Amelioration of radiation esophagitis by orally administered p53/Mdm2/Mdm4 inhibitor (BEB55) or GS-nitroxide.
OBJECTIVE
Esophagitis is a significant toxicity of radiation therapy for lung cancer. In this study, reduction of irradiation esophagitis in mice, by orally administered p53/Mdm2/Mdm4 inhibitor, BEB55, or the GS-nitroxide, JP4-039, was evaluated.


METHODS
BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy × 1 or 11.5 Gy × 4 thoracic irradiation. Progenitor cells were sorted from excised esophagus, and nitroxide was quantified, by electron paramagnetic resonance (EPR). Mice with Lewis lung carcinoma (3LL) orthotopic lung tumors were treated with BEB55 or JP4-039 prior to 20 Gy to determine if the drugs would protect the tumor cells from radiation.


RESULTS
Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively). JP4-039 was detected in esophagus, liver, bone marrow, and orthotopic Lewis lung carcinoma (3LL) tumor. There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively). Thus, BEB55 and JP4-039 safely ameliorate radiation esophagitis in mice.
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.
Hyun
H
Kim
Mark E
ME
Bernard
Michael W
MW
Epperly
Hongmei
H
Shen
Andrew
A
Amoscato
Tracy M
TM
Dixon
Alexander S
AS
Doemling
Song
S
Li
Xiang
X
Gao
Peter
P
Wipf
Hong
H
Wang
Xichen
X
Zhang
Valerian E
VE
Kagan
Joel S
JS
Greenberger
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects; D004941:Esophagitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011832:Radiation Injuries / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors*
C559766:BEB55 compound; D007093:Imidazoles; D007211:Indoles; C544775:JP4-039; C461497:Mdm4 protein, mouse; D009589:Nitrogen Oxides; D011518:Proto-Oncogene Proteins; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases