Pediyatrik kanser tedavisinde kullanılan sisplatine bağlı ototoksisite nedenleri ve önleyici yaklaşımlar

Yıl 2025, Cilt: 34 Sayı: 1, 44 - 60, 31.03.2025

Ceren Güneş , Ahmet Atila

https://doi.org/10.17827/aktd.1554487

Öz

İşitme kaybı, tinnitus ve/veya vertigo olarak kendini gösteren ototoksisite platin kemoterapisinin yan etkilerinden birisidir ve koklea içinde reaktif oksijen türlerinin toksik düzeylerde üretilmesiyle ortaya çıkar. Koklear saç hücresi hasarı genellikle doza bağımlı, iki taraflı ve geri döndürülemezdir. İşitme kaybı tedavi sırasında veya tedavi tamamlandıktan yıllar sonra da ortaya çıkabilir. Ototoksisite kalıcıdır ve düzeltilmediği takdirde çocuklarda okul ve kariyer sorunlarına neden olabilir, yaşlılarda ise bilişsel gerilemeyi hızlandırabilir. Otoksisitenin erken tespitine imkan verecek standartlaştırılmış odyolojik izleme protokolleri faydalı olabilir. Çocuklarda ototoksisiteyi önlemek için FDA onaylı tek tedavi sodyum tiyosülfattır. İşitme cihazlarından yararlanamayan ileri derecede işitme kaybı olan çocuklarda koklear implant önemli fayda sağlayabilir.

