title: IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects.
abstract: There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.
authors.affiliation: a   Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rabender
authors.affiliation: b   Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia 23298.|c   VCU Victoria Johnson Center, Virginia Commonwealth University, Richmond, Virginia 23298.|d   School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: b   Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia 23298.|c   VCU Victoria Johnson Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.affiliation: f   Jubilant Biosys Ltd., Yeshwanthpur, Bangalore-560022, Karnataka, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mullangi
authors.affiliation: b   Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia 23298.|c   VCU Victoria Johnson Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: a   Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Anscher
authors.affiliation: e   Innovation Pathways, Palo Alto, California 94301.
authors.forename: Barry
authors.initials: B
authors.lastname: Hart
authors.affiliation: a   Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Ross
authors.initials: R
authors.lastname: Mikkelsen
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D005260:Female; D006207:Half-Life; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D012119:Respiration / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D011837:Radiation-Protective Agents; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I