Esophageal radioprotection by swallowed JP4-039/F15 in thoracic-irradiated mice with transgenic lung tumors.
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Background/aim To determine whether Gramicidin S (GS)-nitroxide, JP4-039, esophageal radiation protection protected lung tumors in a transgenic model, LoxP-Stoop-LoxP Kristen Rat Sarcoma Viral oncogene (LSL-K-RAS) mice were administered intra-tracheal- Carbapenem-resistant Enterobacteriaceae (CRE) recombinase, bilateral lung tumors were confirmed at 11 weeks, then thoracic irradiation was delivered. Materials and methods Mice received single-fraction 15 Gy or 24 Gy to both lungs, in subgroups receiving intraesophageal administration 10 min before irradiation of JP4-039 (in F15 emulsion) tumor size reduction and survival were investigated. Mice were followed for survival, and reduction in tumor size. Results There was no evidence of tumor radioprotection in mice receiving JP4-039/F15. Conclusion Intraesophageal radioprotective small-molecule antioxidant therapy protects normal tissue but not tumor tissue in mice with transgenic lung tumors.Cite
Abstract Ovarian cancer is the most lethal gynecological cancer worldwide with an estimated 152,000 deaths per year. Despite optimal management with radical cytoreductive surgery and subsequent platinum/taxane-based chemotherapy, most patients, will suffer recurrence within 18 months. Our laboratory has recently discovered a new therapeutic agent for intestinal radiation protection, namely the novel second-generation probiotic Lactobacillus reuteri (LR) genetically engineered to produce the radioprotective cytokine Interleukin-22 (IL-22) (Zhang et al. In Vivo, 34(1):39-50, 2020 Jan-Feb). To demonstrate that LR-IL-22 could protect the intestines from irradiation, we used three mouse models (total body irradiation (TBI), whole abdomen irradiation (WAI) and partial body irradiation (PBI)). For TBI, C57BL/6 mice were irradiated to 9.25 Gy to the entire body. For WAI, C57BL/6 mice were irradiated using a linear accelerator so that only the abdomen was irradiated to 19.75 Gy with the remainder of the body shielded from the irradiation. PBI was performed with the right rear leg shielded with the rest of the body irradiated to 15 Gy. In all three models the mice were gavaged 24 hours after irradiation with 1 × 109 LR-IL-22 cells. The mice were followed for development of either the hematopoietic syndrome (TBI) or gastrointestinal syndrome (WAI or PBI). In separate experiments we determined if mice irradiated as above had decreased irradiation induced inflammation using a Luminex assay on the intestine and blood plasma from mice sacrificed on days 0, 1, 2, 3, 5 and 7 following irradiation. We also determined whether intraoral gavage of LR-IL-22 24 hours prior to irradiation might protect the tumor in a mouse ovarian tumor model. Murine ovarian tumor cells 2F8-cis were injected intraperitoneally into Muc1 transgenic mice. Seventy-two hours later the mice were irradiated to 16 Gy WAI and followed for tumor growth. In the TBI model, mice treated with LR-IL-22 24 hours prior to irradiation had an increased survival of 80% compared to 0% in control irradiated mice (p = 0.0001). In the WAI model, mice treated with LR-IL-22 had a 40% survival following 19.75 Gy compared to 0% in the control irradiated group (p = 0. 0100). Following the PBI dose of 15 Gy, mice treated with LR-IL-22 had a 70% survival compared to 0% for the control irradiation only mice (p = 0.0006). Decreased expression of several inflammatory proteins such as TNF-α, IL-6 and IFN-γ (p = 0.0423, 0.0473 and 0.0024, respectively) was also detected in mice treated with LR-IL-22 24 hours prior to WAI compared to control irradiated mice. Furthermore, two weeks after injecting Muc1 transgenic mice with tumors, the nonirradiated mice had more than 200 small tumor nodules disseminated throughout the peritoneum while control WAI mice or mice treated with intraoral LR-IL-22 prior to WAI had no more than 10 tumor nodules. Hence, intraoral LR-IL-22 prior to chemoradiation may protect the intestines and result in increased survival of ovarian cancer patients. Citation Format: Diala Fatima Hamade, Renee Fisher, Wen Hou, Donna Shields, Michael W. Epperly, Joel S. Greenberger. LR-IL-22 protects the intestine to facilitate whole abdomen irradiation in ovarian cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-081.
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Intratracheal injection of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction or fractionated irradiation of C57BL/6J mouse lung has been demonstrated to protect the lung from irradiation-induced damage.To determine whether irradiation-induced inflammatory cytokine levels influenced the recovery of tumors following single fraction irradiation, mice with orthotopic Lewis Lung Carcinoma (3LL) tumors received MnSOD-PL treatment 24 hours after tumor implantation and 24 hours prior to irradiation. Subgroups were implanted with Alzet pumps continuously replacing levels of inflammatory cytokines over 7 days.In cytokine-treated mice, there was no detectable significant alteration in radiotherapy-mediated improved survival (tumor regrowth delay) compared to irradiated control mice. Each group of mice that received MnSOD-PL had increased survival compared to irradiated controls.These results support the anticipated safety of intrapulmonary MnSOD-PL gene therapy in lung cancer patients for protection of normal lung tissue from irradiation while allowing effective irradiation-mediated tumor control.