Anahtar Kelimeler

Ototoksisite, sisplatin, işitme kaybı, antioksidanlar

Kaynakça

• 1- Taş A, Yağız R. Ototoksisitenin Odyolojik Monitörizasyonu. Trakya Üniversitesi Tıp Fakültesi Dergisi 2005;22:37-41.
• 2-Kızmazoğlu D, Olgun Y, İnce D. Çocukluk Çağında Tedavi İlişkili Ototoksisiteye Yaklaşım. Tepecik Eğit. ve Araşt. Hast. Dergisi 2019;29:211-217.
• 3-Olgun Y. Cisplatin Ototoxicity: Where We Are? Int. Adv. Otol. 2013; 9: 403-416.
• 4- Peyrone M. Ueber die Einwirkung des Ammoniaks auf Platinchlorür. Justus Liebigs Annalen der Chemie. 1844; 51: 1–29.
• 5-Rosenberg B, Vancamp L, Krigas T. Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Platinum Electrode. Nature. 1965; 205: 698–9.
• 6-Rosenberg B, Van Camp L, Grimley EB, Thomson AJ. The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes. J Biol Chem. 1967; 242: 1347–52.
• 7-Rosenberg B, VanCamp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumour agents. Nature. 1969; 222: 385–6.
• 8- Mukherjea D, Dhukhwa A, Sapra A, Bhandari P, Woolford K, Franke J, et al. Strategies to reduce the risk of platinum containing antineoplastic drug-induced ototoxicity. Expert Opin Drug Metab Toxicol. 2020 ; 16: 965–982.
• 9- Frisina RD, Wheeler HE, Fossa SD, Kerns SL, Fung C, Sesso HD, et al. Comprehensive audiometric analysis of hearing impairment and tinnitus after cisplatin-based chemotherapy in survivors of adult-onset cancer. J Clinl Oncol. 2016; 10;34:2712-20.
• 10- Breglio AM, Rusheen AE, Shide ED, Fernandez KA, Spielbauer KK., McLachlin KM.,et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat. Commun. 2017; 8: 1654.
• 11-Gietema JA, Meinardi MT, Messerschmidt J, Gelevert T, Alt F, Uges DR, et al. Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet 2000;355:1075-6.
• 12-Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: Underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005; 23: 8588-96.
• 13-Knight KR, Kraemer DF, Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: Use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol 2007; 25:1190-5.
• 14-Stöhr W, Langer T, Kremers A, Bielack S, Lamprecht-Dinnesen A, Frey E., et al. Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system. Cancer Invest 2005;23(3):201-7.
• 15-Attar M , Alqarni MS , Alsinnari YM, Bukhari ZM, Alshegif H, Alzhrani A, et al. The Incidence and Risk Factors of Cisplatin and Carboplatin Ototoxicity in Pediatric Oncology Patients at Tertiary Oncology Center. Indian J Surg Oncol 2022; 13:925-930.
• 16- Kırkım G, Olgun Y, Aktas S, Kıray M, Kolatan E, Altun Z et al. Is there a gender- related susceptibility for cisplatin ototoxicity? Eur Arch Otorhinolaryngol. 2015;272:2755-63.
• 17-Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 356: 800-8.
• 18- Ross JD, Katzov- Eckert H, Dube MP, Brooks B, Rassekh R, Barhdadi A, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat. Genet. 2009; 41: 1345-9.
• 19- Caronia D, Patina- Garcia A, Milne RL, Zalacain-Dıez M, Pita G, Alonso MR, et al. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J. 2009; 9: 347-5.
• 20 -Li Y, Womer RB, Silber JH. Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 2004; 40:2445–2451.
• 21- Yancey A, Harris MS, Egbelakin A, Gilbert J, Pisoni DB, Renbarger J. Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients. Pediatr. Blood Cancer. 2012; 59: 144–48.
• 22- Langer T, am Zehnhoff-Dinnesen A, Radtke S, Meitert J, Zolk O. Understanding platinum-induced ototoxicity. Trends Pharmacol Sci. 2013; 34:458-69
• 23- Coradini PP, Cigana L, Selistre SG, Rosito LS, Brunetto AL. Ototoxicity from cisplatin therapy in childhood cancer. J Pediatr Hematol Oncol 2007; 29:355–360.
• 24- Waissblutha S, Del Vallea Á, Chuanga A, Beckerb A. Incidence and associated risk factors for platinum-induced ototoxicity in pediatric patients. Int J Pediatr Otorhinolaryngol. 2018; 111:174–179.
• 25- Lanvers-Kaminsky C, Krefeld B, Dinnesen AG, Deuster D, Seifert E, Würthwein G, et al. Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters. Pediatr Blood Cancer. 2006; 47:183–193.
• 26-Bertolini P, Lassalle M, Mercier G, Raquin MA, Izzi G, Corradini N., et al. Platinum Compound-Related Ototoxicity in Children: Long-Term Follow-Up Reveals Continuous Worsening of Hearing Loss. Pediatr Hematol Oncol. 2004;26:649-655.
