Irreversible Ototoxicity Associated with Difluoromethylornithine
- Christopher D. Lao1,
- Patricia Backoff3,
- Lawrence I. Shotland4,
- Deborah McCarty5,
- Tracy Eaton1,
- Frank G. Ondrey6,
- Jaye L. Viner7,
- Stuart Jon Spechler5,
- Ernest T. Hawk7 and
- Dean E. Brenner1,2,3
- 1Departments of Internal Medicine and 2Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan;
- 3Ann Arbor VA Medical Center, Ann Arbor, Michigan;
- 4James H. Quillen VA Medical Center, Mountain Home, Tennessee;
- 5Dallas VA Medical Center, Dallas, Texas;
- 6Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota; and
- 7Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
- Requests for reprints:
Dean E. Brenner, 2150 Cancer Center and Geriatrics Center, University of Michigan Medical Center, Ann Arbor, MI 48109-0930. Phone: (734) 647-1417; Fax: (734) 647-9817. E-mail: dbrenner{at}umich.edu
Abstract
Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines that promote cellular proliferation. DFMO has been tested as a potential cancer therapeutic and chemopreventive agent in clinical trials. Reversible hearing loss is a recognized toxicity of DFMO that usually occurs at doses above 2 g/m2/d, and generally when the cumulative dose exceeds 250 g/m2. In a recently completed Barrett's esophagus chemoprevention trial, a participant developed a 15-dB decrease in hearing at frequencies of 250, 2,000, and 3,000 Hz in the right ear and a ≥20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m2/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m2). The threshold shifts persisted 7 months after DFMO was discontinued. There was no obvious impact on the participant's clinical hearing, but these findings were consistent with irreversible hearing loss. This is the first case reported of irreversible ototoxicity in a clinical trial participant receiving DFMO and, thus, trial participants should be made aware of this small but important risk.
Footnotes
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- Accepted March 8, 2004.
- Received September 3, 2003.
- Revision received November 20, 2003.
