Cisplatin-related Ototoxicity Research Articles

FAM134B-induced endoplasmic reticulum (ER)-phagy exacerbates cisplatin-insulted hair cell apoptosis ：Possible relation to excessive ER stress

AimsFAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin. MethodsImmunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry. ResultsIn the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure. ConclusionsCollectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.

The protective effect of aspirin-induced temporary threshold shift in an animal model of cisplatin-related ototoxicity.

The purpose of this study was to evaluate whether induction of temporary threshold shift (TTS) with aspirin prior to cisplatin exposure can prevent or minimize cisplatin detrimental effects on hearing. We randomly divided BALB mice into three groups: (1) cisplatin only, (2) aspirin only, and (3) combined aspirin/cisplatin. Cisplatin was administered as a single intraperitoneal injection of 14mg/kg. Aspirin was administered for three weeks via intraperitoneal injection of 200mg/kg sodium salicylate, twice daily. Air conduction thresholds were recorded using Auditory Brainstem Responses (ABR). Cochleae were harvested and cochlear hair cells were counted using a scanning electron microscope (SEM). Aspirin-induced TTS have reached an average of 30.05±16.9dB after 2weeks. At 60days, cisplatin-only treated mice experienced an average threshold shifts of 50.7dB at 4kHz, 35.16dB at 8kHz, 70dB at 16kHz, 53.1dB at 32kHz. All threshold shifts were significantly worse than for cisplatin/aspirin treated mice with TTS of 11.85dB at 4kHz, 3.58dB at 8kHz, 16.58 dB at 16kHz, 20.41dB at 32kHz (p < 0.01). Cochlear cell count with SEM has shown reduction in the number of both inner and outer hair cells in the mid-turn in cisplatin treated mice. Aspirin induced TTS can protect from cisplatin-induced ototoxicity. This beneficial effect was demonstrated by auditory thresholds as well as SEM. Larger pre-clinical and clinical studies are still needed to confirm these findings.

Invited Commentary on Vasudevan, et al: Outcomes of children with well differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731

Advances in hepatoblastoma treatment have improved survival but have been accompanied by the chronic toxicities of pediatric cancer therapy. Cisplatin is the cornerstone of chemotherapy treatment for hepatoblastoma. The most frequent long-term complication of hepatoblastoma treatment is cisplatin-related ototoxicity. Among children who receive cisplatin, 25-90% will exhibit measurable hearing loss, impacting language and social development [1]. Therefore, efforts to identify children eligible for reduction or elimination of cisplatin-based chemotherapy while maintaining excellent oncologic outcomes are paramount in reducing the long-term toxicities of hepatoblastoma cancer treatment.

The RADIO trial: Randomized assessment of cisplatin dosing interval for ototoxicity with curative concurrent chemo-radiation for locally advanced head and neck squamous cell carcinoma.

TPS12144 Background: Patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive curative chemoradiation (CRT) with Cisplatin, as a standard of care. A meta-analysis of 52 randomized trials comparing Low Dose (LD) and High Dose (HD) schedules demonstrated differing toxicity profiles but hearing effects were not rigorously studied. Hearing loss associated with HD Cisplatin can result in survivorship challenges. A local study suggested a protective effect for LD Cisplatin in relation to ototoxicity and pharmacogenomic markers, MATE1 and COMT, to be associated with risk for ototoxicity. We hypothesize that LD cisplatin is associated with reduced frequency of hearing loss when compared to the standard HD cisplatin in LASCCHN patients on CRT and that differences in MATE1/COMT can predict for cisplatin-related ototoxicity and be identified prior to treatment. Our goal is to develop an innovative personalized treatment pathway incorporating predictive pharmacogenomics markers to improve the tolerability and survivorship outcomes of curative CRT for LASCCHN. Methods: This is a prospective, open-label, randomized clinical trial. Following informed consent, eligible LASCCHN patients planned for primary CRT will be stratified by tumor p16 status and then randomized in 1:1 fashion to either concurrent LD Cisplatin (40mg/m2 every week) or HD cisplatin (100mg/m2 every 3 weeks). The primary outcome is to measure the change in incidence of CTCAE grade ≥2 hearing loss and hearing-related quality of life (QOL) at 1 year. As part of secondary and exploratory outcomes, differences in survival, loco-regional control, global QOL and other toxicities (e.g. nephrotoxicity, neurotoxicity) will be assessed. The relationship between MATE1 and COMT, as predictors for cisplatin-related ototoxicity will be evaluated. Cost-effectiveness analyses comparing the two regimens will be assessed. Statistical plan: Based on rates of CTCAE grade ≥2 hearing loss in an earlier study (Winquist et al., 2016), assuming a conservative rate of hearing loss, amongst treated patients, of 60% with HD cisplatin and 30% with LD cisplatin, a total sample size of 92 patients would achieve &gt; 80% statistical power, (two-sided, alpha = 0.05 test of two proportions) to detect these differences. 100 patients would be targeted to accrual for an assumed 5% noncompliance rate. For hearing related QOL, a two-sided, alpha = 0.05, two-sample t-test with 50 patients per group would achieve &gt; 80% statistical power to detect an effect size of 0.60 and &gt; 95% power to detect an effect size of 0.75. All analyses will be based primarily on the intent-to-treat population. An arms-length data and safety monitoring committee (DSMC) will review safety data bi-annually. Trial accrual status: 60 participants have been accrued. Clinical trial information: NCT03649048.

Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1–PI3K/AKT pathway

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss. This study aimed to assess the potential effect of the DNA methyltransferase (DNMT) inhibitor RG108 on cisplatin-induced ototoxicity. Immunohistochemistry, apoptosis assay, and auditory brainstem response (ABR) were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells (HCs) and spiral ganglion neurons (SGNs). Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential (MMP) assessment. Reactive oxygen species (ROS) amounts were evaluated by Cellrox green and Mitosox-red probes. Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates (OCRs). The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs, and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation. Furthermore, RG108 upregulated BCL-2 and downregulated APAF1, BAX, and BAD in HEI-OC1 cells, and triggered the PI3K/AKT pathway. Decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1) and high methylation of the LRP1 promoter were observed after cisplatin treatment. RG108 treatment can increase LRP1 expression and decrease LRP1 promoter methylation. In conclusion, RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

Levosimendan ameliorates cisplatin-induced ototoxicity: Rat model

ObjectivesCisplatin is employed for chemotherapeutic purposes in several types of adult and pediatric cancer. However, side-effects including nephrotoxicity, ototoxicity, gastrointestinal effects and neuropathy restrict the use of the drug due to their adverse impacts on quality of life. This study aimed to determine whether levosimendan exhibits a protective effect against cisplatin-related ototoxicity in a rat model by means of functional, biochemical and histochemical analysis. MethodsThe study was employed with 24 female Sprague Dawley rats. After distortion product otoacoustic emissions (DPOAE) tests applied to all rats, rats were randomly assigned into four groups of six animals each. A single intraperitoneal 15 mg/kg dose of cisplatin was administered to Cisplatin group. Levosimendan group received intraperitoneal levosimendan at a dose of 100 mg/kg for five consecutive days. Cisplatin + Levosimendan group received intraperitoneal levosimendan at a dose of 100 mg/kg for five consecutive days and a single intraperitoneal dose of 15 mg/kg cisplatin at 3rd day of the study. Control group received 8 mL/kg/day intraperitoneal saline solution for five consecutive days. The DPOAE test was repeated on the 6th day of the study. All rats were then sacrificed, the cochleas were removed and set aside for biochemical and histopathological analyses. ResultsA significant increase in levels of Malondialdehyde (MDA) and significantly lower activities of superoxide dismutase (SOD) and Glutathione peroxidase (GPx) were observed at rats of cisplatin group. Administration of levosimendan showed significantly lower cochlear MDA levels, while SOD and GPx activities both increased significantly. The DPOAE test performed at 6th day of the study showed a significant impairment in the signal-noise ratio (SNR) levels of rats in Cisplatin group. The SNR levels of rats treated with levosimendan were significantly higher than those of cisplatin group and were similar to those of the control group. Cisplatin impaired the cochlear structure and a severe Caspase 3 and 8-hydroxy-2' -deoxyguanosine (8-OHdG) immunopositivity was observed at cochlea of the rats of cisplatin group. Administration of levosimendan protected the structure of cochlea and there was a mild Caspase 3 and 8OHdG immunopositivity. ConclusionOur data demonstrate that levosimendan protects hearing against cisplatin-induced ototoxicity and obviates cellular degeneration. It also significantly reduces oxidative stress and apoptosis, probable mechanisms involved in ototoxicity.

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

BackgroundCisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. MethodsA total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. ResultsAlthough aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. ConclusionsAspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.

SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.

Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children’s Cancer Center (1987–2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30–7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.

Abstract 5576: MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients

Abstract Purpose: The SOD2 gene encodes manganese superoxide dismutase (MnSOD) and is critical for superoxide anion detoxification. Variants in SOD2 have been associated with noise-induced hearing loss, and animal models suggest MnSOD expression is up-regulated in the cochlea after treatment with platinum-based chemotherapeutic agents. Therefore, we examined the role of SOD2 variants on ototoxicity among cisplatin-treated childhood medulloblastoma patients. Methods: Peripheral blood samples were obtained from 100 patients treated for pediatric medulloblastoma or supratentorial primitive neuroectodermal tumor at Texas Children's Cancer Center or MD Anderson Cancer Center between 1982 and 2009. Demographic, clinical, and treatment information was abstracted from patient medical records. A diagnosis of ototoxicity was assigned to patients whose medical records indicated they had received cisplatin chemotherapy and required the use of a hearing aid ≥1 year following the completion of primary therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip (San Diego, CA). A linkage disequilibrium-based single nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative common variants (minor allele frequency ≥5%). The association between each SNP and ototoxicity was assessed using multivariable logistic regression, assuming a log-additive model. Adjusted models included confounders (age at diagnosis, gender, craniospinal radiotherapy dose, cisplatin dose, amifostine therapy, and ethnicity) selected using a change in estimate approach. Results: Study participants were primarily male (73.2%) and non-Hispanic white (42.3%) with a mean age at diagnosis of 7.3 years. Of the 71 eligible patients with available information, 26 (36.6%) suffered from cisplatin-related ototoxicity. Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, rs4880) identified by the LD-based selection strategy were available in the genotyped data. After correcting for multiple comparisons, the C allele of the rs4880 variant was significantly associated with ototoxicity (OR = 3.00; 95% CI: 1.32-6.82) in adjusted models. Conclusions: In this study, the SOD2 rs4880 variant was associated with ototoxicity. The rs4880 T&amp;gt;C substitution results in a Val&amp;gt;Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. Specifically, the Ala-variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore oxidative stress may be an important mechanism in therapy-related cochlear damage. Characterizing genetic predictors of ototoxicity susceptibility may aid in prevention strategies and potentially identify novel antioxidant therapeutic targets. Citation Format: Austin L. Brown, Philip J. Lupo, Mehmet F. Okcu, Ching C. Lau, Surya P. Rednam, Michael E. Scheurer. MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2015-5576

Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss.

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10(-8), hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.

The protective role of molsidomine on the Cisplatin-induced ototoxicity.

This experimental study was designed to investigate the protective effects of molsidomine (MOL) on against cisplatin-induced ototoxicity (CIO). To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status [including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPX), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] were evaluated. Thirty-two female wistar albino rats were divided into four groups including; control (Group K), cisplatin (Group C), cisplatin plus MOL group (Group CM), and MOL group (Group M). DPOAEs measurements between 0.9961 and 8.0003Hz as DP-gram and input/output (I/O) functions were performed in the same (left) ear of all rats on days 0, 1st, 5th and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. In the C group, statistically significant DPOAE amplitude reductions were detected at 2.5195, 3.1758, 3.9961, 5.0391, 6.3516 and 8.0039Hz frequencies (p<0.05) between 0th and 1st, 0th and 5th and 0th and 12th days' measurements (p<0.05). Serum level of MDA, TAC and OSI levels were significantly higher in the C group versus K group (p<0.05). In the CM group, there were no significant differences at all frequencies between 0th and other days' measurements (p>0.05) and the serum levels of all biochemical parameters were shifted toward normal values, similar to the K group (p<0.05). No significant differences were detected in the either M or K group's measurements. According to these results, cisplatin-related ototoxicity has been significantly prevented by MOL.