• 27-Berg AL, Spitzer JB, Garvin JH Jr. Ototoxic impact of cisplatin in pediatric oncology patients. Laryngoscope 1999; 109:1806–14.
• 28- Neuwelt EA, Brummett RE, Doolittle ND, Muldoon LL, Kroll RA, Pagel MA, et al. First evidence of otoprotection against carboplatin-induced hearing loss with a two compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther. 1998; 286: 77-84.
• 29- Dean JB, Hayashi SS, Albert CM, King AA, Karzon R, Hayashi RJ. Hearing loss in pediatric oncology patients receiving carboplatin- containing regimens. J Pediatr Hematol Oncol. 2008; 30:130–4.
• 30- Clemens E, de Vries AC, Pluijm SF, Zehnhoff-Dinnesen AA, Tissing WJ, Loonen JJ., et al. Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study. Eur J Cancer. 2016; 69:77–85.
• 31- Parsons SK, Neault MW, Lehmann LE, Brennan LL, Eickhoff CE, Kretschmar CS.,et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant. 1998; 22: 669–674.
• 32- Bertolini P, Lassalle M, Mercier G, Raquin MA, Izzi G, Corradini N., et al. Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss J Pediatr Hematol Oncol 2004; 26:649–55.
• 33- Olgun Y, Aktas S, Altun Z, Kırkım G, Kızmazoğlu DÇ, Erçetin AP, et al. Analysis of genetic and non genetic risk factors for cisplatin ototoxicity in pediatric patients. Int J Pediatr Otorhinolaryngol. 2016; 90: 64-69. 34-Blakley BW, Gupta AK, Myers SF, Schwan S. Risk Factors for Ototoxicity due to Cisplatin. Arch Otolaryngol Head Neck Surg. 1994; 120: 541–546. 35- Steyger PS. Mechanisms of Ototoxicity and Otoprotection Otolaryngol Clin North Am. 2021; 54:1101-1115.
• 36-Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier. Sci Transl Med. 2019;11:eaao0935.
• 37-Rubel EW, Furrer SA, Stone JS. A brief history of hair cell regeneration research and speculations on the future. Hear. Res. 2013; 297: 42–51.
• 38- Lee, MP, Waldhaus J. In vitro and in vivo models: What have welearnt about inner ear regeneration and treatment for hearing loss? Mol. Cell. Neurosci. 2022; 120, 103736.
• 39-Liberman MC., Kujawa, SG. (2017). Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. Hear. Res. 349, 138–147. doi:10.1016/j.heares.2017.01.003
• 40-Martinho N, Santos TCB, Florindo HF, Silva LC. Cisplatin-membrane interactions and their influence on platinum complexes activity and toxicity. Front. Physiol. 2019; 9: 1898.
• 41- Gersten BK, Fitzgerald TS, Fernandez KA, Cunningham LL. Ototoxicity and platinum uptake following cyclic administration of platinum-based chemotherapeutic agents. J. Assoc. Res. Otolaryngol. 2020; 21: 303–321.
• 42-Chu YH, Sibrian-Vazquez M, Escobedo JO, Phillips AR, Dickey DT, Wang Q.,et al. Systemic delivery and biodistribution of cisplatin in vivo. Mol. Pharm. 2016; 13:2677–2682.
• 43- Ishida S, Lee J, Thiele DJ, Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc. Natl. Acad. Sci. 2002; 99: 14298–14302.
• 44- Sheth S, Mukherjea D, Rybak LP, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and otoprotection. Front. Cell. Neurosci. 2017; 11: 338.
• 45- Ciarimboli G. Membrane transporters as mediators of cisplatin effects and side effects. Scientifica (Cario) 2012; 2012: 473829.
• 46- Tan WJT, Vlajkovic SM. Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions. International J Mol Sci. 2023;24: 16545.
• 47- Martin JL, Terry SJ, Gale JE, Dawson SJ. The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition. J. Cell Sci. 2023; 136: jcs260590.
• 48-Dutta S, Rivetti C, Gassman NR, Young CG, Jones BT,Scarpinato K,.et al. Analysis of single, cisplatin-induced DNA bends by atomic force microscopy and simulations. J. Mol. Recognit. 2018;31: E2731.
• 49-Tanida S, Mizoshita T, Ozeki K, Tsukamoto H, Kamiya T, Kataoka H., et al. Mechanisms of cisplatin induced apoptosis and of cisplatin sensitivity: Potential of BIN1 to act as a potent predictor of cisplatin sensitivity in gastric cancer treatment. Int. J. Surg. Oncol. 2012; 2012: 862879.
• 50- Someya S, Prolla TA. Mitochondrial oxidative damage and apoptosis in age-related hearing loss. Mech. Ageing Dev. 2010; 131: 480–486.
