Ototoxic Effects Of Cisplatin Research Articles

Cisplatin ototoxicity histopathology.

This study investigates the histopathological changes of the cochlea and vestibular end organs of a patient who received cisplatin for Hodgkin's lymphoma. He experienced acute high-frequency sensorineural hearing loss and tinnitus after receiving treatment. Using histopathological analysis of his temporal bones after he unfortunately succumbed to his disease, we found that the ototoxic effect of cisplatin is primarily within the cochlea, with significant damage located at the organ of Corti at the base-hook region, consistent with findings in animal models. The effects of cisplatin were minimal when reviewing the vestibular end organs.

Naringin attenuates cisplatin- and aminoglycoside-induced hair cell injury in the zebrafish lateral line via multiple pathways.

Exposure to ototoxic drugs is a significant cause of hearing loss that affects about 30 thousand children with potentially serious physical, social and psychological dysfunctions every year. Cisplatin (CP) and aminoglycosides are effective antineoplastic or bactericidal drugs, and their application has a high probability of ototoxicity which results from the death of hair cells (HCs). Here, we describe the therapeutic effect of the flavonoid compound naringin (Nar) against ototoxic effects of cisplatin and aminoglycosides include gentamicin (GM) and neomycin (Neo) in zebrafish HCs. Animals incubated with Nar (100‐400 μmol/L) were protected against the pernicious effects of CP (150‐250 μmol/L), GM (50‐150 μmol/L) and Neo (50‐150 μmol/L). We also provide evidence for the potential mechanism of Nar against ototoxicity, including antioxidation, anti‐apoptosis, promoting proliferation and hair cell regeneration. We found that mRNA levels of the apoptotic‐ and pyroptosis‐related genes are regulated by Nar both in vivo and in vitro. Finally, by proving that Nar does not affect the anti‐tumour efficacy of CP and antibacterial activity of aminoglycosides in vitro, we highlight its value in clinical application. In conclusion, these results unravel a novel therapeutic role for Nar as an otoprotective drug against the adverse effects of CP and aminoglycosides.

The protective effect of coumaric acid against cisplatin-induced ototoxicity in rats

Cis-diammineedichloroplatinum (cisplatin) is a chemotherapeutic agent used for the treatment of several types of cancer. However, severe side-effects such as ototoxicity, nephrotoxicity and neurotoxicity restrict its use. p-Coumaric acid (PCA) is a phenol class compound obtained from various plants in nature such as grape, carrot and tomato and from beverages such as tea and beer. It was shown to have antioxidant and free radical scavenging, anti-inflammatory and neuroprotective effects. The purpose of this study was to perform a biochemical and histopathological evaluation of the protective efficacy of PCA in ototoxicity induced with cisplatin in rats. To the best of our knowledge, no previous research has investigated the protective effect of PCA against cisplatin-induced ototoxicity. 28 Wistar rats were used. The animals were randomly divided into four groups of seven members each. No drug was administered to the rats in the control group, while the cisplatin group received a single intraperitoneal dose of 10 mg/kg cisplatin. PCA was administered to the PCA group rats by the intraperitoneal route for three days at a dose of 100 mg/kg. In the cisplatin+PCA group, intraperitoneal PCA at 100 mg/kg was administered one hour after injection of 10 mg/kg intraperitoneal cisplatin for three consecutive days. Rats were sacrificed 24 h after the final drug administration. The cochlear tissues were removed and MDA levels, GPx and SOD activities were measured to evaluate the oxidative stress status and histopathological evaluation was performed to reveal cochlear damage. The results showed that PCA protects the cochlea from ototoxic effect of cisplatin. PCA is a reliable agent that provides significant biochemical and histopathological protection against cisplatin-induced ototoxicity in rats.

