title: Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia.
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. Esophagoscopy 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 polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P = 0.02) and spermidine (P = 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 Krüppel-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 = 1), stable disease (n = 8), and progression to high-grade dysplasia (n = 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 polyamines 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.
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA. sinicrope.frank@mayo.edu
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.forename: Nina
authors.initials: N
authors.lastname: Joshi
authors.forename: Eugene
authors.initials: E
authors.lastname: Gerner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Half
authors.forename: Ilan
authors.initials: I
authors.lastname: Kirsch
authors.forename: Jan
authors.initials: J
authors.lastname: Lewin
authors.forename: Bruce
authors.initials: B
authors.lastname: Morlan
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000518:Eflornithine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000187:drug effects* / Q000473:pathology*; D011073:Polyamines / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines; D000518:Eflornithine