Chemoprevention of carcinogenic progression to esophageal adenocarcinoma by the manganese superoxide dismutase supplementation.
OBJECTIVE
Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation.


METHODS
Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid-reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining.


RESULTS
Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP.


CONCLUSIONS
MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.
Martin
Robert C G
RC
Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. Robert.martin@louisville.edu .
Liu
Qiaohong
Q
Wo
John M
JM
Ray
Mukunda B
MB
Li
Yan
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004938:Esophageal Neoplasms / Q000517:prevention & control*; D004947:Esophagus / Q000473:pathology; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000378:metabolism