Chemopreventive studies in Barrett's esophagus: a model premalignant lesion for esophageal adenocarcinoma.
Barrett's esophagus is a premalignant lesion in which the lower esophagus is lined with metaplastic columnar epithelium rather than the normal stratified squamous epithelium. It is a precursor lesion for adenocarcinoma of the esophagus. We are studying Barrett's esophagus as a model premalignant lesion for adenocarcinoma from the standpoint of identifying biologic markers of increased cancer risk as well as therapeutic strategies for eradicating the lesion. Ornithine decarboxylase (ODC) activity in Barrett's mucosa was significantly higher than in normal adjacent mucosa from the same patient. However, polyamine content was not significantly altered, suggesting dysregulation of the polyamine pathway. Flow cytometry is being used to assess the presence of aneuploidy and its significance in a premalignant lesion. Initial results have demonstrated that aneuploidy and dysplasia can be discordant. Cytogenetic analysis using short-term epithelial cultures established from endoscopic biopsies of the lesion has demonstrated the presence of clonal karyotypic abnormalities. The clinical significance of aneuploidy and abnormal karyotype, however, remains to be proved. Chemopreventive intervention trials have included use of 13-cis-retinoic acid. Considerable toxicity was encountered, and the lesion showed no change in extent in 11 evaluable patients. A subsequent clinical trial with a biologic endpoint used alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to test whether a low dose could produce changes in polyamine content in gastrointestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
Garewal
H S
HS
Department of Medicine, Tucson Veterans Affairs Medical Center, Ariz. 85723.
Sampliner
R E
RE
Fennerty
M B
MB
D000230:Adenocarcinoma / Q000517:prevention & control*; D000782:Aneuploidy; D001471:Barrett Esophagus / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D004938:Esophageal Neoplasms / Q000517:prevention & control*; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011230:Precancerous Conditions / Q000188:drug therapy*
D009955:Ornithine Decarboxylase