In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.

Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence.

Fatal cisplatin overdose in the treatment of mediastinal lymphoma with the ESHAP regimen - analysis of the causes of the adverse drug event.

BACKGROUND: Cisplatin is a chemotherapeutic agent that may cause acute (or chronic) organ toxicity. As there is no antidote, prevention of adverse drug events is essential for patients' safety. CASE REPORT: The authors present the case of a 33-year-old woman treated for lymphoma with the ESHAP regimen, who died of an overdose of cisplatin. The drug was administered at a rate 4 times greater than the recommended maximum dose. The first symptom of overdose - partial hearing loss - appeared after administration of the last dose of the drug on day 4 of the chemotherapy course. The initiation of intensive treatment with plasmapheresis and dialyses was ineffective. The patient died 18 days after receiving the last dose of cisplatin. The medication schedule had been prepared by an inexperienced physician. The information on cisplatin dosage had been sourced from a vague instruction in a clinical oncology manual: '100 mg/m(2) continuous i.v. infusion d.1-4'. The instruction was misinterpreted. The patient was given 100 mg/m(2) on each of the 4 days of the treatment. CONCLUSION: Special care must be taken when preparing a medication schedule; the treatment must be checked by an experienced physician and verified by the nursing staff. The patient should be monitored for symptoms of cisplatin intoxication.

Matricaria chamomilla attenuates cisplatin nephrotoxicity.

Matricaria chamomilla is extensively consumed as a tea or tonic. Despite its widespread use as a home remedy, relatively few trials evaluated its benefits in nephro protection. Hence, this study evaluates the protective role of M. chamomilla in cisplatin nephrotoxicity rat model. The study was conducted on 32 rats divided into four groups. The first group (G1) was injected with saline intra-peritoneally (IP); G2 was injected with 5 mg/kg cisplatin on day 0 of the experiment and repeated four times, with five days free interval. G3 and G4 were injected daily with M. chamomilla (50 mg/kg) IP, starting five days before the experiment (-5 day); in addition, G4 was injected with cisplatin. On day 16, animals were scarified and serum and/or kidney tissue was used to determine: (a) kidney function tests (serum urea, creatinine, gamma glutamyl transferase (GGT), NAG, ß-gal), (b) oxidative stress indices (NO, LPO), (c) antioxidant activities (SOD, GSH, total thiols), (d) apoptotic indices (Cathepsin D, DNA fragmentation) and (e) mineral (calcium). M. chamomilla significantly increased the body weight, normalized the kidney functions, improved the apoptotic markers, reduced the oxidative stress markers and corrected the hypo-calcemia that resulted from cisplatin nephrotoxicity. M. chamomilla is a promising nephro-protective compound reducing cisplatin nephrotoxicity most probably by its antioxidant activities and inhibition of gamma glutamyl transferase activity.

Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit.

In this study, it was aimed to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on cisplatin hepatotoxicity. Thirty New Zealand rabbits were divided into 5 groups as group 1 (saline-injected control, C), group 2 (1% ethanol; vehicle for CAPE, E), group 3 (CAPE), group 4 (cisplatin, CS) and group 5 (cisplatin plus CAPE, CS+CAPE). Cisplatin caused increased immunoreactivity against inducible nitric oxide synthase (iNOS), but CAPE treatment reduced the immunoreactive hepatocytes. Liver malondialdehide (MDA), nitric oxide (NO(.)) levels and xanthine oxidase (XO) activities were higher in CS than in groups C and E. Cisplatin treatment also significantly decreased the tissue reduced glutathione (GSH) concentration compared to groups C and E. CAPE administration normalized the tissue GSH level and XO activity in group CS+CAPE, whereas CAPE treatment did not affect MDA level in group CS+CAPE. In addition, CAPE treatment significantly depressed the cisplatin-induced NO(.) increase in group CS+CAPE. Histopathologically, cisplatin caused hydropic degenerations, necrosis in hepatocytes, sinusoidal congestion, Kupffer cell proliferation and mononuclear cell infiltration. These alterations were less severe in rabbits receiving CS+CAPE. Parallel to histopathology, cisplatin increased serum AST and ALT levels, whereas CAPE treatment significantly reduced cisplatin-induced AST and ALT rise in the serum. Results suggest that cisplatin causes oxidative and nitrosative damage to hepatocytes. Cisplatin-induced increase in XO and NO(.) could contribute oxidative stress in the hepatotoxicity. CAPE shows partial protection against cisplatin-associated biochemical and histopathological alterations.

