Leukotriene A4 hydrolase inhibition may curb GERD-related esophageal cancer

Leukotriene A4 hydrolase (LTA4H) is over-expressed in the early stages of rat and human esophageal adenocarcinomas (EAC), and its inhibition reduces the incidence of EAC in a rat model, according to a report in the July 16th Journal of the National Cancer Institute.

EAC, often preceded by gastroesophageal reflux (GERD), is “increasing at the most rapid rate of any cancer in the United States,” the authors note. A previous study identified LTA4H as an over-expressed protein in a rat model of EAC, they explain, but the 5-lipoxygenase pathway that includes LTA4H has not been studied in EAC. Dr. Chung S. Yang from Rutgers, the State University of New Jersey in Piscataway, and colleagues first compared LTA4H expression in EAC tumor and non-tumor esophageal tissues from rats and humans. All 10 sets of rat samples of EAC tumors and four of six human EAC tumors overexpressed LTA4H, the authors report, as compared with expression in adjacent non-tumor esophageal tissues.The researchers also investigated the effects of bestatin, an LTA4H inhibitor, in a rat model of EAC in which surgical esophagogastroduodenal anastomosis mimics the effects of human gastroesophageal reflux.Bestatin treatment lowered the incidence of EAC tumors from 57.7% (15 of 26 rats) to 26.1% (6 of 23 rats; p=0.042), the investigators report, and tumor volume was significantly lower in bestatin-treated rats.”LTA4H overexpression appears to be an early event in esophageal adenocarcinogenesis and is a potential target for the chemoprevention of EAC,” Dr. Yang and colleagues conclude. “Recent studies of the crystal structure and molecular biology of LTA4H suggested that LTA4H epoxide hydrolase activity could be targeted efficiently and specifically by some potent LTA4H epoxide hydrolase inhibitors,” they add. “We urge that future studies test the chemopreventive effects of these inhibitors on EAC.” (Source: J Natl Cancer Inst 2003;95:1053-1061: Reuters Health: July 31, 2003: Oncolink)