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.