A low‐dose regimen of cisplatin before high‐dose cisplatin potentiates ototoxicity

Harrison, Ryan T.; DeBacker, J. Riley; Bielefeld, Eric C.

doi:10.1002/lary.24948

Cited by 21 publications

(7 citation statements)

References 32 publications

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“…In human clinical protocols, Cpt is usually administered in several treatment sessions [ 1 , 2 ] and hearing impairment is directly correlated to high cumulative doses [ 2 , 40 ]. Our results show that our rat model is more similar to these protocols, thus better suitable for clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats

et al. 2016

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Cisplatin (Cpt) is known to induce a high level of oxidative stress, resulting in an increase of reactive oxygen species damaging the inner ear and causing hearing loss at high frequencies. Studies on animal models show that antioxidants may lower Cpt-induced ototoxicity. The aim of this study is to evaluate the ototoxic effects of two different protocols of Cpt administration in a Sprague-Dawley rat model, and to test in the same model the synergic protective effects of a solution of coenzyme Q10 terclatrate and Acuval 400®, a multivitamin supplement containing antioxidant agents and minerals (Acu-Qter). The Cpt was administered intraperitoneally in a single dose (14 mg/kg) or in three daily doses (4.6 mg/kg/day) to rats orally treated or untreated with Acu-Qter for 5 days. The auditory function was assessed by measuring auditory brainstem responses from 2 to 32 kHz at day 0 and 5 days after treatment. Similar hearing threshold and body weight alterations were observed in both Cpt administration protocols, but mortality reduced to zero when Cpt was administered in three daily doses. The Acu-Qter treatment was able to prevent and completely neutralize ototoxicity in rats treated with three daily Cpt doses, supporting the synergic protective effects of coenzyme Q terclatrate and Acuval 400® against Cpt-induced oxidative stress. The administration protocol involving three Cpt doses is more similar to common human chemotherapy protocols, therefore it appears more useful for long-term preclinical studies on ototoxicity prevention.

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Section: Discussionmentioning

confidence: 99%

Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats

et al. 2016

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“…Cisplatin is one of the drugs which is best known to have this side effect [7,8] . To the best of our knowledge, trastuzumab and lapatinib have not been assessed for ototoxicity.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

Eryılmaz

Demirci²,

Günel³

et al. 2016

Int Adv Otol

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Original Article INTRODUCTIONTrastuzumab (Herceptin®; Genentech, California, San Francisco, USA) is used for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Trastuzumab is a humanized recombinant monoclonal antibody that acts on the extracellular portion of the HER2 protein [1] . Lapatinib (Tykerb®; Glaxo-Smith Kline) is a tyrosine kinase inhibitor that suppresses epidermal growth factor 1 (EGF-1) and intracellular phosphorylation of the HER-2/neu receptor. In studies with trastuzumab, cardiotoxicity is stated as the most common side effect [2] . The known side effects of lapatinib are the reduction of the left ventricular ejection fraction, interstitial lung disease/pneumonitis, dizziness, fatigue, severe diarrhea, dry cough, white sores in the mouth or lips, nosebleeds, nausea, stomach pain, jaundice, loss of appetite, aspartate aminotransferase (AST) changes, alanine aminotransferase (ALT) changes, and hematological changes [3,4] . To our knowledge, the ototoxicity of these chemotherapeutic agents has not yet been studied. The aim of this study is to identify whether these agents are ototoxic in rats and to determine the dose dependency of the ototoxicity. MATERIALS and METHODSThe study was approved by the Animal Experiments Ethical Committee of Adnan Menderes University (64583101/2013/038). A total of 48 male rats aged 4-8 months were randomly divided into six groups. All rats were subjected to distortion product otoacoustic emissions (DPOAE) on the first day after being anesthetized with ketamine/xylazine. Group 1 (control group) received Evaluation of Lapatinib and Trastuzumab for Ototoxic EffectsOBJECTIVE: Trastuzumab and lapatinib are widely used chemotherapeutic agents. Our aim in this study was to assess the possible ototoxicity of these chemotherapeutic agents. MATERIALS and METHODS:Forty-eight rats were divided into six groups: Group 1 (control, n=8) received intraperitoneal saline for 7 days. Group 2 (n=8) and Group 3 (n=8) received 10 mg/kg and 30 mg/kg single doses of intraperitoneal trastuzumab, respectively. Lapatinib was administered by oral gavage to Group 4 (n=8) at 100 mg/kg/day and to group 5 (n=8) at 300 mg/kg/day for 7 days. Group 6 (n=8) received only one dose of 10 mg/kg intraperitoneal trastuzumab; subsequently, Group 6 received one dose of lapatinib at 100 mg/kg/day by oral gavage for 7 days. Before any medication was administered, distortion product emissions (DPOAE) were obtained. DPOAE tests were performed again on the rats on day 7, after which the mastoid bullas were harvested. The apoptosis degree was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure. RESULTS:The lapatinib 300 and lapatinib+trastuzumab groups (p=0.008 and p=0.001, respectively) were significantly different from the control group according to the spiral ganglion TUNEL. Apoptosis in the organ of corti was statistically different compared with the control group in the lapatinib 100, lapatinib 300, and lapatinib+trastuzu...

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“…A significant degree of high-frequency hearing loss occurs even after the first course of cisplatin chemotherapy [Stavroulaki et al, 2001], and a close relationship exists between hearing impairment and an elevated cumulative dose of cisplatin [Harrison et al, 2015]. The animal model of cisplatininduced hearing loss used in our study, which involves the administration of 3 injections of the drug on consecutive days, was established by Astolfi et al [2016] and better mimics the cisplatin chemotherapeutic process in humans while simultaneously producing no mortality in animals.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

Zong¹,

Liu²,

Wan³

et al. 2017

Audiol Neurotol

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Endoplasmic reticulum (ER) stress arises when excessive improperly folded proteins accumulate in the ER lumen. When ER stress occurs, the unfolded protein response (UPR) is subsequently activated to restore ER proteostasis. However, severe ER stress leads to apoptosis. Recent studies have suggested that cisplatin cytotoxicity may be related to ER stress. The purpose of this study was to determine whether ER stress participates in cochlear cell apoptosis in a cisplatin-induced ototoxicity rat model and to also determine the possible relationship between ER stress and hearing loss. Our results revealed that treatment with cisplatin upregulated the expression of active caspase-12 in cochlear cells, which is indicative of cisplatin-induced activation of ER-specific apoptosis. Increased expression of C/EBP homologous protein (CHOP) and cleaved caspase-9 suggested a close relationship between severe ER stress and mitochondria-dependent apoptosis in the cochlear cells of cisplatin-treated rats. In addition, we found that tauroursodeoxycholic acid (TUDCA), a promoter of ER proteostasis, had a protective effect on cisplatin-induced hearing loss. These results demonstrate that ER stress is involved in the cisplatin-induced apoptosis of cochlear cells in vivo.

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A low‐dose regimen of cisplatin before high‐dose cisplatin potentiates ototoxicity

Abstract: NA.

Cited by 21 publications

References 32 publications

Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats

Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

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