Understanding platinum-induced ototoxicity

doi:10.1016/j.tips.2013.05.006

Trends in Pharmacological Sciences

Volume 34, Issue 8, August 2013, Pages 458-469

https://doi.org/10.1016/j.tips.2013.05.006 Get rights and content

Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients’ quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized.

Section snippets

Ototoxicity, a platinum-associated side effect, receives renewed attention

The US Food and Drug Administration (FDA) approved cisplatin in 1978 and carboplatin in 1989, despite knowledge of their ototoxic and nephrotoxic side effects. Platinum ototoxicity can manifest in both children and adults. Children, however, are more susceptible to platinum-induced hearing loss than adults, resulting in higher incidence rates (Figure 1). Moreover, deafness due to platinum treatment in childhood is particularly challenging with respect to speech and language development,

Mechanisms

Basic mechanisms of platinum-induced cytotoxicity in normal tissues such as the inner ear are presumably not completely different from those in tumor cells. It is well known that the antineoplastic efficiency of this class of drugs results from the interaction with the nuclear DNA of tumor cells. Platinum compounds such as cisplatin initially induce monoadducts at nucleophilic sites (e.g., of guanine or adenine) and can subsequently lead to intrastrand and interstrand crosslinks in the DNA.

Incidence, risk factors, and clinical presentation

Cisplatin, carboplatin, and oxaliplatin are the only FDA-approved platinum compounds. Because they have been used long-term world-wide, most post-marketing surveillance data are available for these drugs. Overall, the data indicate that cisplatin carries a higher risk of hearing impairment than carboplatin. Nevertheless, treatment with carboplatin still carries a significant risk of mild to severe ototoxicity. Young patients and patients receiving high cumulative doses are at greater risk of

Diagnosis

Structural alterations in the outer hair cells and spinal ganglion neurons of the basal cochlear turn represent the earliest event in cisplatin-induced ototoxicity. These structural alterations are accompanied by reduced auditory sensitivity. High-frequency testing (>6 kHz) permits the early detection of platinum-induced ototoxic damage well before impairments become evident in conventional frequency ranges relevant to everyday life of the child. At present, pure tone audiometry (up to 10 kHz),

Non-genetic risk factors

Established non-genetic risk factors that increase the susceptibility to ototoxic side effects and hearing loss associated with platinum compounds are summarized in Box 1 (see also [8]). An important risk factor is the dose. At a population level, higher cumulative doses of cisplatin are associated with higher rates of ototoxic side effects; the incidence of cisplatin-dependent ototoxicity increases by an average of 5–7% per additional 100 mg/m² cumulative cisplatin (Figure 1A).

Although clinical

Pharmacogenetics

To date, genetic association studies of ototoxicity have been based on the candidate gene approach. Genes were selected on the basis of established or postulated mechanisms of platinum ototoxicity and a restricted number of polymorphisms in these genes that affect the function or the expression of the encoded protein were evaluated (Figure 2).

The first pharmacogenetic association study was performed by Peters et al. more than one decade ago and focused on polymorphisms in genes of the GST

Prevention strategies

The use of lower cumulative cisplatin doses or replacing cisplatin with a second- or third-generation analog with a lower ototoxic potential has not been implemented as a preventative strategy for cisplatin-induced ototoxicity in routine clinical practice, because it is unclear whether these alternative treatments would fully retain the antitumor efficacy and thus survival rates of standard cisplatin regimens. Nevertheless, recommendations for dose adjustments or the replacement of cisplatin

Concluding remarks

Currently available clinical data were used to develop statistical regression models that predict the risk of developing cisplatin ototoxicity by integrating established clinical variables, namely, patient age and cumulative cisplatin dose. Although these models accurately predict the average risk in a cohort of patients at a given age and cumulative cisplatin dose, they do not precisely map the risk in an individual patient [11]. The reason for this is that only a small fraction of the

References (63)

