IPW-5371 Mitigates the Delayed Effects of Acute Radiation Exposure in WAG/RijCmcr Rats when Started 15 Days After PBI with Bone Marrow Sparing

Overview

Journal Int J Radiat Biol

Specialty Radiology

Date 2023 Feb 16

PMID 36794325

Authors

Brian L Fish

Barry Hart

Tracy Gasperetti

Jayashree Narayanan

Feng Gao

Dana Veley

Lauren Pierce

Heather A Himburg

Thomas MacVittie

Meetha Medhora

Affiliations

Soon will be listed here.

Abstract

Purpose: To test IPW-5371 for the mitigation of the delayed effects of acute radiation exposure (DEARE). Survivors of acute radiation exposure are at risk for developing delayed multi-organ toxicities; however, there are no FDA-approved medical countermeasures (MCM) to mitigate DEARE.

Methods: WAG/RijCmcr female rat model of partial-body irradiation (PBI), by shielding part of one hind leg, was used to test IPW-5371 (7 and 20 mg kgd) for mitigation of lung and kidney DEARE when started 15 d after PBI. Rats were fed known amounts of IPW-5371 using a syringe, instead of delivery by daily oral gavage, sparing exacerbation of esophageal injury by radiation. The primary endpoint, all-cause morbidity was assessed over 215 d. Secondary endpoints: body weight, breathing rate and blood urea nitrogen were also assessed.

Results: IPW-5371 enhanced survival (primary endpoint) as well as attenuated secondary endpoints of lung and kidney injuries by radiation.

Conclusion: To provide a window for dosimetry and triage, as well as avoid oral delivery during the acute radiation syndrome (ARS), the drug regimen was started at 15 d after 13.5 Gy PBI. The experimental design to test mitigation of DEARE was customized for translation in humans, using an animal model of radiation that was designed to simulate a radiologic attack or accident. The results support advanced development of IPW-5371 to mitigate lethal lung and kidney injuries after irradiation of multiple organs.

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References

Deas S, Huprikar N, Skabelund A . Radiation exposure and lung disease in today's nuclear world. Curr Opin Pulm Med. 2016; 23(2):167-172. DOI: 10.1097/MCP.0000000000000349. View

Ask K, Bonniaud P, Maass K, Eickelberg O, Margetts P, Warburton D . Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3. Int J Biochem Cell Biol. 2007; 40(3):484-95. PMC: 2350199. DOI: 10.1016/j.biocel.2007.08.016. View

Anscher M, Murase T, Prescott D, Marks L, Reisenbichler H, Bentel G . Changes in plasma TGF beta levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1994; 30(3):671-6. DOI: 10.1016/0360-3016(92)90954-g. View

Rosenthal R, Fish B, Hill R, Huffman K, Lazarova Z, Mahmood J . Salen Mn complexes mitigate radiation injury in normal tissues. Anticancer Agents Med Chem. 2011; 11(4):359-72. PMC: 3814176. DOI: 10.2174/187152011795677490. View

Vujaskovic Z, Anscher M, Feng Q, Rabbani Z, Amin K, Samulski T . Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys. 2001; 50(4):851-5. DOI: 10.1016/s0360-3016(01)01593-0. View

Gao F, Narayanan J, Joneikis C, Fish B, Szabo A, Moulder J . Enalapril mitigates focal alveolar lesions, a histological marker of late pulmonary injury by radiation to the lung. Radiat Res. 2013; 179(4):465-74. PMC: 3697111. DOI: 10.1667/RR3127.1. View

Ghobadi G, van der Veen S, Bartelds B, de Boer R, Dickinson M, de Jong J . Physiological interaction of heart and lung in thoracic irradiation. Int J Radiat Oncol Biol Phys. 2012; 84(5):e639-46. DOI: 10.1016/j.ijrobp.2012.07.2362. View

Buijs J, Juarez P, Guise T . Therapeutic strategies to target TGF-β in the treatment of bone metastases. Curr Pharm Biotechnol. 2011; 12(12):2121-37. DOI: 10.2174/138920111798808293. View

Cohen E, Hankey K, Bennett A, Farese A, Parker G, MacVittie T . Acute and Chronic Kidney Injury in a Non-Human Primate Model of Partial-Body Irradiation with Bone Marrow Sparing. Radiat Res. 2017; 188(6):661-671. PMC: 7737227. DOI: 10.1667/RR24857.1. View

10.

Cohen E, Fish B, Moulder J . Mitigation of radiation injuries via suppression of the renin-angiotensin system: emphasis on radiation nephropathy. Curr Drug Targets. 2010; 11(11):1423-9. PMC: 3814179. DOI: 10.2174/1389450111009011423. View

11.

Aqeel M, Medhora M, Gore E, Borkenhagen J, Klawikowski S, Eastwood D . Evaluation of Radiation-induced Pleural Effusions after Radiotherapy to Support Development of Animal Models of Radiation Pneumonitis. Health Phys. 2021; 121(4):434-443. PMC: 8500166. DOI: 10.1097/HP.0000000000001462. View

12.

Moulder J, Fish B, Cohen E . Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy. Bone Marrow Transplant. 1997; 19(7):729-35. DOI: 10.1038/sj.bmt.1700732. View

13.

Satyamitra M, DiCarlo A, Hollingsworth B, Winters T, Taliaferro L . Development of Biomarkers for Radiation Biodosimetry and Medical Countermeasures Research: Current Status, Utility, and Regulatory Pathways. Radiat Res. 2021; 197(5):514-532. PMC: 9119904. DOI: 10.1667/RADE-21-00157.1. View

14.

Chung E, Hudak K, Horton J, White A, Scroggins B, Vaswani S . Transforming growth factor alpha is a critical mediator of radiation lung injury. Radiat Res. 2014; 182(3):350-62. PMC: 4169125. DOI: 10.1667/RR13625.1. View

15.

Unthank J, Ortiz M, Trivedi H, Pelus L, Sampson C, Sellamuthu R . Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance. Radiat Res. 2019; 191(5):383-397. PMC: 6538064. DOI: 10.1667/RR15130.1. View

16.

Kma L, Gao F, Fish B, Moulder J, Jacobs E, Medhora M . Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax. J Radiat Res. 2012; 53(1):10-7. PMC: 3616750. DOI: 10.1269/jrr.11035. View

17.

Fish B, MacVittie T, Gao F, Narayanan J, Gasperetti T, Scholler D . Rat Models of Partial-body Irradiation with Bone Marrow-sparing (Leg-out PBI) Designed for FDA Approval of Countermeasures for Mitigation of Acute and Delayed Injuries by Radiation. Health Phys. 2021; 121(4):419-433. PMC: 8577554. DOI: 10.1097/HP.0000000000001444. View

18.

Cohen E, Hankey K, Farese A, Parker G, Jones J, Kane M . Radiation Nephropathy in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing-Part 1: Acute and Chronic Kidney Injury and the Influence of Neupogen. Health Phys. 2019; 116(3):401-408. PMC: 7323852. DOI: 10.1097/HP.0000000000000960. View

19.

Moulder J, Cohen E, Fish B, Hill P . Prophylaxis of bone marrow transplant nephropathy with captopril, an inhibitor of angiotensin-converting enzyme. Radiat Res. 1993; 136(3):404-7. View

20.

Fish B, MacVittie T, Szabo A, Moulder J, Medhora M . WAG/RijCmcr rat models for injuries to multiple organs by single high dose ionizing radiation: similarities to nonhuman primates (NHP). Int J Radiat Biol. 2018; 96(1):81-92. DOI: 10.1080/09553002.2018.1554921. View