Effect of intratympanic dimethyl sulphoxide (DMSO) in an in vivo model of cisplatin-related ototoxicity

Although dimethyl sulfoxide (DMSO) is one of the most common solvents employed in otoprotection studies, its effect on the inner ear remains unknown. Only a few in vitro studies have addressed the effect of DMSO in cochlear cells. Up to the date, no in vivo functional studies have been reported. To determine the effect of intratympanic DMSO application in the inner ear, and to evaluate its effect in combination with cisplatin in Wistar rats, twelve Wistar rats were randomly assigned into two groups. Group A received intratympanic 1 % DMSO in both ears. Group B received intraperitoneal cisplatin (10 mg/kg) and intratympanic 0.5 % DMSO in the right ear and saline solution in the left ear. Functional changes were evaluated with Auditory Steady-State Responses before and 5 days after the procedure. Morphological changes were studied by means of confocal laser scanning microscopy following the removal of the temporal bones and cochlear dissection. Hearing threshold levels in group A did not show any statistically significant changes after the treatment. In group B, significant differences between pre- and post-treatment were found, with no statistically significant variations between right (DMSO) and left ear (saline solution). We suggest that DMSO could be safely used to dissolve hydrophobic compounds in otoprotection studies without interfering with the cochlear damage produced by cisplatin.

The Protective Effect of Chrysin Against Cisplatin İnduced Ototoxicity in Rats.

Ototoxicity is a common side effect of cisplatin chemotherapy. The aim of this study was to investigate the potential protective effect of chrysin against cisplatin-induced ototoxicity. Thirty-four adult female Wistar albino rats were separated into four groups: a cisplatin group (Group A), with cisplatin administered to ten rats once daily for three consecutive days at doses of 8mg/kg body weight intraperitoneally (i.p.); a cisplatin plus chrysin group (Group B), with 8mg/kg of cisplatin administered i.p. daily to ten rats for three consecutive days and 25mg/kg of chrysin administered via oral gavage in a corn oil for 5days: a chrysin group (Group C), with 25mg/kg of chrysin administered via oral gavage in corn oil for 5days to seven rats; and a control group (Group D), with 5ml/kg of corn oil administered to seven rats via oral gavage for 5days. Distortion product otoacoustic emission measurements were performed in the same ear of the rats under general anesthesia at baseline and on the first and fifth days after drug administration. No significant differences were noted between the measurements either in the chrysin group or in the control group. In the cisplatin group, there was a significant worsening of hearing compared to baseline and the measurements on the fifth day at all frequencies. In the statistical analysis, a statistically significant difference was observed at 5039, 6351, 8003, and 10078Hz frequencies between the measurements on the first and fifth days. In the cisplatin plus chrysin group, there were statistically significant differences at frequencies of 2,003 and 5,039Hz between the measurements at baseline and on the fifth day, at 3,175 and 5,039Hz between the measurements on the first and fifth days, and at 8,003 and 100,078Hz between the measurements at baseline and on the first day. According to these results, this study demonstrates that cisplatin-related ototoxicity can be prevented in rats by the administration of chrysin.

The effects of lycopene on cisplatin-induced ototoxicity

To investigate the potential preventive effect of lycopene in cisplatin-related ototoxicity. Thirty-five healthy 3-3.5-month adult female Sprague-Dawley rats were randomly divided into three groups and treated as follows: Group 1 (n = 10), received no cisplatin or lycopene. Both group 2 (n = 10) and; Group 3 (n = 15) received a single dose of 12 mg/kg cisplatin intraperitoneally. Lycopene was administered via gavage feeding in group 2 for 15 days. Prior to any medication administration, the baseline distortion product emissions were obtained in three groups. The animals were tested again at 15th day. The resulting distortion product otoacoustic emissions (DPOAE) were evaluated at 1.5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 kHz. On day 0, prior to any medications, the initial DPOAEs measurement results gave similar values in the three groups (p > 0.05). In group 2 and 3, statistically significant differences were recorded for all frequencies between day 0 and day 15 values (p < 0.05). Lycopene group demonstrated significantly higher DP-grams except for 1.5 kHz frequency when compared to cisplatin group (p < 0.05). There was a statistically significant difference in basal and mid turn external ciliated cells number (p < 0.05), but there was no statistically significant difference in apical turn between three groups (p > 0.05). Stria vascularis changes were statistically significant between the groups, and the median score for stria vascularis injury was significantly greater in group 3 than in group 2 (p < 0.05). The median scores for spiral ganglion cells changes were significantly greater in group 3 than in group 2 (p < 0.05). The analyses of the results revealed statistically significant differences between two groups (p < 0.05), suggesting lycopene's possible protective effect against cisplatin ototoxicity. The present study revealed that administration of lycopene may demonstrate a protective role against cisplatin-induced ototoxicity in rats.

