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.
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