• 51- Mohri H, Ninoyu Y, Sakaguchi H, Hirano S, Saito, N, Ueyama T. Nox3-derived superoxide in cochleae induces sensorineural hearing loss. J. Neurosci. 2021;41: 4716–4731.
• 52- Bánfi B, Malgrange B, Knisz J, Steger K,Dubois-Dauphin M, Krause KH. NOX3, a superoxide-generating NADPH oxidase of the inner ear. J. Biol. Chem. 2004; 279: 46065–46072.
• 53- Jamesdaniel S, Coling D, Hinduja S, Ding D, Li J, Cassidy L.,et al. Cisplatin-induced ototoxicity is mediated by nitroxidative modification of cochlear proteins characterized by nitration of Lmo4. J. Biol. Chem. 2012; 287:18674–86.
• 54-Zhao H, Xu Y, Song X, Zhang Q, Wang Y, Yin H., et al. Cisplatin induces damage of auditory cells: Possible relation with dynamic variation in calcium homeostasis and responding channels. Eur. J. Pharmacol. 2022; 914: 174662.
• 55-Ramkumar V, Mukherjea D, Dhukhwa A, Rybak LP. Oxidative stress and inflammation caused by cisplatin ototoxicity. Antioxidants 2021; 10: 1919.
• 56-Kalinec GM, Lomberk G, Urrutia RA, Kalinec F. Resolution of cochlear inflammation: Novel target for preventing or ameliorating drug-, noise-, and age-related hearing loss. Front. Cell. Neurosci. 2017; 11: 192.
• 57- Domingo IK, Latif A, Bhavsar AP. Pro-inflammatory signalling PRRopels cisplatin-induced toxicity. Int. J. Mol. Sci. 2022; 23: 7227.
• 58-So H, Kim H, Lee JH, Park C, Kim Y, Kim E.,et al. Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-B. J. Assoc. Res. Otolaryngol. 2007; 8: 338–355.
• 59- So H, Kim H, Kim Y, Kim E, Pae HO, Chung HT., et al. Evidence that cisplatin-induced auditory damage is attenuated by down regulation of pro-inflammatory cytokines via Nrf2/HO-1. J. Assoc. Res. Otolaryngol. 2008; 9:290–306.
• 60- Al Aameri RFH, Alanisi EMA, Oluwatosin A, Al Sallami D, Sheth S, Alberts I.,et al. Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity. Front. Immunol. 2023; 14:1125948.
• 61-Bhatta P, Dhukhwa A,Sheehan K, Al Aameri RFH, Borse V, Ghosh S., et al. Capsaicin protects against cisplatin ototoxicity by changing the STAT3/STAT1 ratio and activating cannabinoid (CB2) receptors in the cochlea. Sci. Rep. 2019; 9: 4131.
• 62-Yin H, Sun Y,Ya B, Guo Y, Zhao H, Zhang L., et al. Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3. Arch. Toxicol. 2023; 97: 2477–2493.
• 63- Levano S, Bodmer D. Loss of STAT1 protects hair cells from ototoxicity through modulation of STAT3, c-Jun, Akt, and autophagy factors. Cell Death Dis. 2015; 6: E2019.
• 64- Kaur T, Mukherjea D, Sheehan K, Jajoo S, Rybak LP, Ramkumar V. Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation. Cell Death Dis. 2011; 2: E180
• 65-Davis JM, Elfenbein J, Schum R,. Bentler RA. Effects of mild and moderate hearing impairments on language, educational, and psychosocial behavior of children. J. Speech Hear. Disord.1986; 51: 53–62.
• 66--Bess FH, Dodd-Murphy J, Parker RA. Children with minimal sensorineural hearing loss: prevalence, educational performance, and functional status. Ear Hear. 1998; 19:339–54.
• 67-Yoshinaga-Itano C, Sedey AL, Coulter DK, Mehl AL. Language of early- and later-identified children with hearing loss Pediatrics. 1998;102 :1161-71.
• 68-Yoshinaga-Itano C. Benefits of early intervention for children with hearing loss. Otolaryngol Clin North Am. 1999;32: 1089-102.
• 69-Downs MP, Yoshinaga-Itano C. The efficacy of early identification and intervention for children with hearing impairment. Pediatr Clin North Am. 1999; 46:79-87.
• 70- Chang KW. Clinically accurate assessment and grading of ototoxicity. Laryngoscope 2011; 121: 2649–2657.
• 71-Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: A practical grading system. Med Pediatr Oncol 1991; 19:295-300.
• 72-American Speech-Language-Hearing Asociation: Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 2004; 35:11-19.
• 73- Schmidt CM, Bartholomous E, Deuster D, Heinecke A, Dinnesen AG. The ‘’Muenster Classification’’ of high frequency hearing loss following cisplatin chemotherapy. HNO. 2007; 55: 299-306.
• 74-Brock PR, Knight KR, Freyer DR, Campbell KC, Steyger PS, Blakley BW, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012;30:2408-17.