A. Nitz
Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients
Oncol. Lett.
(2013)
P.R. Brock
Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale
J. Clin. Oncol.
(2012)
G. Ciarimboli
Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions
Am. J. Pathol.
(2010)
L. Riedemann
Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin
Pharmacogenomics J.
(2008)
X. Xu
Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients
Lung Cancer
(2012)
I. Qaddoumi
Carboplatin-associated ototoxicity in children with retinoblastoma
J. Clin. Oncol.
(2012)
I. Ali
Platinum compounds: a hope for future cancer chemotherapy
Anticancer Agents Med. Chem.
(2013)
A. Yancey
Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients
Pediatr. Blood Cancer
(2012)
P. Eiamprapai
Effect of cisplatin on distortion product otoacoustic emissions in Japanese patients
Laryngoscope
(2012)
K.R. Knight
Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions
J. Clin. Oncol.
(2007)

Y. Li

Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose

Eur. J. Cancer

(2004)

P.R. Brock

Cisplatin ototoxicity in children: a practical grading system

Med. Pediatr. Oncol.

(1991)

J.G. Gurney

Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group

Pediatrics

(2007)

L.P. Rybak

Mechanisms of cisplatin-induced ototoxicity and prevention

Hear. Res.

(2007)

S. Grewal

Auditory late effects of childhood cancer therapy: a report from the Children's Oncology Group

Pediatrics

(2010)

A.M. Tharpe

Unilateral and mild bilateral hearing loss in children: past and current perspectives

Trends Amplif.

(2008)

M. Sprauten

Impact of long-term serum platinum concentrations on neuro- and ototoxicity in cisplatin-treated survivors of testicular cancer

J. Clin. Oncol.

(2012)

E.E. Brouwers

Long-term platinum retention after treatment with cisplatin and oxaliplatin

BMC Clin. Pharmacol.

(2008)

W. Stöhr

Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system

Cancer Invest.

(2005)

T. Al-Khatib

Cisplatinum ototoxicity in children, long-term follow up

Int. J. Pediatr. Otorhinolaryngol.

(2010)

A.L. Abujamra

The use of high-frequency audiometry increases the diagnosis of asymptomatic hearing loss in pediatric patients treated with cisplatin-based chemotherapy

Pediatr. Blood Cancer

(2013)

N. Beahan

High-frequency pure-tone audiometry in children: a test–retest reliability study relative to ototoxic criteria

Ear Hear.

(2012)

R. Singh Chauhan

The role of ultrahigh-frequency audiometry in the early detection of systemic drug-induced hearing loss

Ear Nose Throat J.

(2011)

A. Weissenstein

Progressive hearing loss after completion of cisplatin chemotherapy is common and more pronounced in children without spontaneous otoacoustic emissions before chemotherapy

Int. J. Pediatr. Otorhinolaryngol.

(2012)

C.M. Schmidt

[The “Muenster classification” of high frequency hearing loss following cisplatin chemotherapy]

HNO

(2007)

A.B. Khan

Cisplatin therapy in recurrent childhood brain tumors

Cancer Treat. Rep.

(1982)

L. Lafay-Cousin

Early cisplatin induced ototoxicity profile may predict the need for hearing support in children with medulloblastoma

Pediatr. Blood Cancer

(2013)

L.P. Rybak et al.

Ototoxicity

Kidney Int.

(2007)

C. Lanvers-Kaminsky

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

Pediatr. Blood Cancer

(2006)

U. Peters

Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

Anticancer Drugs

(2000)

J. Oldenburg

Cisplatin-induced long-term hearing impairment is associated with specific glutathione S-transferase genotypes in testicular cancer survivors

J. Clin. Oncol.

(2007)

