Research Article See perspective on p. 783 Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett’s Esophagus and Mucosal Dysplasia Frank A. Sinicrope 1 , Russell Broaddus 2 , Nina Joshi 3 , Eugene Gerner 4 , Elizabeth Half 2 , Ilan Kirsch 3 , Jan Lewin 2 , Bruce Morlan 1 , and Waun Ki Hong 2 Abstract Patients with Barrett’s esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m 2 /d) given continuously for 6 months. Esopha- goscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal poly- amines were measured by high-performance liquid chromatography. Microarray-based gene expres- sion was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P ¼ 0.02) and spermidine (P ¼ 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Kr € uppel- like factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n ¼ 1), stable disease (n ¼ 8), and progression to high-grade dysplasia (n ¼ 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal poly- amines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted. Cancer Prev Res; 4(6); 829–39. Ó2011 AACR. Introduction Barrett’s esophagus (BE) is a premalignant condition that is related to chronic gastroesophageal reflux disease and confers an increased risk of developing esophageal adeno- carcinoma (1). It is estimated that BE increases the risk of developing esophageal adenocarcinoma by a factor of 30 to 40 times compared with patients without this condition. BE is a metaplastic change characterized by replacement of the normal squamous mucosa with gastric type columnar epithelium that is at risk for progression to low- and high- grade dysplasia (HGD) and cancer (1). The incidence of esophageal adenocarcinoma has been increasing rapidly in North America and Europe (2). Of the estimated that 16,400 new cases of esophageal cancer that will be diag- nosed in the United States in 2009, approximately 60% will be adenocarcinomas (3). The majority of these ade- nocarcinomas are believed to arise either within Barrett’s epithelium or in the gastric cardiac mucosa of the distal esophagus. Although the prevalence of BE in the general population within the United States is unknown, extra- polating data from a population-based study from Swe- den (4) would suggests that 1.5 to 2.0 million adults in the United States have this condition. Endoscopic sur- veillance of BE patients is the current standard of care that is aimed at detecting dysplasia and early malignancy. However, endoscopic surveillance is costly and labor- intensive and remains controversial owing to a lack of randomized trials supporting its efficacy in reducing cancer incidence (1). Furthermore, dysplasia and progres- sion to cancer can occur in otherwise typical appearing Barrett’s epithelium and biopsy sampling error is also a limitation of current endoscopic surveillance. Accord- ingly, patients with BE and mucosal dysplasia are prime candidates for secondary prevention approaches, includ- ing chemoprevention, given their increased risk for devel- oping esophageal adenocarcinoma. Authors' Affiliations: 1 Mayo Clinic, Rochester, Minnesota; 2 MD Anderson Cancer Center, Houston, Texas; 3 National Cancer Institute, Bethesda, Maryland; and 4 Arizona Cancer Center, Tucson, Arizona Corresponding Author: Frank A. Sinicrope, Mayo Clinic, 200 First Street, SW, Guggenheim 10, Rochester, MN 55905. Phone: 507-266-0132; Fax: 507-255-6318. E-mail: sinicrope.frank@mayo.edu doi: 10.1158/1940-6207.CAPR-10-0243 Ó2011 American Association for Cancer Research. Cancer Prevention Research www.aacrjournals.org 829 for Cancer Research. on June 6, 2020. © 2011 American Association cancerpreventionresearch.aacrjournals.org Downloaded from