Whole abdominal radiotherapy (WART) is a primary method for managing gastrointestinal cancers that have disseminated into intra-abdominal tissues. While effective, this approach is limited since combination of WART with full-dose chemotherapy regimens increase toxicity to normal tissue. Recent studies have demonstrated a survival advantage in a novel treatment paradigm that allows for the safe use of full-dose systemic chemotherapy in combination with Low Dose Fractionated Radiotherapy (LDFRT). Traditionally, radiotherapy used doses greater than 1.20 Gy because it was thought that lower radiation doses would be ineffective for tumor therapy. We now know that LDFRT can produce hyper-radiosensitivity (HRS), a phenomenon where cells undergo apoptosis at radiation doses as low as 0.15 Gy, in a number of proliferating cells. Our objectives are to develop pre-clinical studies to investigate the therapeutic potential of chemopotentiation by LDFRT in disseminated intra-abdominal cancer. Our data indicate that three consecutive daily fractions of 0.15 Gy produced HRS in gastric cancer cells and potentiated a modified regimen of Docetaxel, Cisplatin, and 5’-fluorouracil (mDCF). Colony survival assays indicated that 0.15 Gy was sufficient to kill 90% of the cells when LDFRT was combined with mDCF whereas an almost ten times higher dose (1.35 Gy) was needed to achieve the same rate when using conventional radiotherapy alone. RT2 PCR Profiler Array analysis of more than 300 genes indicated that Dual Oxidase 2 (DUOX2), an enzyme functioning in the production of hydrogen peroxide, was by far the most upregulated gene in response to this combined regimen while genes involved in DNA repair were apparently not involved. Moreover, down regulation of DUOX2 increased radioresistance at every radiation doses tested. In addition, our data indicate that Reactive Oxygen Species increase up to 3.5 fold in cells exposed to LDFRT and mDCF. Furthermore, inhibition of NAD(P)H oxidase abrogated the killing efficiency of this combined regimen. These findings are particularly important given that DUOX2 is only expressed in about 50% of gastric carcinoma (preliminary data). DUOX2 could thus be used as a biomarker to potentially stratify gastric cancer patients with advanced and metastatic intra-abdominal cancers for clinical applications of chemopotentiation by LDFRT. Our working hypothesis is that Chemopotentiation by LDFRT is mediated by DUOX2 in gastric cancers. In order to test this hypothesis three Specific aims have been developed. Aim 1. Determine the role of DUOX2 on human gastric cancer cells progression in response to chemopotentiation by LDFRT in vivo. We will use human gastric cancer cells expressing endogenous and reduced levels of DUOX2 and a fluorescence marker in mouse xenograft models. Cancer progression will be monitored with a Xenogen IVIS optical imager following treatments. In addition, we will determine whether activation of DUOX2 can be used as a biomarker ...