Characterization of the Ototoxicity of Difluoromethylornithine and Its Enantiomers

Abstract

Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the essential enzyme in mammalian polyamine biosynthesis (Pasic et al., 1997, Arch. Otolaryngol. Head Neck Surg. 123[12], 1281-1286). This cancer chemotherapeutic agent has significant ototoxic potential. Because the DFMO enantiomers differ in their ability to block ODC, the present study was designed to compare the ototoxic potential of each enantiomer with the racemic form of this drug for the rat and guinea pig. Determining differential ototoxicity of the enantiomers is one preliminary step in determining the optimal form of DFMO to use in human cancer chemotherapy. Daily intubation with D,L-DFMO does not produce any auditory dysfunction in rats with doses between 200 mg/kg/day and 1. 2 g/kg/day for up to 8 weeks, despite the fact that doses of 800 and 1200 mg/kg/day depressed body weight gain. In contrast to the data observed in rats, substantial ototoxicity was observed when guinea pigs were injected ip with doses of D,L-DFMO between 500 mg/kg/day and 1 g/kg/day. D,L-DFMO produced loss of compound action potential sensitivity, but not of cochlear microphonic amplitude. This finding correlated with histological data revealing loss of both outer and inner hair cells in the cochlea with inner more affected than outer hair cells, particularly in the basal turn. Higher exposure doses (2-3 g/kg/day) resulted in significant general toxicity including impaired growth and some mortality. When the enantiomers were evaluated in the guinea pig, it was found that 1 g/kg/day D-DFMO did not produce any significant hearing impairment, whereas 1 g/kg/day of the L-enantiomer of DFMO generated a threshold shift that surpassed that of 1 g/kg/day of the D,L-DFMO treatment.

Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery

“…Different species of laboratory animal are differentially sensitive to ototoxic drugs (10), with guinea pigs being one of the more sensitive rodent species (11,12). Guinea pigs have frequently been used to predict the ototoxicity of drugs in human administration.…”

Utility of the auditory brainstem response evaluation in non-clinical drug safety evaluations

“…ABR threshold increases were noted in both species, but rats required lower doses to produce the desired ABR threshold increases, suggesting greater sensitivity. Similar studies comparing the sensitivity of guinea pigs and rats to known ototoxins suggest that guinea pigs are the most sensitive rodent species for assessing otic drug safety (McWilliams, Chen, & Fechter, 2000;Sockalingam, Freeman, Cherny, & Sohmer, 2000). The body of ototoxicity literature suggests that the order of suitable rodent models for otic drug safety studies is guinea pig N rat N mouse.…”

Transcript Levels of the Eukaryotic Translation Initiation Factor 5A Gene Peak at Early G 1 Phase of the Cell Cycle in the Dinoflagellate Crypthecodinium cohnii

“…ODC inhibitor difluoromethylornithine (DFMO), which effectively depletes polyamines in yeast and mammalian cells, was also used to evaluate the possible effects of depleting polyamines in dinoflagellates. The two enantiomers of DFMO differ in their abilities to inhibit ODC, with the L form being more potent than the D form (25). The D form is used here as a control for the ODC inhibitory function.…”