HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY WITH VASCULAR TARGETING

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近有强烈的兴趣，在新的使用高剂量单次分割或少部分（hypofractionated）放射治疗脑外肿瘤。一旦降级到病变在大脑中，放射外科治疗颅外肿瘤越来越受欢迎，其放射生物学的优势，重要的是，与实施适当的技术，其安全交付。关于其在治疗原发性和转移性肝肿瘤、早期肺肿瘤、前列腺癌和胰腺癌中的有效用途的多项研究最近已发表或正在进行中（1-3）。在一次或几次治疗中使用高剂量辐射与常规辐射治疗相反，常规辐射治疗通常在许多周内每天进行，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结合的生物学，还没有很好的定义。临床前模型将大大有助于更好地理解这种生物学，并将在临床试验中深入了解适当的辐射-药物组合。通过这项研究，我们试图研究和比较单剂量和大分割放射治疗在大鼠模型中生长的肝肿瘤的管理，并评估在这种治疗中加入抗血管药物的价值或损害。本研究将有助于为单次或大分割放射治疗奠定临床前的科学基础，确定：1）适当的放射剂量（即肿瘤根除需要单次或大分割疗程的剂量？）; 2)在高剂量治疗中加入抗血管剂的效果; 3）肿瘤破坏的机制（即，内皮细胞杀伤、肿瘤细胞杀伤或两者）。 我们正在研究大鼠肝癌细胞系（RH 7777）原位生长在大鼠肝脏。对原位植入肿瘤的研究可能会比在其自然环境（微环境）之外植入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。 这种研究的核心，以及一般的放射治疗，是肿瘤靶点的充分可视化，以允许适当的放射束计划。我们想利用小动物CT扫描仪与多碘化甘油三酯造影剂，以前已经显示出描绘肿瘤从正常肝实质在肝脏肿瘤模型（5）。我们希望开始一项初步研究，包括在肿瘤植入后使用1-2只动物。我们希望在植入后的1周、2周和3周间隔扫描动物，以观察肿瘤生长，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.