PH-sensitive polymeric nanoparticles with antioxidant and anti-inflammatory properties against cisplatin-induced hearing loss

Polymeric nanoparticles (NPs) based on smart synthetic amphiphilic copolymers are used to transport and controlled release dexamethasone in the inner ear to protect against the ototoxic effect of cisplatin. The NPs were based on a mixture of two pseudo-block polymer drugs obtained by free radical polymerization: poly(VI-co-HEI) and poly(VP-co-MVE) or poly(VP-co-MTOS), being VI 1-vinylimidazole, VP N-vinylpyrrolidone, and HEI, MVE and MTOS the methacrylic derivatives of ibuprofen, α-tocopherol and α-tocopheryl succinate, respectively. The NPs were obtained by nanoprecipitation with appropriate hydrodynamic properties, and isoelectric points that matched the pH of inflamed tissue. The NPs were tested both in vitro (using HEI-OC1 cells) and in vivo (using a murine model) with good results. Although the concentration of dexamethasone administered in the NPs is around two orders of magnitude lower that the conventional treatment for intratympanic administration, the NPs protected from the cytotoxic effect of cisplatin when the combination of the appropriate properties in terms of size, zeta potential, encapsulation efficiency and isoelectric point were achieved. To the best of our knowledge this is the first time that pH sensitive NPs are used to protect from cisplatin-induced hearing loss by intratympanic administration.

Role of autophagy in cisplatin-induced ototoxicity

ObjectiveHearing loss is a major side effect of cisplatin chemotherapy. Although cell death in cisplatin-induced ototoxicity is primarily caused by apoptosis, the exact mechanism behind the ototoxic effects of cisplatin is not fully understood. Autophagy is generally known as a pro-survival mechanism that protects cells under starvation or stress conditions. However, recent research has reported that autophagy plays a functional role in cell death also. This study aimed to investigate the role of autophagy in cisplatin-induced ototoxicity in an auditory cell line. MethodsCultured HEI-OC1 cells were exposed to 30μM cisplatin for 48h, and cell viability was tested using MTT assays. To evaluate whether autophagy serves to cell death after cisplatin exposure, western blotting and immunofluorescence staining for LC3-II were performed. Markers of two autophagy-related pathways, mTOR and class III PI3K, were also investigated. ResultsThe formation of the autophagic protein LC3-II in response to 30μM cisplatin increased with time. The early upregulation of autophagy exerted cytoprotective activity via the class III PI3K pathway. But later increase in autophagy induced cell death by suppressing the mTOR pathway. ConclusionOur results prove that autophagy could induce cell death during cisplatin-induced ototoxicity, and modulating the autophagic pathway might be another strategy against cisplatin-induced ototoxicity.

Evaluation of ototoxicity in patients treated with hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and sodium thiosulfate.

Ototoxic hearing loss associated with intravenous or intra-arterial administration of cisplatin is well documented. However, there is limited data regarding the ototoxic effect of cisplatin when perfused into the abdominal cavity using hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this study is to assess and describe ototoxicity in patients treated with HIPEC with cisplatin and sodium thiosulfate for peritoneal surface malignancies. We performed a retrospective chart review (2007-2012) of patients treated for advanced peritoneal malignancies at a tertiary care center using HIPEC with cisplatin and sodium thiosulfate infusion. Thirteen patients (12 males, 1 female) met study criteria. Audiometric thresholds were compared before and after treatment. A 20 dB loss at any single frequency, 10 dB decrease at any two adjacent frequencies, or loss of response at three consecutive test frequencies defined a significant ototoxic change (). Despite minimal hearing change in six patients, none of the 13 patients in our study exhibited a significant ototoxic change in hearing sensitivity post HIPEC with cisplatin at any test interval in any test frequency. Our findings represent the first objective assessment of ototoxic effect after HIPEC with cisplatin and sodium thiosulfate infusion. Our results suggest that peritoneal perfusion of cisplatin with intravenous perfusion of sodium thiosulfate is not associated with ototoxic changes in hearing sensitivity. Further investigation of the administration and systemic mechanism of absorption of sodium thiosulfate as a potential protection against cisplatin ototoxicity is needed to confirm these findings.

