Strategies to reduce the risk of platinum containing antineoplastic drug-induced ototoxicity

ABSTRACT

Introduction

Cisplatin is a highly effective chemotherapeutic agent against a variety of solid tumors in adults and in children. Unfortunately, a large percentage of patients suffer permanent sensorineural hearing loss. Up to 60% of children and at least 50% of adults suffer this complication that seriously compromises their quality of life. Hearing loss is due to damage to the sensory cells in the inner ear. The mechanisms of cochlear damage are still being investigated. However, it appears that inner ear damage is triggered by reactive oxygen species (ROS) formation and inflammation 34.

Areas covered

We discuss a number of potential therapeutic targets that can be addressed to provide hearing protection. These strategies include enhancing the endogenous antioxidant pathways, heat shock proteins, G protein coupled receptors and counteracting ROS and reactive nitrogen species, and blocking pathways that produce inflammation, including TRPV1 and STAT1 36.

Expert opinion

Numerous potential protective agents show promise in animal models by systemic or local administration. However, clinical trials have not shown much efficacy to date with the exception of sodium thiosulfate. There is an urgent need to discover safe and effective protective agents that do not interfere with the efficacy of cisplatin against tumors yet preserve hearing 151.

KEYWORDS:

• Cisplatin
• ototoxicity
• cochlea
• clinical trials
• drug targets
• mechanisms
• transtympanic
• hearing loss

Article highlights

• Cisplatin is an ‘essential’, chemotherapeutic drug that is widely used to treat solid tumors, with severe side effects including dose limiting ototoxicity and neurotoxicity.

• This manuscript discusses a brief history, pharmacology, toxicities, drug interactions, mechanisms of ototoxicity and molecular targets in pre-clinical and clinical trials.

• Cisplatin induced chronic ROS generation and inflammation are cross connected and seem to be one of the major pathways for related ototoxicity.

• Most pre-clinical and clinical experimental drugs that are otoprotective belong to two broad categories of anti-oxidants and anti-inflammatory agents.

• The pre-clinical use of new drugs such as CDK2 inhibitors, GPCR agonists and lovastatin provide exciting new areas of focus in prevention of cisplatin induced hearing loss.

• An intriguing trend in treatment of cisplatin induced hearing loss seems to be the localized route of drug delivery by transtympanic injections.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institute on Deafness and Other Communication Disorders [grant numbers: R01DC002396, R01DC016835, R43DC018258].