Phase I study of alpha-difluoromethylornithine and methyl-GAG

Splinter, Ted A.W.; Romijn, J. A.

doi:10.1016/0277-5379(86)90343-3

Cited by 21 publications

(3 citation statements)

References 10 publications

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“…The typical circling behaviour of Gy\Y mice, which results from inner-ear abnormalities, as well as their other neurological disorders [22], might relate to the finding that spermine is a modulator of ion channels in the brain [40]. Another parallel is that Gy\Y males seem to be deaf, as indicated by an absent Preyer reflex [22], and most patients treated with DFMO experience reversible deafness [41]. Electrophysiological and histological studies on guinea pigs suggest that the anatomical site of DFMO-induced hearing loss is the organ of Corti [42], which is consistent with the fact that Gy\Y mice have abnormalities in the organ of Corti.…”

Section: Discussionmentioning

confidence: 99%

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

Nilsson

Gritli-Linde

Heby

2000

Biochemical Journal

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Hemizygous gyro male (Gy/Y) mice are a model for X-linked hypophosphataemic rickets. As in humans, the disease is caused by deletions in the Phex gene, a phosphate-regulating gene having homologies with endopeptidases on the X chromosome. Some phenotypic abnormalities in Gy/Y mice have recently been attributed to the fact that the Gy deletion also includes the neighbouring spermine synthase gene, resulting in spermine deficiency. Spermine and its precursors spermidine and putrescine are essential for cell growth and differentiation. As a novel method for studying the function of spermine, we established primary cultures of skin fibroblasts from hemizygous Gy/Y mice. The Gy/Y cells contained no detectable spermine. In view of the fact that spermine is a free-radical scavenger in vitro, we were surprised to find that Gy/Y cells were more resistant to oxidative stress than their normal (X/Y) counterparts. However, our finding that spermidine accumulates markedly in the spermine-deficient Gy/Y cells can probably explain this increased resistance. It is the first indication that spermidine can serve as a free-radical scavenger in vivo and not only in vitro. When subjecting the Gy/Y cells to UV-C irradiation we made another interesting finding: the mutant cells were more sensitive than the normal X/Y cells. This finding indicates that spermine, probably because of its high-affinity binding to DNA, is important in protection against chromatin damage.

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Section: Discussionmentioning

confidence: 99%

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

Nilsson

Gritli-Linde

Heby

2000

Biochemical Journal

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“…[12][13][14][15][16][17][18][19]23,24 Fortunately, hearing loss associated with DFMO has been reversible in all reports with the exception of one. 25 A number of studies have evaluated the dose and ototoxic effects of DFMO on hearing thresholds [11][12][13][14][15][16][17][18][19]23,24,[26][27][28] ; however, none have investigated the longterm effects of daily DFMO administration. In this phase III randomized, double-blind, placebo-controlled trial, we compared the effects of prolonged administration of DFMO and placebo for up to 5 years.…”

Section: Introductionmentioning

confidence: 99%

“…A number of studies have evaluated the dose and ototoxic effects of DFMO on hearing thresholds 11–19,23,24,26–28 ; however, none have investigated the long‐term effects of daily DFMO administration. In this phase III randomized, double‐blind, placebo‐controlled trial, we compared the effects of prolonged administration of DFMO and placebo for up to 5 years.…”

Section: Introductionmentioning

confidence: 99%

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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An Animal Model of Hearing Loss From -Difluoromethylornithine

Jansen

Mattox²,

Miller³

et al. 1989

Archives of Otolaryngology - Head and Neck Surgery

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\s=b\ \g=a\-Difluoromethylornithineis a new antineoplastic and antiparasitic drug that inhibits the synthesis of polyamines. It causes a sensorineural hearing loss in humans. We have established an animal model for \g=a\-difluoromethylornithine-induced hearing loss. The time course for onset and recovery of the hearing loss in animals was similar to that seen in humans.Electrophysiologic and histologic data suggest that the anatomic site of \g=a\-difluoromethylornithine-induced hearing loss is the organ of Corti. Unlike other drugs with ototoxic effects, the specific enzymatic site of action of \g=a\-difluoromethylornithine is known, making it a potentially important tool in auditory research. (Arch Otolaryngol Head Neck Surg. 1989;115:1234-1237 S~\l -Difluoromethylornithine (DFwV MO) is a new antineoplastic and antiparasitic drug that inhibits the synthesis of polyamines.1 Early clinical trials using DFMO to treat human tumors revealed an unexpected side effect; a significant number of pa¬ tients suffered a sensorineural hearing

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Phase I study of alpha-difluoromethylornithine and methyl-GAG

Cited by 21 publications

References 10 publications

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

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

An Animal Model of Hearing Loss From -Difluoromethylornithine

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