Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

Drögemöller, Britt I.; Wright, Galen E.B.; Lo, Cody; Le, Tan T.; Brooks, Beth; Bhavsar, Amit P.; Rassekh, Shahrad R.; Ross, Colin J.D.; Carleton, Bruce

doi:10.1002/cpt.1483

Cited by 26 publications

(22 citation statements)

References 67 publications

(194 reference statements)

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“…Two GWASs reported SNPs that are associated with an increased risk of ototoxicity: rs1872328 in ACYP2 [113] and rs62283056 in WFS1 [114]. The clinical evidence for those SNPs was also supported with functional validation studies [115].…”

Section: Impact Of Pharmacogenetic Variants In Octs In Precision Medimentioning

confidence: 86%

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Zazuli

Duin

Jansen

et al. 2020

IJMS

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A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.

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Section: Impact Of Pharmacogenetic Variants In Octs In Precision Medimentioning

confidence: 86%

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Zazuli

Duin

Jansen

et al. 2020

IJMS

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“…Alongside intensifying hearing screening any other intervention would require careful clinical risk assessment aided by thoughtful discussions with parents, carers and older children themselves. This could then lead to agreeing on an alternative cancer treatment plan for the child [29].…”

Section: Genetic Susceptibility To Hearing Impairmentmentioning

confidence: 99%

Cisplatin Ototoxicity in Children

Brock¹,

Rajput²,

Edwards³

et al. 2021

Hearing Loss - From Multidisciplinary Teamwork to Public Health

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Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many long-term effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of a child growing up with high frequency hearing loss.

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“…These observations were made on small cohorts and independent replication is required. Additionally, high-throughput screens have been applied to search genomic biomarkers (TPMT, COMT, ABCC3, ACYP2) for cisplatin-induced hearing loss; however, independent cohorts for validation are necessary ( Lanvers-Kaminsky and Ciarimboli, 2017 ; Drogemoller et al., 2019 ).…”

Section: Mechanisms Of Cisplatin-induced Ototoxicitymentioning

confidence: 99%

Current Strategies to Combat Cisplatin-Induced Ototoxicity

Chen

et al. 2020

Front. Pharmacol.

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Cisplatin is widely used for the treatment of a number of solid malignant tumors. However, ototoxicity induced by cisplatin is an obstacle to effective treatment of tumors. The basis for this toxicity has not been fully elucidated. It is generally accepted that hearing loss is due to excessive production of reactive oxygen species by cells of the cochlea. In addition, recent data suggest that inflammation may trigger inner ear cell death through endoplasmic reticulum stress, autophagy, and necroptosis, which induce apoptosis. Strategies have been extensively explored by which to prevent, alleviate, and treat cisplatin-induced ototoxicity, which minimize interference with antitumor activity. Of these strategies, none have been approved by the Federal Drug Administration, although several preclinical studies have been promising. This review highlights recent strategies that reduce cisplatin-induced ototoxicity. The focus of this review is to identify candidate agents as novel molecular targets, drug administration routes, delivery systems, and dosage schedules. Animal models of cisplatin ototoxicity are described that have been used to evaluate drug efficacy and side effect prevention. Finally, clinical reports of otoprotection in patients treated with cisplatin are highlighted. For the future, high-quality studies are required to provide reliable data regarding the safety and effectiveness of pharmacological interventions that reduce cisplatin-induced ototoxicity.

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Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

Cited by 26 publications

References 67 publications

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Cisplatin Ototoxicity in Children

Current Strategies to Combat Cisplatin-Induced Ototoxicity

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