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Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.
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As an anticancer drug, cisplatin is widely used, but its clinical application is restricted due to its severe side effects of ototoxicity. Therefore, this study was dedicated to assessing the benefit of ginsenoside extract, 20(S)-Ginsenoside Rh1 (Rh1), on cisplatin-induced ototoxicity. HEI-OC1 cells and neonatal cochlear explants were cultured. Cleaved caspase-3, TUNEL, and MitoSOX Red were observed in vitro by immunofluorescence staining. CCK8 and LDH cytotoxicity assays were detected to measure cell viability and cytotoxicity. Our results showed that Rh1 significantly increased cell viability, reduced cytotoxicity, and alleviated cisplatin-induced apoptosis. In addition, Rh1 pretreatment decreased the excessive accumulation of intracellular reactive oxygen species. Mechanistic studies indicated that Rh1 pretreatment reversed the increase of apoptotic protein expression, accumulation of mitochondrial ROS, and activation of the MAPK signaling pathway. These results suggested that Rh1 can act as an antioxidant and anti-apoptotic agent against cisplatin-induced hearing loss by suppressing the excessive accumulation of mitochondrial ROS, activation of MAPK signaling pathway and apoptosis.
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Intravitreal Carboplatin as Salvage Treatment for Progressive Vitreous Disease in Retinoblastoma: A Phase I Clinical Trial
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Trends in Pharmacological Sciences

ReviewUnderstanding platinum-induced ototoxicity

Section snippets

Ototoxicity, a platinum-associated side effect, receives renewed attention

Mechanisms

Incidence, risk factors, and clinical presentation

Diagnosis

Non-genetic risk factors

Pharmacogenetics

Prevention strategies

Concluding remarks

Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients

Oncol. Lett.

Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale

J. Clin. Oncol.

Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions

Am. J. Pathol.

Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

Pharmacogenomics J.

Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients

Lung Cancer

Carboplatin-associated ototoxicity in children with retinoblastoma

J. Clin. Oncol.

Platinum compounds: a hope for future cancer chemotherapy

Anticancer Agents Med. Chem.

Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients

Pediatr. Blood Cancer

Effect of cisplatin on distortion product otoacoustic emissions in Japanese patients

Laryngoscope

Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions

J. Clin. Oncol.

Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose

Eur. J. Cancer

Cisplatin ototoxicity in children: a practical grading system

Med. Pediatr. Oncol.

Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group

Pediatrics

Mechanisms of cisplatin-induced ototoxicity and prevention

Hear. Res.

Auditory late effects of childhood cancer therapy: a report from the Children's Oncology Group

Pediatrics

Unilateral and mild bilateral hearing loss in children: past and current perspectives

Trends Amplif.

Impact of long-term serum platinum concentrations on neuro- and ototoxicity in cisplatin-treated survivors of testicular cancer

J. Clin. Oncol.

Long-term platinum retention after treatment with cisplatin and oxaliplatin

BMC Clin. Pharmacol.

Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system

Cancer Invest.

Cisplatinum ototoxicity in children, long-term follow up

Int. J. Pediatr. Otorhinolaryngol.

The use of high-frequency audiometry increases the diagnosis of asymptomatic hearing loss in pediatric patients treated with cisplatin-based chemotherapy

Pediatr. Blood Cancer

High-frequency pure-tone audiometry in children: a test–retest reliability study relative to ototoxic criteria

Ear Hear.

The role of ultrahigh-frequency audiometry in the early detection of systemic drug-induced hearing loss

Ear Nose Throat J.

Progressive hearing loss after completion of cisplatin chemotherapy is common and more pronounced in children without spontaneous otoacoustic emissions before chemotherapy

Int. J. Pediatr. Otorhinolaryngol.

[The “Muenster classification” of high frequency hearing loss following cisplatin chemotherapy]

HNO

Cisplatin therapy in recurrent childhood brain tumors

Cancer Treat. Rep.

Early cisplatin induced ototoxicity profile may predict the need for hearing support in children with medulloblastoma

Pediatr. Blood Cancer

Ototoxicity

Kidney Int.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

Pediatr. Blood Cancer

Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

Anticancer Drugs

Cisplatin-induced long-term hearing impairment is associated with specific glutathione S-transferase genotypes in testicular cancer survivors

J. Clin. Oncol.

Review
Understanding platinum-induced ototoxicity