Cisplatin overdose: toxicities and management.

Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumour and haematological malignancies, including cancers of the testes, ovary, bladder, head and neck, oesophagus, stomach and lung, as well as lymphoma and osteosarcoma. Its non-specific targeting commonly results in adverse effects and toxicities affecting the gastrointestinal, renal, neurological and haematological systems even when administered at standard doses. Since cisplatin-related toxicities are dose-dependent, these may be more pronounced in the setting of a cisplatin overdose, resulting in significant morbidity and/or mortality. The incidence of cisplatin overdoses is unknown; however, early-phase clinical trials utilizing high-dose cisplatin, and case reports in the overdose setting have characterized the clinical features associated with cisplatin overdoses, highlighting some therapeutic strategies for consideration. To date, no published guidelines exist for managing a cisplatin overdose. The major toxicities of a cisplatin overdose include nausea and vomiting, renal insufficiency, electrolyte abnormalities, myelosuppression, ototoxicity, peripheral neuropathy, hepatotoxicity and retinopathy. Diarrhoea, pancreatitis, seizures and respiratory failure have also been reported. No specific antidote for cisplatin exists. Key management principles and strategies to lessen toxicities include renoprotection and enhancing drug elimination with aggressive intravenous hydration with or without the use of an osmotic diuretic, and avoidance of nephrotoxic medications. Sodium thiosulfate and plasmapheresis, with or without haemodialysis support, should be strongly considered. Close monitoring of clinical and laboratory parameters, and institution of supportive therapies, including antiemetics and haematopoietic colony stimulating factor support, are warranted. Based on the current literature, experimental therapies such as amifostine, ditiocarb sodium (diethyldithiocarbamate), acetylcysteine, fosfomycin and colestipol are of limited clinical effectiveness and remain investigational. This review serves to highlight the clinical spectrum of toxicities resulting from a cisplatin overdose, to critically appraise the available literature and to present a suggested algorithmic approach for the initial management of a cisplatin overdose.

Pica as an adaptive response: Kaolin consumption helps rats recover from chemotherapy-induced illness.

Clay consumption can occur during illness but there has been little work to understand why. To investigate whether consuming clay confers an advantage to the sick animal, we compared the recovery from illness of adult male rats with or without access to kaolin. Illness was induced by injection of 6 mg/kg, ip, cisplatin, a toxic chemotherapy agent, and recovery was assessed by changes in daily food intake, water intake, and body weight. Relative to saline-injected controls, cisplatin-injected rats reduced food and water intake and lost weight. However, those with access to kaolin ate more food and lost less body weight than did those without access to kaolin. Thus, clay consumption appeared beneficial in that it either protected the rats from illness or enhanced recovery and might prove useful as an adjunct therapy for other animals, including humans, experiencing visceral malaise.

[Combined application of hemodialysis and hemosorption for the treatment of acute cisplatin poisoning].

Overdose of cisplatin, a preparation with potentially high nephrotoxicity results in the damage of renal tubules, development of irreversible acute renal insufficiency, and death. Acute cisplatin poisoning requires maintenance and symptomatic treatment; antidotes are unknown. We report a case of successful therapy of acute cisplatin overdose in a 49 year-old patient by hemodialysis with successive inclusion of a column with hemosorbent before the dialyzer in the extracorporeal contour.

The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity.

The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity.

Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity.

Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use; however, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In this study, we investigated the role of anaphylatoxin C5a in the pathogenesis of cisplatin-mediated nephrotoxicity. Our data show that cisplatin-induced renal injury is significantly reduced in C5- or C5aR-deficient mice. However, pretreatment with C5 or C5a restores sensitivity to cisplatin-induced nephrotoxicity in C5-deficient mice. In wild-type mice, administration of cisplatin triggers the increased renal expression of multiple cytokines and caspases. This induction is diminished in C5-deficient mice, which is restored by pretreatment with C5 or C5a proteins. Interestingly, renal injury induced by cisplatin is similar between wild-type and CD59ab double knockout mice, and the formation of membrane attack complexes (MACs) by cisplatin in the kidney is diminished in C5-deficient mice, but not in C5aR-deficient mice. In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results.

Acceleration of cisplatin ototoxicity by perilymphatic application of 4-methylthiobenzoic acid.

