Difluoromethylornithine‐Induced Reversible Hearing Loss Across a Wide Frequency Range

Smith, Mark C.; Tinling, Steven P.; Doyle, Karen Jo

doi:10.1097/00005537-200406000-00029

Cited by 8 publications

(4 citation statements)

References 21 publications

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“…These side effects are not observed at lower doses of DFMO (26,27). Ototoxicity has been demonstrated to occur in experimental animals treated with DFMO including rats (35), guinea pigs (36), gerbils (37), and mice (38). Using immunohistochemistry, a high level of ornithine decarboxylase was observed in the inner ear of the rat, with the highest in the organ of Corti and lateral wall followed by the cochlear nerve (39).…”

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confidence: 99%

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Wang

Levic

Gratton

et al. 2009

Journal of Biological Chemistry

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Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken ␤-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor ␣-difluoromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes for ornithine decarboxylase and S-adenosylmethionine decarboxylase, which are enzymes needed for the synthesis of putrescine, spermidine, and spermine, are lethal at early stages of embryonic development (1, 2). There is convincing evidence that the formation of hypusine in eIF5A, which requires spermidine as a precursor, is essential for eukaryotes (3). However, the function(s) of spermine is not so well established. Yeast mutants with inactivated spermine synthase grow at a normal rate (4). Mammalian cells in culture also grow normally in the presence of inhibitors of spermine synthase (5) or after inactivation of the spermine synthase gene (SpmS) (6 -8

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confidence: 99%

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Wang

Levic

Gratton

et al. 2009

Journal of Biological Chemistry

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“…Although these numbers were not significant, it is plausible that DFMO does affect the higher frequency region of the cochlea (base) with greater capacity than the lower frequencies given the increased threshold shift observed in this region. Animal studies support this observation, where DFMO toxicity has been reported to affect the basal high‐frequency region of the cochlea most 35–37 . Collectively, average threshold shifts were greater in the experimental group relative to the control group across the frequency range; however, additional investigation with a larger study population is warranted to determine the extent of this threshold shift.…”

Section: Discussionmentioning

confidence: 65%

“…Animal studies support this observation, where DFMO toxicity has been reported to affect the basal highfrequency region of the cochlea most. [35][36][37] Collectively, average threshold shifts were greater in the experimental group relative to the control group across the frequency range; however, additional investigation with a larger study population is warranted to determine the extent of this threshold shift. Sufficient data were available for 250 participants to carry out statistical analysis; 117 in the DFMO group and 133 in the placebo group.…”

Section: Discussionmentioning

confidence: 93%

Ototoxicity of Long‐Term α‐Difluoromethylornithine for Skin Cancer Prevention

et al. 2022

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Objective Evaluate the effects of α‐difluoromethylornithine (DFMO) on hearing thresholds as part of a randomized, double‐blind, placebo‐controlled trial. Methods Subjects were randomized and assigned to the control (placebo) or experimental (DFMO) group. DFMO or placebo were administered orally (500 mg/m2/day) for up to 5 years. Results Subjects taking DFMO had, on average, increased hearing thresholds from baseline across the frequency range compared to subjects in the control group. Statistical analysis revealed this was significant in the lower frequency range. Conclusions This randomized controlled trial revealed the presence of increased hearing thresholds associated with long‐term DFMO use. As a whole, DFMO may help prevent and treat certain types of cancers; however, it can result in some degree of hearing loss even when administered at low doses. This study further highlights the importance of closely monitoring hearing thresholds in subjects taking DFMO. Laryngoscope, 133:676–682, 2023

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“…Another possible mechanism for the vestibular toxicity is damage to vestibular hair cells. DFMO has long been known to damage cochlear hair cells leading to reversible hearing loss in all species 21 . In human clinical trials using doses of DFMO comparable to those used in this study, hearing loss is common and may be incomplete or fluctuate over time 22 .…”

Section: Discussionmentioning

confidence: 88%

Phase I/II clinical trial of 2‐difluoromethyl‐ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma^*

Skorupski

O’Brien

Guerrero

et al. 2011

Vet Comparative Oncology

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Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumor regression in mouse models of SCC. The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase inhibitor, DFMO, and to determine whether this therapy results in reduction in tumor polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumor biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose of MQT 1426 when combined with DFMO was determined. Dose limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, 2 cats experienced objective tumor regression, and 6 cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted.The polyamines putrescine, spermidine, and spermine are required for cell proliferation and growth. They are produced as a result of myc oncogene signaling and play a role in epigenetic gene regulation through DNA stabilization and RNA processing. Polyamine metabolism is known to be dysregulated in many cancers and neoplastic cells require higher levels of polyamines than normal tissues for growth and replication. 1 Polyamines are obtained by cells through de novo synthesis as well as through transport from the extracellular fluid. 2 Ornithine decarboxylase (ODC) is the main enzyme involved in polyamine production within the cell and is overexpressed in many cancers, including breast and colon

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Difluoromethylornithine‐Induced Reversible Hearing Loss Across a Wide Frequency Range

Abstract: An 18-day regimen of 750 mg/kg per day of DFMO given subcutaneously in neonatal gerbils causes minimal side effects with broad-frequency HL that, after 3 weeks of recovery, is fully reversible.

Cited by 8 publications

References 21 publications

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Ototoxicity of Long‐Term α‐Difluoromethylornithine for Skin Cancer Prevention

Phase I/II clinical trial of 2‐difluoromethyl‐ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma^*

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Difluoromethylornithine‐Induced Reversible Hearing Loss Across a Wide Frequency Range

Abstract: An 18-day regimen of 750 mg/kg per day of DFMO given subcutaneously in neonatal gerbils causes minimal side effects with broad-frequency HL that, after 3 weeks of recovery, is fully reversible.

Cited by 8 publications

References 21 publications

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Ototoxicity of Long‐Term α‐Difluoromethylornithine for Skin Cancer Prevention

Phase I/II clinical trial of 2‐difluoromethyl‐ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma*

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Product

Resources

About

Phase I/II clinical trial of 2‐difluoromethyl‐ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma^*