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Amelioration of radiation esophagitis by orally administered p53/Mdm2/Mdm4 inhibitor (BEB55) or GS-nitroxide

Kim, H and Bernard, ME and Epperly, MW and Shen, H and Amoscato, A and Dixon, TM and Doemling, AS and Li, S and Gao, X and Wipf, P and Wang, H and Zhang, X and Kagan, VE and Greenberger, JS (2011) Amelioration of radiation esophagitis by orally administered p53/Mdm2/Mdm4 inhibitor (BEB55) or GS-nitroxide. In Vivo, 25 (6). 841 - 848. ISSN 0258-851X

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Abstract

Background/Aim: 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. Materials and Methods: BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy x 1 or 11.5 Gy x 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kim, H
Bernard, ME
Epperly, MW
Shen, Hhos1@pitt.eduHOS1
Amoscato, Aaaa5@pitt.eduAAA5
Dixon, TM
Doemling, AS
Li, S
Gao, X
Wipf, Ppwipf@pitt.eduPWIPF
Wang, Hhow8@pitt.eduHOW80000-0003-0477-2908
Zhang, Xxichen@pitt.eduXICHEN
Kagan, VEkagan@pitt.eduKAGAN
Greenberger, JSjoelg@pitt.eduJOELG
Date: 1 January 2011
Date Type: Publication
Journal or Publication Title: In Vivo
Volume: 25
Number: 6
Page Range: 841 - 848
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0258-851X
MeSH Headings: Animals; Carcinoma, Lewis Lung--radiotherapy; Cell Cycle--drug effects; Esophagitis--etiology; Esophagitis--pathology; Esophagitis--prevention & control; Imidazoles--pharmacology; Indoles--pharmacology; Mice; Mice, Inbred C57BL; Nitrogen Oxides--pharmacology; Proto-Oncogene Proteins--antagonists & inhibitors; Radiation Injuries--prevention & control; Radiation-Protective Agents--pharmacology; Tumor Suppressor Protein p53--antagonists & inhibitors; Ubiquitin-Protein Ligases--antagonists & inhibitors
Other ID: NLM NIHMS426453, NLM PMC3521513
PubMed Central ID: PMC3521513
PubMed ID: 22021675
Date Deposited: 28 May 2013 14:56
Last Modified: 13 Apr 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/18735

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