Cisplatin-induced ototoxicity and the role of pharmacogenetic testing.

A 10-year-old white male presented with a chief complaint of swelling and pain in the left distal femur that worsened when he participated in sports at school. After several weeks of continued pain and swelling an x-ray was performed and revealed the presence of a large mass. Magnetic resonance imaging confirmed a large primary bone tumor located on the left femur, and open biopsy subsequently confirmed the diagnosis of osteosarcoma. The tumor was 9 cm long in the axis and 7 cm in diameter. Further tests revealed that the disease was localized to that area. The patient weighed 36 kg and was 145 cm tall at the time of diagnosis, placing him in the 75th percentile for age and sex. The patient was started on chemotherapy based on a standard Children’s Oncology Group (COG) treatment protocol of high-dose methotrexate, doxorubicin, and cisplatin. He received cisplatin at a dose of 120 mg/m2 approximately every 5 weeks for a total of 4 treatments. For each treatment, cisplatin 60 mg/m2/day was administered via intravenous infusion on 2 consecutive days. Based on the patient’s body surface area of 1.2 m2, he received a cumulative dose of 576 mg of cisplatin (480 mg/m2). He was also placed on an appropriate antiemetic regimen per COG protocol. He was not on any other medications known to cause ototoxicity or nephrotoxicity. His renal function was normal at baseline and all subsequent lab tests thereafter. Genotyping for thiopurine S-methyltransferase (TPMT) mutations was not performed prior to initiation of cisplatin therapy. Standard audiometric monitoring was performed prior to administration of the first cisplatin dose, and the results were all within the normal range (Brock Grade 0 [Table]).1 The patient completed the full cisplatin treatment course, and audiometric monitoring was performed prior to administration of the second and third cisplatin treatments with no significant hearing impairment noted. On follow-up 2 months after completing the third treatment course, the patient reported having trouble hearing. The loss manifested initially as bilateral tinnitus and ultimately progressed to bilateral hearing loss. Audiometric monitoring performed at this visit revealed moderate to severe hearing loss, defined as a Brock score ≥2 (Table). This translates to educationally significant hearing loss presumed to be caused by the ototoxic effects of cisplatin. Hearing tests performed 6 months and 1 year later revealed that the patient’s hearing had declined slightly but remained in Brock Grade 2, suggesting that the initially observed hearing deficit was likely progressive and irreversible.

Spontaneous otoacoustic emissions (SOAE) changes in testicular cancer patients treated with cisplatin: A pilot study of whether the acute ototoxic effect of cisplatin treatment can be detected

15581 Background: We studied the acute ototoxic effect of cisplatin in testicular cancer patients with two highly sensitive new methods for detecting high frequency hearing loss: distorsion product otoacoustic emissions (DPOAE), and spontaneous otoacoustic emissions (SOAE). Methods: Checking the acute effect, 32 (63 ears) testicular cancer patients (median age: 33 years, range: 16–59 years) were measured on the first day of their first cycle and after one week of their last cycle of cisplatin treatment. 20 mg/m2 cisplatin was administered for five days, in BEP chemotherapy regimen. The patients got on the average 2.19 cycles (2–3 cycles). We also measured the SOAE of ten healthy control persons (without chemotherapy) matching sex and age distribution of this group. A detailed medical history evaluated audiological risk factors and hearing problems. Tympanometry, DPOAE and SOAE were measured, to detect the acute changes in the inner ear after low cumulative dose of cisplatin treatment. Paired t-test, and sign test was used for statistical analysis. Results: The DPOAE did not show any changes close after cisplatin treatment (average: 2.19 cycles, 2–3 cycles), similarly to our earlier results with pure tone audiometry (PTA) and transiently evoked otoacoustic emission (TOAE). But the SOAE showed significant, early changes in incidence, shape and amplitude, in the treated group. 66% of the SOAE changed after treatment (p=0,006). In the control group (20 ears) the SOAE never changed in a three months period. (It behaves as a fingerprint) Conclusions: DPOAE did not change significantly after 2 or 3 cycles of cisplatin treatment, similarly to our earlier results with PTA, and TOAE, but the change of the SOAE-incidence, shape and amplitude close after cisplatin treatment shows acute changes in the inner ear function (first described in the literature) after administration of low cumulative dose of cisplatin. This case is the first indication of the possible clinical relevance of SOAE. Our observation has to be confirmed in further studies, with larger number of patients. No significant financial relationships to disclose.

