发和转移性肝癌、早期肺癌、前列腺癌和胰腺癌中的有效使用的多项研究最近已经发表或正在进行中(1-3)。在一个或几个治疗中使用高剂量辐射与常规放射治疗不同，常规放射治疗通常在数周内每天进行，每次治疗的辐射剂量相对较小。然而，高剂量辐射的生物学，特别是与抗血管药物联合使用，还没有很好的定义。临床前模型将极大地帮助更好地理解这一生物学，并将在临床试验中洞察适当的放射-药物组合。通过这项研究，我们试图研究和比较单次剂量和低分割放射治疗在治疗在大鼠模型中生长的肝肿瘤中的作用，并评估在这些治疗中添加抗血管药物的价值或损害。这项研究将有助于为单分割或低分割放射治疗奠定临床前的科学基础，通过确定：1)适当的放射剂量(即，消除肿瘤所需的单分割或低分割疗程的剂量？)；2)在高剂量治疗中添加抗血管药物的效果；3)大剂量治疗+/-使用抗血管药物时肿瘤破坏的机制(即，内皮细胞杀伤、肿瘤细胞杀伤，或两者兼而有之)。我们正在研究一种在大鼠肝脏内原位生长的大鼠肝细胞癌细胞系(RH7777)。对原位移植肿瘤的研究可能会比在其自然(微)环境之外移植的肿瘤产生更多的临床相关信息。最近的研究表明，肿瘤中不同的基因表达模式取决于它们生长的微环境。这种研究的中心，以及一般放射治疗的中心，是对肿瘤靶点的充分可视化，以允许适当的放射束计划。我们希望利用带有多碘甘油三酯造影剂的小动物CT扫描仪来区分肝脏肿瘤模型中的肿瘤和正常肝实质(5)。我们想从一项先导性研究开始，该研究涉及在肿瘤植入后使用1-2只动物。我们希望在植入后的1周、2周和3周对动物进行扫描，观察肿瘤的生长情况，然后帮助制定治疗计划。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is recent intense interest in the novel use of high-dose single fraction or few-fraction (hypofractionated) radiation therapy for tumors outside of the brain. Once relegated to lesions in the brain, radiosurgery for treatment of extracranial tumors is increasingly popular with its radiobiologic advantages and, importantly, with implementation of appropriate technology for its safe delivery. Multiple studies on its effective use in the treatment primary and metastatic liver tumors, early-stage lung tumors, prostate cancer, and pancreatic cancer have recently been published or are underway (1-3). The use of high doses of radiation in one or a few treatments is in contrast to conventional radiation treatments, which usually take place on a daily basis over many weeks with relatively small doses of radiation with each treatment. The biology of high-dose radiation, especially in conjunction with anti-vascular drugs, however, is not well defined. Preclinical models will help greatly in better understanding this biology and will give insight into appropriate radiation-drug combinations in clinical trials. With this study we seek to study and compare single-dose and hypofractionated radiation treatments in the management of liver tumors growing in a rat model, and to assess the value or detriment of adding anti-vascular agents to such treatments. This study will help lay a pre-clinical scientific basis for single-fraction or hypofractionated radiotherapy by determining: 1) Appropriate doses of radiation (that is, what dose in single fraction or hypofractionated courses is needed for tumor eradication?); 2) The effect of adding anti-vascular agents to high-dose treatments; 3) The mechanism of tumor destruction (i.e., endothelial cell kill, tumor cell kill, or both) when high-dose treatments +/- the use of anti-vascular agents are used. We are studying a rat hepatocellular cancer cell line (RH7777) growing orthotopically in rat liver. Studies of tumors implanted in orthotopic locations will likely yield more clinically relevant information than tumors implanted outside of their ¿natural¿ (micro)environment. Recent studies have shown different gene expression patterns in tumors depending upon the microenvironment in which they are growing. Central to such a study, and to radiotherapy in general, is adequate visualization of the tumor target to allow for appropriate radiation beam planning. We would like to utilize the small animal CT scanner with a polyiodinated triglyceride contrast agent that has been previously shown to delineate tumor from normal liver parenchyma in a liver tumor model (5). We would like to begin with a pilot study involving the use of 1-2 animals following tumor implantation. We would like to scan the animals at 1-, 2-, and 3-week intervals following implantation, both to observe the tumor growth and then to aid in treatment planning.