The antitumor agent cisplatin has dose-limiting side effects such as ototoxicity. Systemical co-treatment with anti-oxidants like 4-methylthiobenzoic acid (MTBA) and sodium thiosulfate (STS) provides protection against cisplatin ototoxicity. However, systemically administered protective agents may reduce the chemotherapeutic effect of cisplatin. Local application of the protective agents could avoid this undesirable effect. In the present study, we aimed at suppressing cisplatin-induced ototoxicity in guinea pigs by administering MTBA or STS perilymphatically through cochlear perfusion. Guinea pig cochleas were perfused for 10 min with artificial perilymph (ArtP) containing cisplatin at 0.3 mg/ml, either alone, or in combination with MTBA (0.1 or 1.0 mg/ml) or STS (0.75 or 3.0 mg/ml). The compound action potential (CAP) and the summating potential (SP), evoked by 8 kHz tone bursts, and the endocochlear potential (EP; MTBA only) were measured just before and 1, 2, 3 and 4 h after perfusion. Cisplatin gradually reduced the CAP amplitude in time. Adding MTBA only accelerated this ototoxic effect. After cisplatin treatment a decline was found in the EP, irrespective of co-treatment, i.e., addition of MTBA did not accelerate the EP decrease. In contrast to MTBA, STS ameliorated the ototoxic effect of cisplatin. In conclusion, local application of anti-oxidants can ameliorate cisplatin ototoxicity but this is not a feature of all anti-oxidants.

Cytokine single nucleotide polymorphism. Role in acute renal failure.

Although the pathogenesis of ARF is heterogeneous and results from a combination of different environmental influences and host responses, there is overwhelming data to suggest a common pathway that involves pro- and anti-inflammatory molecules, which in turn, determines the extent of tissue injury. The number of recognized cytokine gene polymorphisms is growing daily. The development of cytokine gene mapping may help identify patients in whom an excessive systemic inflammatory response may follow a therapeutic intervention (e.g. CABG, contrast administration), and who may be at increased risk for developing acute organ dysfunction. Through these advances, tools may be developed to better understand, prevent and treat ARF. Genetic epidemiology studies may help characterize the importance of genetic markers in the development of ARF. This would require large prospective cohort studies aimed at examining associations between genetic markers, urinary (urine KIM-1 and NAG) and circulating (serum creatinine) markers of kidney injury. Once firmly established, the association of a particular genetic profile and outcome could be used to risk stratify patients for the development of ARF (fig. 4). Ultimately, cytokine-modulating therapies could be employed on the basis of genotypic risk stratification with the goal to prevent kidney injury or minimize its deleterious effects on patient outcome.

Nephrotoxicity of platinum complexes is related to basolateral organic cation transport.

BACKGROUND: Cisplatin and its analogs oxaliplatin and carboplatin are widely used antitumor drugs. Nephrotoxicity is a common and relevant adverse effect that occurs especially in cisplatin therapy. Cellular and molecular mechanisms of cisplatin-induced nephrotoxicity are not completely understood. The nephrotoxicity of platinum complexes was evaluated by a new in vitro system that utilizes the high Trans Epithelial Electrical Resistance (TEER) of the C7 clone of the MDCK (Madin-Darby canine kidney) cells. By means of this assay system we addressed the question whether the side of application of renal epithelia influences platinum complex toxicity. METHODS: C7 cells were grown in membrane filter cups, and the apical or basolateral membranes were exposed to 100-micromol/L cis-, oxali-, or carboplatin. TEER and caspase-3 activity were determined. Cimetidine was used as an inhibitor of organic cation transporters (OCTs). C7 cell lysates were analyzed for OCT-1 and -2 by Western blot analysis. RESULTS: TEER dropped by 89.5 +/- 9.3% (mean +/- SEM; N= 6) within 24 hours after addition of cisplatin to the basolateral side of C7 cells, while caspase activity increased up to 840.6 +/- 17.4% (mean +/- SEM; N= 6) compared to control cells. Exposure of the apical membrane to cisplatin reduced TEER by only 13.4 +/- 8.7% (mean +/- SEM; N= 6), and increased caspase-3 activity up to 213.9 +/- 7.6% (mean +/- SEM; N= 6). Oxaliplatin and carboplatin reduced TEER to a lesser extent than cisplatin. Oxaliplatin lowered TEER stronger than carboplatin. In general, basolateral application led to higher caspase activities and lower TEERs. The OCT-inhibitor cimetidine inhibited the TEER decrease induced by platinum complexes. Immunoblotting confirmed the presence of OCT-2 in C7 cells. CONCLUSION: Toxic effects of platinum complexes on renal epithelia depend on the platinum complex used and the site of application. We conclude that cell polarity and basolateral transport mechanisms are essential in nephrotoxicity of platinum drugs.

Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model.

Cisplatin (CDDP) is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for CDDP ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving CDDP. Long Evans rats were treated with CDDP 6 mg/kg delivered to the aorta via a retrograde right external carotid artery infusion, 15 min after intravenous (IV) infusion of saline (n=8) or NAC 400 mg/kg (n=8), such that the vertebral arteries were perfused. Subsequent groups were similarly treated with NAC 30 min before (n=7) and 4 h after (n=7) CDDP. Auditory brainstem response (ABR) thresholds were tested at 4-20 kHz, 7 days after treatment and compared to baseline ABR values. The NAC-treated rats exhibited no significant change from baseline values at all time intervals, while the saline-treated rats showed marked ototoxicity, especially at higher frequencies. Furthermore, the rats treated with NAC 15 min before CDDP exhibited less overall toxicity to CDDP, as evidenced in weight loss 7 days post-treatment (mean for saline=-39.63 g; mean for NAC=-21.13 g; p=0.0084). These data show that treatment with NAC can prevent CDDP-induced ototoxicity in rats.

Fatal overdosage with cisplatin.

This paper presents a case of fatal overdosage due to an accidental massive administration (750 mg instead of 170 mg) of cisplatin, an anticancer agent, to a 63-year-old patient suffering from lymphoma. Platinum was measured in various postmortem samples by means of inductively coupled plasma mass spectrometry. Heart and peripheral blood concentrations of platinum were 1515 and 1253 micro g/L, respectively. Concentrations in urine and bile were 1038 and 501 micro g/L, respectively. Renal dialysis was started immediately after the end of cisplatin perfusion, when the mistake was noticed, but the patient deceased at day 16, presenting renal and hepatic insufficiency, ototoxicity, and pancytopenia.

Chemical and biological considerations in the treatment of metal intoxications by chelating agents.

Effective chelation treatment of metal intoxications requires that the pharmacokinetics of the administered chelator in fact leads to chelation of the toxic metal, preferably forming a less toxic species which is effectively excreted. This depends on physical and chemical characteristics of metals and chelators as e.g. ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, administration route, bioavailability, metabolism, organ and intra/extra cellular compartmentalization, and excretion. In vivo chelation is unlikely to reach equilibrium determined by the standard stability constant, as rate effects and ligand exchange reactions as well as the pharmacokinetics of the chelator considerably influence complex formation. Hydrophilic chelators enhance renal metal excretion, but mainly their extracellular distribution limit their effect to mainly extracellular metal pools. Lipophilic chelators can decrease intracellular stores, but may redistribute toxic metals to e.g. the brain. In chronic metal induced disease, necessitating life-long chelation, toxicity and side effects of the chelator may limit the treatment. The metal selectivity of chelators is important, due to the risk of essential metals depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate are presently gaining increased acceptance among clinicians, undoubtedly improving the management of human metal intoxications including lead, arsenic and mercury compounds. Still, development of new safer chelators suited for long-term oral administration for chelation of metal deposits, mainly iron, is an important challenge to the future research.

Round window pH manipulation alters the ototoxicity of systemic cisplatin.

The effect of manipulation of pH on the ototoxicity of systemic cisplatin was studied in Wistar rats. After control auditory brainstem responses (ABR) were performed, the auditory bullae were opened and acidic (pH 6.0), neutral (pH 7.4) or basic (pH 9.0) phosphate-buffered saline (PBS) was applied to fill the round window niche (RWN). After 30 min, 13 mg/kg cisplatin solution or saline was administered intraperitoneally. After 3 days, follow-up ABRs were performed and cochleae were processed for morphological analysis. Animals that received basic PBS on the RWN and cisplatin intraperitoneally had significantly smaller ABR threshold shifts compared to rats pretreated with neutral pH buffer (P<0.05). Animals that received acidic PBS on the RWN and systemic cisplatin showed significantly greater ABR threshold shifts compared to those pretreated with neutral pH buffer (P<0.05). No significant threshold changes were observed in animals that received buffer of any pH on the RWN, followed by saline intraperitoneally. Semiquantitative analysis of hair cell survival confirmed a protective effect by basic PBS against cisplatin and a synergistic effect by acidic PBS on cisplatin ototoxicity (P<0.05). It appears that changes in cochlear pH can modulate the ototoxic effects of systemically applied cisplatin.