Detection of late ototoxic side effect of cisplatin by distortion otoacoustic emission (DPOAE)

Cisplatin-based chemotherapy results in high cure rate in testicular cancer. The issue of toxicity is of special concern in young men with a probability of cure of at least 70-80% even in disseminated disease. As the literature shows, the ototoxic side effects of cisplatin have been studied mostly by conventional method. The authors used distortion product otoacoustic emission to detect the long-term ototoxic effect of cisplatin in 223 patients with a median follow-up time of 4.27 years (range 0.5-20 years) and a median age of 37 years (range 18-55 years). Cisplatin (20 mg/m(2) body surface) was administered for five days per cycle, in combination with other antitumor drugs. The control group consisted of 40 testicular cancer patients who did not receive chemotherapy, with a median age of 35 years (range 16-54 years). A detailed medical history based on a standardized questionnaire evaluated hearing complaints and audiological risk factors, such as head injuries, chronic otitis media, previous noise exposure and familial hearing loss. DPOAE was measured at 8 frequencies from 750 to 8000 Hz. No amplitude changes were detected in patients receiving =300 mg/m(2) cisplatin. At higher doses, contrary to the literature, not only high frequencies were affected: our method could detect significant hearing impairment at lower frequencies important for speech perception in patients receiving at least 400 mg/m(2) cisplatin. The lower frequencies where significant amplitude changes were detected were 3000 Hz at 400 mg/m(2), and 1500, 2000 and 3000 Hz at 500-600 mg/m(2). We detected the worst hearing in the case of patients who had symptomatic ototoxicity. Age and the cumulative dose of cisplatin proved statistically significant risk factors, while smoking or noise exposure did not have predictive value. As a conclusion, DPOAE is a fast, noninvasive and reliable method for the detection of late ototoxicity in testicular cancer patients. In our study hearing loss correlated with the cumulative dose of cisplatin. Hearing impairment contributes to the already compromised situation of cancer patients.

Ototoxic effects of cisplatin in a Sprague–Dawley rat animal model as revealed by ABR and transiently evoked otoacoustic emission measurements

The ototoxic effects of cisplatin in a Sprague–Dawley rat model were evaluated by recordings of auditory brainstem responses (ABR) and transiently evoked otoacoustic emissions (TEOAEs). The ABR responses were evoked from alternating clicks and 8, 10, 12, 16, 20 and 30 kHz tone pips in a range from 40 to 100 dB SPL range. The TEOAEs were recorded with a non-linear protocol, and were evoked by a 63.5 dB SPL click stimulus. Twenty five male Sprague–Dawley rats were used in the study, 20 animals were treated with cisplatin (16 mg/kg, body weight) and five animals served as controls. The data showed that 72 h after the cisplatin administration, the TEOAE and ABR variables were significantly altered. The relationship between the ABR and TEOAE variables was shown to be non-linear. The most significant relationships were observed between the TEOAE correlation and the ABR threshold values at 10, 12, and 16 kHz.