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Abstract Radiotherapy of locally-advanced non-small cell lung cancer (NSCLC) is limited by pneumonitis and fibrosis caused by radiation-induced injury to normal lung tissue. We have investigated the effect of a high thoracic dose of radiation combined with soy isoflavones in a pre-clinical model of orthotopic A549 human lung carcinoma xenografts in nude mice. Mice bearing established lung tumors (>300µm) were pretreated with soy for 3 days starting day 15 after A549 cell injection, and then received 10 Gy irradiation administered to the whole lung. Soy treatment, given orally at 1mg/day (50mg/kg) was continued for 5 days per week for 4 more weeks, then lungs were perfused with formalin and processed for histology. The effect of the therapy on the tumor cells, the surrounding tumor microenvironment and lung tissue structures was further analyzed using novel immunostaining and quantitative techniques. Compared to large invasive lung tumor nodules (up to 1-2 x 106 µm2) in untreated mice, the combined therapy caused a significant inhibition of tumor progression in lungs resulting in few residual small tumor nodules (0.02-0.07 x 106 µm2, p<0.05) with a low index of proliferation (mean of 16 positive nuclei for Ki-67 compared to 147 in control tumors, p<0.001). Pneumonitis was evaluated by morphometric measurements of the thickness of alveolar septa on H&E stained lung tissue sections. Soy isoflavones reduced the extent of pneumonitis induced by radiation resulting in 30% of the lung tissue with thickened septa compared to 45% observed in lungs treated with radiation only. Fibrosis staining using Masson's Trichrome revealed that radiation caused a dramatic increase in collagen fibers supporting the vessel and bronchiole walls and this effect was mitigated by soy isoflavones. Triple immunofluorescent staining of lung vessel walls was performed on lung tissue sections using antibodies specific to endothelial cells (anti-CD31), pericytes (anti-SMA) and collagen (anti-collagen IV). This technique revealed that soy isoflavones combined with radiation decreased the fraction of vessels with damaged basement membrane to 25% down from 42% in radiation-alone treated lungs. Thus, these studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while acting as radioprotectors for the surrounding lung tissue. Soy isoflavones reduced pneumonitis and fibrosis, and preserved the integrity of lung structures including alveolar septa, bronchioles and vessels, probably by mitigation of the inflammatory response induced by radiation. Complementing cancer radiotherapy with soy isoflavones has the potential to improve its effectiveness on the tumor target and reduce dose-limiting radiotoxicity to the normal lung and could be applied in the treatment of advanced stage NSCLC. Citation Format: Gilda Gali Hillman, Vinita Singh-Gupta, David J. Hoogstra, Lisa Abernathy, Joseph Rakowski, Christopher Yunker, Fazlul H. Sarkar, Andre A. Konski, Fulvio Lonardo, Michael C. Joiner. Soy improves radiotherapy for lung tumors and mitigates radiation-induced injury to lung tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-358. doi:10.1158/1538-7445.AM2013-LB-358
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OBJECTIVE:To explore the immunotherapy effect of peripheral γδT cells in lung cancer nude mice model.METHODS: Xenografted animal model of human lung cancer was established by innoculating human lung cancer A549 cells into BALB/c nude mice subcutaneously.And then the mice were divided into two groups randomly,γδ T cells and control group.γδT cells or RPMI-1640 were respectively injected into abdominal cavity of mice,Tumor volume and he survival rate of two groups were compared.The expression of c-jun was tested on tumor cell.RESULTS: The nude mice inoculated with 5×106 lung cancer cells,after fourteen days in the inoculation site a diameter of 2-3 mm tumor was formed.In the first 49 days after treatment determined two group tumor average size were(0.97±0.32) cm3 and(0.46±0.25) cm3 respectively,the treatment groups with a very significant difference compared with the control group in the tumor size(P0.05).After 75 days,all the mice in control group died,The survival time of treat ment group was longer than that of control group(P0.05).CONCLUSION: Human peripheral γδT cells can inhibit the growth of human lung cancer xenograft in nude mice effectively.
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Objective To investigate the establishment of lung cancer animal model and evaluation of its response to the therapy with different drugs.Methods The mice lung cancer models were established by thoracic cavity(group A) or subcutaneous implanting(group B) with Lewis lung carcinoma cells 5×106/ml.After treated with different drugs,the survival status of mice was observed and the expressions of VEGF and PCNA in the xenografts were detected by immunohistochemical method.Results Compared to group B,the survival status after treatment was better and the VEGF expression and PCNA positive cells in the xenografts were lower in group A.Conclusion Compared to mice lung cancer model by subcutaneous implantation,the thoracic cavity implanted mice lung cancer model is better in reflecting the therapeutic efficacy of antitumor drugs.
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this study evaluated esophageal radioprotection by the Gramicidin S (GS) derived-nitroxide, JP4-039, a mitochondrial targeting peptide-isostere covalently-linked to 4-amino-Tempo, delivered in a novel swallowed oil-based (F15) formulation.
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The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2–/– mice, comparing this to Fancd2 /– and Fancd2 / mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10–12-week-old mice, of FVB/N background Fancd2–/–, Fancd2 /– and Fancd2 / were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2–/– mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2 / mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2–/– mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2 / mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2–/– mice compared to Fancd2 / controls. Fancd2–/– mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2 / mice. In radiosensitive Fancd2–/– mice, biomarkers of both local oral cavity and distant marrow radiation toxicity were ameliorated by intraoral JP4-039/F15. We propose that Fancd2–/– mice are a valuable radiosensitive animal model system, which can be used to evaluate potential radioprotective agents.
Mucositis
FANCD2
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Intratracheal instillation
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Clonogenic assay
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