Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia

Frank A Sinicrope, Russell Broaddus, Nina Joshi, Eugene Gerner, Elizabeth Half, Ilan Kirsch, Jan Lewin, Bruce Morlan, Waun Ki Hong

Research output: Contribution to journalArticle

16 Citations (Scopus)

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/m2/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 Krüuppellike 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.

Original languageEnglish (US)
Pages (from-to)829-839
Number of pages11
JournalCancer Prevention Research
Volume4
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Eflornithine
Barrett Esophagus
Chemoprevention
Polyamines
Spermidine
Esophagoscopy
Audiology
Gene Expression
Cyclins
Putrescine
Spermine
Proliferating Cell Nuclear Antigen
Esophageal Neoplasms
Cell Adhesion
Genes
Cell Cycle
Transcription Factors
Down-Regulation
Complementary DNA
Color

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia. / Sinicrope, Frank A; Broaddus, Russell; Joshi, Nina; Gerner, Eugene; Half, Elizabeth; Kirsch, Ilan; Lewin, Jan; Morlan, Bruce; Hong, Waun Ki.

In: Cancer Prevention Research, Vol. 4, No. 6, 06.2011, p. 829-839.

Research output: Contribution to journalArticle

Sinicrope, Frank A ; Broaddus, Russell ; Joshi, Nina ; Gerner, Eugene ; Half, Elizabeth ; Kirsch, Ilan ; Lewin, Jan ; Morlan, Bruce ; Hong, Waun Ki. / Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 6. pp. 829-839.
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