The effect of resveratrol on the prevention of cisplatin ototoxicity

One of the most important adverse effects of cisplatin, a chemotherapeutic agent which is widely used in the treatment of cancer patients, is hearing loss. This has primarily been associated with the loss of inner ear hairy and spiral ganglion cells due to oxidative stress. Resveratrol is known to be an antioxidant agent, which has the theoretical potential of preventing cisplatin-related ototoxicity. This experimental study was approved by Animal Ethics Committee of Inonu University (2008-20) and supported by Inonu University Scientific Research Projects Support Fund (2009-17). Thirty-four 3-month-old Wistar albino female rats weighing 210-270 g were used in the study. The animals were allocated into four groups: in cisplatin group (Group A), a single dose of 12 mg/kg cisplatin was administered intraperitoneally to 10 rats; in cisplatin + resveratrol group (Group B), a single dose of 12 mg/kg cisplatin and 10 mg/kg resveratrol were administered intraperitoneally for 5 days to 10 rats; in resveratrol group (Group C), 10 mg/kg resveratrol was administered intraperitoneally for 5 days to seven rats and in control group (Group D), resveratrol solvent (5% alcohol-95% physiological saline) was administered intraperitoneally for 5 days to seven rats. Resveratrol administration has begun 1 day before cisplatin administration in the group treated with cisplatin and resveratrol combination. Distortion product otoacoustic emission (DPOAE) (Grason Stadler, Madison, USA) measurements were performed in the same ear of all rats (right ear) under general anesthesia at baseline, 1st and 5th days after drug administration. Statistically significant distortion product amplitude reductions were found in the cisplatin group at 1,418, 2,003, 3,363, 5,660, 8,003 and 9,515 Hz frequencies. Whereas in the cisplatin + resveratrol group, statistically significant difference was found between 1st and 5th day measurements only at 3,996 Hz frequency. No significant differences were noted between the measurements either in the resveratrol or in the control groups. According to these results, cisplatin-related ototoxicity has been greatly prevented by resveratrol use.

Carboplatin: a new cisplatin analog.

Carboplatin, a new antineoplastic agent with a spectrum of antitumor activity similar to cisplatin, has shown appreciable activity in patients with ovarian carcinoma, head and neck cancer, and small-cell lung cancer. This platinum complex is less nephrotoxic, ototoxic, and neurotoxic than cisplatin. Myelosuppression may be severe and dose-limiting. Carboplatin distributes into a volume approximating total body water, and is slowly bound to plasma proteins; its elimination is a biphasic process. Renal clearance of free platinum from carboplatin correlates highly with creatinine clearance in patients with normal or impaired renal function. The recommended iv dose of carboplatin as a single agent in previously untreated patients is 400-500 mg/m2; dosage must be reduced in patients with decreased renal function, low initial platelet count, or extensive prior chemotherapy or radiation therapy. Carboplatin will be most useful in patients with decreased renal function and those who cannot tolerate high-volume hydration regimens. Patients at higher risk for development of cisplatin-related ototoxicity or neurotoxicity (e.g., patients expected to receive cumulative cisplatin doses exceeding 600-800 mg/m2) may be ideal candidates for carboplatin as initial therapy. Large-scale comparative trials are needed before carboplatin can be recommended as a replacement for cisplatin.

Very high-dose cisplatin-induced ototoxicity: a preliminary report on early and long-term effects.

Acute and subacute audiometric hearing changes were evaluated in 12 patients receiving 35 courses of very high-dose (vhd) cisplatin (200 mg/m2 per course) in hypertonic saline at 4 or 8-week intervals. Audiogical evaluations were performed both before and immediately after each course of chemotherapy, and again after the discontinuation of treatment. A significant drop of the mean hearing threshold (P less than 0.01) at high frequencies was observed even within 48 h from the end of the first course of therapy, with 50% of the patients presenting a hearing loss of more than 15 dB. At the same total dose (200 mg/m2), one course of this regimen provided an incidence of hearing loss of more than 15 dB, which was four times greater than that reported with two courses of standard-dose regimens. The incidence and severity of the hearing impairment progressed further with subsequent courses of chemotherapy. Compared with baseline levels, most patients (75%) receiving at least two courses had a moderate to severe hearing loss, especially involving 4 and 8 kHz. At the end of treatment, 33% of the patients complained of a nondisabling functional hearing impairment. No recovery occurred after chemotherapy had been discontinued for 9-28 weeks. At this dose level cisplatin is markedly ototoxic. The use of hypertonic saline and vigorous hydration are effective means of minimizing the risk of nephrotoxicity, but seem to have no effect on cisplatin-related ototoxicity.