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Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss Robert Alan Hazlitt, Jaeki Min, and Jian Zuo J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b01653 • Publication Date (Web): 23 Jan 2018 Downloaded from http://pubs.acs.org on January 23, 2018
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Journal of Medicinal Chemistry
Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss Robert A. Hazlitt,†,‡ Jaeki Min,‡ Jian Zuo*,† †
Dept. of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN
38105, USA ‡
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital,
Memphis, TN 38105, USA
ABSTRACT: Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and not interfere with its antitumoral activity. Many therapies have been successful in preclinical work, but only a few have shown any protection in the clinic, and none have been approved by the FDA. This review summarizes the clinical and preclinical studies of the most effective small molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field.
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Since its approval by the FDA in 1978, cisplatin has become a cornerstone in chemotherapeutic regimens and has been included on the World Health Organization’s list of essential medicines. However, its therapeutic benefits are often coupled with potentially debilitating ototoxicity, with some degree of hearing loss occurring in about 63% of patients.1 Despite the high incidence and the enormous social and economic consequences of the ototoxic side effects, no FDA approved therapies for prevention of cisplatin-induced hearing loss have been developed. Still, numerous protective compounds have been identified in preclinical studies and several are currently undergoing clinical trials (Table 1 and Figure 1). Table 1. List of all clinical candidates for protection against cisplatin-induced ototoxicity
Name
Mechanism
Delivery
Outcomes and Considerations
Completed
Ref.
I.V.
2017
Sodium thiosulfate
Lowered incidence of hearing loss; Lowered survival for disseminated cancer
2
inactivates cisplatin; antioxidant; protects antioxidant enzymes
I.V.
No results reported
ETC 2018
3
I.A.
No impact on incidence of hearing loss
2007
4
Acetylcysteine
D-methionine
Amifostine
inactivates cisplatin; antioxidant; protects antioxidant enzymes; promotes glutathione synthesis
I.V.
Dose finding study; no results reported
ETC 2019
5
Local
Significant hearing protection only at 8 kHz
2013
6
Local
No significant hearing protection
2014
7
inactivates cisplatin; antioxidant; protects antioxidant enzymes
Oral
Reported hearing protection at >10 kHz; No peer-reviewed data published
2009
8
I.V.
Non-randomized; hearing protection in average-risk, but not high-risk medulloblastoma
2014
9
I.V.
Ototoxicity in amifostine group (9%) vs untreated (16%)
1996
10
I.V.
(5 Trials) No significant hearing protection
1999-2009
11-15
Oral
Ongoing study; No results reported
ETC 2018
16
Local
Negative efficacy results in a related study
Terminated
17
Local
Significant hearing protection only at 6 kHz
2013
18
inactivates cisplatin; antioxidant
Ebselen
antioxidant; glutathione peroxidase mimetic; anti-inflammatory
Dexamethasone
regulates cytokines; protects antioxidant enzymes
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Journal of Medicinal Chemistry
Flunarizine
inhibits MPT and NF-κB activation
Oral
Significant hearing protection at
