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

低剂量分割放射治疗播散性腹腔内癌症的化学增强作用

• 批准号: 9349730
• 负责人: France Carrier
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349730
• 关键词: Abdomen; Afghanistan; Apoptosis; Attention; Biological Assay; Biological Markers; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; Cancer Patient; Carcinogens; Carcinomatosis; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical stratification; Collaborations; Combined Modality Therapy; DNA Repair; Data; Disease; Dose; Down-Regulation; Enzymes; Exposure to; Fluorescence; Fluorouracil; Fractionated radiotherapy; Fukushima; Gastric Adenocarcinoma; Genes; Genetic Transcription; Human; Hydrogen Peroxide; Hypoxia; Immune; Immune response; Immunocompetent; Immunologist; Infiltration; Injectable; Injection of therapeutic agent; Intra-abdominal; Ionizing radiation; Iraq; Japan; Knowledge; Low Dose Radiation; Malignant neoplasm of abdomen; Malignant neoplasm of gastrointestinal tract; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Morphology; Mus; Normal tissue morphology; Nuclear Accidents; Nude Mice; Oxidases; Pathologist; Patients; Perfusion; Peritoneal; Post-Transcriptional Regulation; Production; Proliferating; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Radioresistance; Reactive Oxygen Species; Rectal Cancer; Recurrence; Regimen; Regulatory T-Lymphocyte; Research; Role; Serum; Stem cells; Stomach; Stomach Carcinoma; Testing; Therapeutic; Time; Tissues; Toxic effect; Up-Regulation; Work; Xenograft Model; Xenograft procedure; cancer cell; cancer therapy; chemotherapy; clinical application; density; docetaxel; in vivo; insight; killings; macrophage; malignant stomach neoplasm; mouse model; novel; optical imager; oxidative damage; patient stratification; preclinical study; programs; radiosensitive; response; treatment response; tumor; tumor microenvironment; tumor progression

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 for the combined regimen by measuring Reactive Oxygen Species (ROS) and oxidative damage to proteins by measuring protein carbonyl levels in mice serum. Aim 2: Delineate the molecular mechanisms leading to DUOX2 upregulation in response to chemopotentiation by LDFRT. Emphasis will be on DUOX2 transcriptional and post-transcriptional regulation. In Aim 3, we will evaluate the effect of DUOX2 on the immune response and the tumor microenvironment. This will be performed in a syngeneic mouse model where DUOX2 effect on vasculature, hypoxia, immune cells infiltration, and stem cells will be monitored. The unique aspect of this proposal is the identification of DUOX2 as a major contributor to chemopotentiatoin by LDFRT and the possibility to revisit WART with radiation doses ten times lower than the conventional dose in an attempt to decrease intra- abdominal recurrence of the disease. In addition to providing insight into the molecular mechanisms underlying therapeutic responses to low dose radiation, these studies could also be used to identify markers for exposure to ionizing radiation.

全腹放射治疗（WART）是治疗胃肠道肿瘤的主要方法