Alterations in the stria vascularis in relation to cisplatin ototoxicity and recovery.

We have investigated whether or not cisplatin-induced depression of the endocochlear potential (EP), and its subsequent recovery, possesses a morphological correlate in the stria vascularis. Guinea pigs implanted with round window electrodes were treated daily with cisplatin (1.5 mg/kg/day) until the compound action potential showed a profound hearing loss (> or =40 dB at 8 kHz after 5-18 days). Animals were either sacrificed immediately after the shift in hearing threshold ('SHORT' group) or allowed to recover for > or =4 weeks and subsequently sacrificed ('LONG' group). Control animals ('CONTROL' group) were not treated with cisplatin. Using stereological methods we measured the total strial cross-sectional area together with the areas occupied by the different strial components: the marginal, intermediate and basal cells. The total strial cross-sectional area in the basal turn of the LONG group was found to be significantly smaller than that of the SHORT and the CONTROL groups, whereas the EP was normal in the LONG group (in comparison to the CONTROL group) and markedly decreased in the SHORT group. The smaller area in the LONG group was mainly due to a decrease in the area occupied by the intermediate cells and to a lesser extent to a decrease in the marginal cell area. The area occupied by the basal cells did not change. Thus, the marked decrease in EP after 5-18 days of cisplatin administration was not related to shrinkage of the stria vascularis. Moreover, 4 weeks later the EP showed full recovery, whereas the stria vascularis had shrunk markedly.

TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.

Cisplatin produces acute renal failure in humans and mice. Previous studies have shown that cisplatin upregulates the expression of TNF-alpha in mouse kidney and that inhibition of either the release or action of TNF-alpha protects the kidney from cisplatin-induced nephrotoxicity. In this study, we examined the effect of cisplatin on the expression of TNF receptors TNFR1 and TNFR2 in the kidney and the role of each receptor in mediating cisplatin nephrotoxicity. Injection of cisplatin into C57BL/6 mice led to an upregulation of TNFR1 and TNFR2 mRNA levels in the kidney. The upregulation of TNFR2 but not TNFR1 was blunted in TNF-alpha-deficient mice, indicating ligand-dependent upregulation of TNFR2. To study the roles of each receptor, we administered cisplatin to TNFR1- or TNFR2-deficient mice. TNFR2-deficient mice developed less severe renal dysfunction and showed reduced necrosis and apoptosis and leukocyte infiltration into the kidney compared with either TNFR1-deficient or wild-type mice. Moreover, renal TNF-alpha expression, ICAM-1 expression, and serum TNF-alpha levels were lower in TNFR2-deficient mice compared with wild-type or TNFR1-deficient mice treated with cisplatin. These results indicate that TNFR2 participates in cisplatin-induced renal injury in mice and may play an important role in TNF-alpha-mediated inflammation in the kidney in response to cisplatin.

Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig.

Amelioration of cisplatin-induced side-effects is of great clinical importance. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. The ideal substance for local administration has yet to be identified. Thiourea (TU) has unique properties that make it an interesting candidate. This study was initiated to test the hypothesis that TU given by local administration protects against cisplatin ototoxicity in the guinea pig. After baseline auditory brainstem response (ABR) assessment, the left cochlea was implanted with a microtip catheter connected to an osmotic pump filled with either 27 mg/ml TU in artificial perilymph (AP), or AP administered for the full duration of the study. Three days post-implant, animals with normal ABRs received an intravenous injection of 8 mg/kg body-weight cisplatin. Five days after the cisplatin treatment ABRs were reassessed, animals decapitated and bilateral cytocochleograms prepared. TU-treated ears demonstrated significantly lower outer hair cell (OHC) loss as compared to contralateral untreated ears, and significantly lower OHC loss compared to AP-treated ears. ABR threshold shift did not differ significantly between the two groups. It can be postulated that TU demonstrates partial protection against cisplatin-induced ototoxicity.

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.