Blood-Perilymph Barrier and Ototoxicity: An In Vivo Study in the Rat

Cisplatin and gentamicin are two ototoxicants that are supposed to be transported by the paracellar route, i.e. via cellular junctions, to the perilymphatic compartment. This study was initiated to test the hypothesis that susceptive variation of individuals to ototoxic drugs may be explained by variability in transport properties. The transport of radioactive mannitol through the blood-perilymph barrier was correlated in vivo with the acute effect of cisplatin and gentamicin on auditory function. Transport of radioactive mannitol across the blood-perilymph barrier was monitored by sampling of scala vestibuli perilymph at 60 and 120 min after an intravenous infusion of the tracer to nephrectomized Long Evans rats. Counting of hair cell loss was performed in the animals receiving 16 mg/kg body weight cisplatin. The transport of radioactive mannitol across the blood-perilymph barrier did not correlate with the ototoxic effect of cisplatin, evaluated as changes in the auditory-evoked brainstem response thresholds or loss of outer hair cells. The results provide evidence that the barrier function is not involved in the interindividual variability of the ototoxic effect of cisplatin. Furthermore, it can be postulated that neither cisplatin nor gentamicin induce a disruption of endothelial cell junction stability in the inner ear.

Evaluation of cisplatin ototoxicity in a rat animal model.

The ototoxic effects of cisplatin were evaluated by otoacoustic emissions and evoked auditory responses. A transient otoacoustic emissions protocol indicated no significant ototoxic effects in rats treated intravenously with 7.5 mg/kg/week for 2-weeks. A chronic 6-week treatment (2.5 mg/kg/week) monitored by 2F1-F2 distortion product emissions presented significant SNR alterations in a narrow range of frequencies (5.04-5.66 kHz). An acute treatment of 15 mg/kg, using slow 30-min intraperitoneal infusion, presented the highest DP and ABR alterations. The SNR at the 2F1-F2 frequencies 6.34, 7.13, and 7.56 kHz was found significantly decreased, and ABR latency measurements from 8-kHz burst stimuli verified these alterations.

The combined effects of ototoxic drugs and noise

Cisplatin is a widely used chemotherapeutic drug which causes ototoxicity. Previous studies from this laboratory using the rat have shown that cisplatin ototoxicity may be mediated by the production of free oxygen radicals. The ototoxic effects of cisplatin can be reduced by treatment with reducing agents such as diethyldithiocarbamate, methylthiobenzoic acid, ebselen, D-methionine, or sodium thiosulfate. The injury to the inner ear caused by cisplatin is potentiated by noise exposure. The greatest degree of cochlear damage in the guinea pig was observed when noise exposure precedes the administration of cisplatin [G. Laurell, Ann. Otol. 101, 969–976 (1992)]. These findings could be explained by an increase in oxidative stress produced by noise exposure, which could predispose to further injury by subsequent cisplatin administration. [Work supported by NIH.]

Blood Flow-independent Accumulation of Cisplatin in the Guinea Pig Cochlea

Considerable interindividual variability in the ototoxic effect of cisplatin has become the unpredictable dose-limiting factor in its use as curative as well as palliative therapy. The drug accumulates in highly vascular areas in the cochlea, causing dose-related hair cell loss. The purpose of this study was to assess blood flow-dependent aspects of cisplatin absorption in the cochlea in order to better understand factors that may influence cisplatin-induced ototoxicity. The effect of reduced cochlear blood flow on the ototoxic action of cisplatin was studied in guinea pigs. Before cisplatin administration the cochlear vasculature in each animal was unilaterally pre-constricted, by the application of 2% epinephrine to the round window. A 20-30% reduction in cochlear blood flow, assessed by laser Doppler flowmetry, was maintained before and after intravenous infusion of 0.1% cisplatin. Cisplatin infusion affected cochlear blood flow but not vessel conductivity. The cochlear blood flow decrease, maintained by local epinephrine application to the round window during cisplatin infusion, did not alter the cisplatin-induced hearing loss. In addition, the concentration of free cisplatin in scala tympani perilymph did not differ between epinephrine-treated and non-treated ears. Our results indicate that cisplatin transport into the cochlea is not an energy-dependent process in the lateral wall vasculature.

