# Chemopotentiation by Low Dose Fractionated Radiation Therapy for disseminated intra-abdominal cancers

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

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 ...

## Key facts

- **NIH application ID:** 9932271
- **Project number:** 5I01BX003437-04
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** France Carrier
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932271

## Citation

> US National Institutes of Health, RePORTER application 9932271, Chemopotentiation by Low Dose Fractionated Radiation Therapy for disseminated intra-abdominal cancers (5I01BX003437-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932271. Licensed CC0.

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