Review articleMechanisms of cisplatin-induced ototoxicity and prevention
Introduction
Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat a variety of soft tissue neoplasms, including ovarian, testicular, cervical, head and neck, lung and bladder cancer. Serious side effects include nephrotoxicity, neurotoxicity and ototoxicity. In order to effect cures, the dosing of cisplatin has been increased in recent treatment protocols. Some audiometric studies have reported elevated hearing thresholds in 75–100% of patients treated with cisplatin (McKeage, 1995). This is particularly problematic in children receiving cisplatin. Risk factors that increase the risk for ototoxicity from cisplatin in children include: younger age, larger cumulative doses, pre-existing hearing loss and renal disease (Li et al., 2004, Knight et al., 2005) and irradiation of the brain or skull base (Chen et al., 2006).
Ototoxicity of cisplatin can be reduced by various protective agents. This paper reviews recent research findings that provide new insights into the mechanisms for cisplatin ototoxicity and the effects of various protective agents that may ameliorate cisplatin ototoxicity.
Section snippets
Effects on cochlear function
Adverse effects of cisplatin on auditory function have been documented in numerous reports. Ototoxicity has been demonstrated in animal experiments by reduction of the endocochlear potential (EP) (Ravi et al., 1995, Tsukasaki et al., 2000, Klis et al., 2000) and elevation of the thresholds for both the compound action potential (CAP) and cochlear microphonic (CM) after ototoxic doses of cisplatin. The CAP amplitude is reduced to a greater extent than the (CM) amplitude. The greater effect of
Effects on cochlear morphology
Cisplatin ototoxicity has been shown to have at least three major tissue targets in the cochlea: organ of Corti, spiral ganglion cells and lateral wall (stria vascularis and spiral ligament). Studies in guinea pig reveal that cisplatin affects both the organ of Corti (primarily the outer hair cells) and the spiral ganglion cells (Van Ruijven et al., 2005a). Type I spiral ganglion cells undergo detachment of their myelin sheaths. The time sequence of damage to spiral ganglion cells and outer
Biochemical and molecular effects
Cisplatin interacts with cochlear tissue explants to generate reactive oxygen species (ROS) (Clerici et al., 1995, Clerici et al., 1996, Kopke et al., 1997) such as superoxide anion (Dehne et al., 2001, Banfi et al., 2004). Cochlear tissues from animals receiving ototoxic doses of cisplatin were depleted of glutathione and antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase and glutathione reductase) with a reciprocal increase in malondialdehyde levels, an indicator
Prevention of ototoxicity
The cochlea has endogenous mechanisms to deal with oxidative stress caused by agents like cisplatin. Protective molecules include: glutathione and the antioxidant enzymes, heat shock proteins, adenosine A1 receptors, NRF2 and heme-oxygenase-1, and the kidney injury molecule (KIM-1) (Mukherjea et al., 2006). Although these cytoprotective molecules are expressed in the cochlea, and are up-regulated following oxidative stress, oxidative stress imposed by cisplatin can overwhelm these intrinsic
Interference with cisplatin therapy
Authors have expressed concerns about protective agents interfering with the antitumor effect of cisplatin. They have suggested caution in the use of these drugs in patients receiving cisplatin (Blakley et al., 2001). Sodium thiosulfate interferes with the antitumor effects of cisplatin. Simultaneous application of sodium thiosulfate and cisplatin to a human squamous cell carcinoma line in vitro reduced the tumoricidal activity of cisplatin (Viallet et al., 2006). There appears to be no
Conclusions
Cisplatin ototoxicity appears to be triggered by ROS that initiate a cascade of molecular events that lead to apoptosis of outer hair cells, resulting in loss of DPOAEs and elevation of high frequency thresholds for CAP and ABR. Ototoxic effects on the stria vascularis are transient, resulting in temporary reduction of EP associated with strial edema. The EP recovers but residual shrinkage of cells in the stria persist. Spiral ganglion cells are the least affected. The effects of cisplatin on
Future directions
To date, the Food and Drug Administration in the US has not approved any drugs as protective agents against cisplatin ototoxicity. However, it is likely that in the near future clinical trials will be initiated to study potential drugs to prevent cisplatin ototoxicity.
From this review of the literature, several ideas for prevention of cisplatin ototoxicity can be gleaned.
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Thiols are highly effective in antagonizing cisplatin ototoxicity. Unfortunately, some thiols also reduce its antitumor
Acknowledgements
Hair cell lines derived from the Immortomouse (OC-k3 and HEI-OC1) were obtained from Dr. Federico Kalinec at the House Ear Institute. UB/OC-1 cells were provided by Dr. Matthew Holley at the Institute of Molecular Physiology in Sheffield, UK.
The authors acknowledge the support of the National Institutes of Health, NIDCD, grant # R01-DC 02396.
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