Carboplatin and Cisplatin Ototoxicity in Guinea Pigs: Les effets ototoxiques du cisplatine et du carboplatine chez le cobaye

Ototoxic effects of cisplatin (1.5 mg/kg), cisplatin with mannitol (1.5 mg/kg cisplatin with 15 mg/kg mannitol) and carboplatin (6 mg/kg) were compared in guinea pigs treated 5 days a week for 5 consecutive weeks. Auditory thresholds were measured in awake animals by means of the compound action potential recorded from electrodes implanted near the round window. The endocochlear potential (EP) was measured in the first turn through the round window, and hair cell counts were estimated by the surface specimen technique. The most pronounced ototoxicity (threshold shifts and hair cell loss) was observed with pure cisplatin. Cisplatin with mannitol appeared to be less toxic than pure cisplatin, and carboplatin the least toxic. Even carboplatin produced significant threshold shifts, particularly at high frequencies, but they were not accompanied by hair cell loss. Values of EP were not different from those in normal control animals.

Ototoxic Effect of Cisplatin in Children with Brain Tumors

Thirty-four children, age 2-19 years, with brain tumors were treated with surgical resection, irradiation, and a cisplatin (CDDP) containing regimen. Audiologic assessments were conducted prior to each cycle of CDDP to monitor the ototoxic effects of CDDP. Twenty-eight patients with posterior fossa (PF) tumors received 5,040 to 5,650 cGy irradiation to the PF and 0-3,600 cGy to the remainder of the craniospinal (CS) axis. Six patients with supratentorial tumors received 5,140-5,580 cGy to the tumor site and 3,600-4,500 Gy to the remainder of the CS axis. Cycles of CDDP (68 mg/m2), lomustine (75 mg/m2), and vincristine (1.5 mg/m2 weekly for 3 weeks) were given every 6 weeks to 30 children immediately following irradiation, and to 4 at relapse. CDDP was infused over 8 h. Significant hearing loss, defined as a greater than 20-dB change from baseline in the hearing level (HL), occurred in the 250- to 2,000-Hz range in 4 of 29 patients receiving a cumulative dose (CD) of 410 mg/m2, and in 14 of 25 patients receiving a CD of 474 mg/m2. At 4,000 Hz, hearing sensitivity progressed from a HL of 20 +/- 2 dB at a CD of 203 mg/m2 to 31 +/- 6 dB (p less than 0.05) at a CD of 474 mg/m2 (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

The ototoxic effect of cisplatin on guinea pigs in relation to dosage

The effect on the electrophysiological hearing thresholds and the endocochlear DC potential (EP) was studied in four groups of guinea pigs receiving different doses of cisplatin. By multiple low-dose intraperitoneal injections a permanent hearing loss was produced without a permanent decrease of the EP. On the other hand, when cisplatin was given as a single high-dose intravenous injection, there was an impairment of the electrophysiological hearing thresholds and EP, depending upon the level of cisplatin dose. It is concluded that cisplatin-induced hearing loss is not necessarily a sequela to a loss of EP.

Cis-platin ototoxicity in previously noise-exposed guinea pigs.

The ototoxic effect of Cis-platin on guinea pigs was assessed with frequency-specific brainstem audiometry in the frequency range 0.8-20 kHz. The animals had a noise-induced hearing loss in one ear before Cis-platin treatment. The loss of threshold showed a large inter-individual variability, with a rapid increase above a hypothetic threshold dose. In the noise-exposed ear the total loss was larger, but the additional ototoxic effect was smaller than on the non-exposed side. The hearing loss was independent of pigmentation. in conclusion, there is no potentiation between noise-induced hearing loss and Cis-platin. The data support regular audiometric control before and during Cis-platin treatment for easy detection of incipient hearing loss, before the speech frequency range is affected.