Irreversible ototoxicity associated with difluoromethylornithine.
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/m(2)/d, and generally when the cumulative dose exceeds 250 g/m(2). 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 > or =20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m(2)/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m(2)). 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.
Lao
Christopher D
CD
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.
Backoff
Patricia
P
Shotland
Lawrence I
LI
McCarty
Deborah
D
Eaton
Tracy
T
Ondrey
Frank G
FG
Viner
Jaye L
JL
Spechler
Stuart Jon
SJ
Hawk
Ernest T
ET
Brenner
Dean E
DE
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001471:Barrett Esophagus / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000009:adverse effects; D000518:Eflornithine / Q000008:administration & dosage / Q000009:adverse effects*; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D065108:Ornithine Decarboxylase Inhibitors; D016032:Randomized Controlled Trials as Topic / Q000009:adverse effects
D000970:Antineoplastic Agents; D065108:Ornithine Decarboxylase Inhibitors; D000518:Eflornithine