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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 because of the increased toxicity to normal tissue associated with combined WART and full-dose chemotherapy regimens. 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, radiation doses greater than 120 cGy have been used in radiotherapy because lower doses were thought to be ineffective for tumor therapy. However, we now know that LDFRT can produce hyper-radiosensitivity (HRS), a phenomenon where cells undergo apoptosis at radiation doses as low as 15 cGy, in a number of proliferating cells. The objectives of our current study were to determine whether LDFRT can induce HRS in gastrointestinal cancer cells and to identify biomarkers of chemopotentiation by LDFRT. Our data indicate that three consecutive daily fractions of 15 cGy produced HRS in gastric cancer cells and potentiated a modified regimen of docetaxel, cisplatin and 5'-fluorouracil (mDCF). Colony survival assays indicated that 15 cGy was sufficient to kill 90% of the cells when LDFRT was combined with mDCF whereas a dose almost 10 times higher (135 cGy) was needed to achieve the same rate when using conventional radiotherapy alone. RT(2) PCR Profiler™ array analysis indicated that this combined regimen upregulated dual oxidase 2 (DUOX2), an enzyme functioning in the production of hydrogen peroxide, without upregulating genes involved in DNA repair. Moreover, downregulation of DUOX2 increased radioresistance at every radiation dose tested. In addition, our data indicate that reactive oxygen species (ROS) increase up to 3.5-fold in cells exposed to LDFRT and mDCF. Furthermore, inhibition of NADPH oxidase abrogated the killing efficiency of this combined regimen. Taken together these data suggest that chemopotentiation by LDFRT in gastric cancer cells may be due, at least in part, to increased ROS production (DUOX2) without upregulation of the DNA repair machinery. These data thus provide a rationale for further explorations of potential clinical applications of LDFRT, such as in WART, as a chemopotentiator for advanced and metastatic gastric cancers.

Contribution of Dual Oxidase 2 (DUOX2) to Hyper-Radiosensitivity in Human Gastric Cancer Cells