• 75- Bass JK, Huang J, Onar-Thomas A, Chang KW, Bhagat SP, Chintagumpala M, et al. Concordance Between the Chang and the International Society of Pediatric Oncology (SIOP) Ototoxicity Grading Scales in Patients Treated With Cisplatin for Medulloblastoma. Pediatr Blood Cancer 2014;61:601–605
• 76- Grewal S, Merchant T, Reymond R, McInerney M, Hodge C, Shearer P. Auditory late effects of childhood cancer therapy: a report from the Children’s Oncology Group. Pediatrics. 2010;125:E938-50.
• 77-Trung NT, Hien TT, Huyen TT, Van Son T, Hoan PQ, Phuong NT, et al. Enrichment of bacterial DNA for the diagnosis of blood stream infections. BMC Infect Dis. 2016;16:235.
• 78-McDermot t JH, Wolf J, Hoshitsuki K, Huddart R, Caudle KE, Whirl-Carrillo M., et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of aminoglycosides based on MT-RNR1 genotype. Clin Pharmacol Ther. 2022;111:366-372.
• 79-Garinis AC, Poling GL, Rubenstein RC, Konrad-Martin D, Hullar TE, Baguley DM., et al. Clinical Considerations for Routine Auditory and Vestibular Monitoring in Patients with Cystic Fibrosis. Am J Audiol. 2021; 30: 800-809.
• 80-Pierson MG, Gray BH. Superoxide dismutase activity in the cochlea. Hearing Research.1982; 6: 141–151.
• 81- Usami S, Hjelle OP, Ottersen OP. Differential cellular distribution of glutathione--an endogenous antioxidant--in the guinea pig inner ear. Brain Res. 1996; 743: 337–40.
• 82-Lynch ED, Gu R, Pierce C, Kilet J. Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res. 2005; 201: 81–9
• 83- Paciello F, Fetoni AR, Mezzogori D, Rolesi R, Di Pino A, Paludetti G.,et al. The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity. Sci Rep, 2020; 10: 1063.
• 84-Kemp G, Rose P, Lurain J, Berman M, Manetta A, Roullet B., eyt al. Amifostine pretreatment for protection against cyclophosphamide induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14:2101–2112.
• 85-Glover D, Glick JH, Weiler C, Hurowitz S, Kligerman MM. WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 1986;4:584–588.
• 86-Romanul FCA, Bannister RG. Histochemistry:localized areas of high alkaline phosphatase activity in endothelium of arteries. Nature 1962;195:611–612.
• 87- Calabro-Jones PM, Aguilera JA, Ward JF, et al. Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res 1988;48:3634–3640.
• 88-Turrisi AT, Glover DJ, Hurwitz S, et al. Final report of the phase I trial of single-dose WR-2721 [S-2-(3- aminopropylamino)ethylphosphorothioic acid]. Cancer Treat Rep 1986;70:1389–1393.
• 89-Betticher DC, Anderson H, Ranson M, et al. Carboplatin combined with amifostine, a bone marrowprotectant, in the treatment of non-small-cell lung cancer: a randomised phase II study. Br J Cancer1995;72:1551–1555.
• 90-Budd GT, Lorenzi V, Ganapathi R, Delstein D, Pelley R, Olencki T., et al. Amifostine: potential for clinically useful cytoprotection.Support Care Cancer 1994;2:380–384.
• 91- Fouladi M, Stempak D, Gammon J, Klein J, Grant R, Greenberg ML.,et al. Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma. Cancer 2001;92:914–923.
• 92-Ekborn A, Hansson J, Ehrsson H, Eksborg S, Wallin I, Wagenius G., et al. High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics. Laryngoscope 2004; 114:1660–1667.
• 93- Fouladi M, Chintagumpala M, Ashley D, Kellie S, Gururangan S, Hassall T., et al. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol. 2008;26:3749-55.
• 94- Marina N, Chang KW, Malogolowkin M, London WB, Frazier AL, Womer RB., et al. Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children’s Oncology Group study. Cancer 2005;104:841–847.
• 95-Fisher MJ, Lange BJ, Needle MN, Janss AJ, Shu HK, Adamson PC., et al. Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy. Pediatr Blood Cancer 2004;43:780–784.
• 96- Katzenstein HM, Chang K, Krailo M, Chen Z, Finegold MJ, Rowland J., et al. Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma: a report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children's Oncology Group. Cancer 2009; 15;115:5828-35.
• 97- Freyer DR, Brock PR, Chang KW, Dupuis LL, Epelman S, Knight K, et al. Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline. Lancet Child Adolesc Health. 2020; 4: 141–150.
• 98-Hu B, Liu Y, Chen X, Zhao, J, Han J, Dong H., et al. Ferrostatin-1 protects auditory hair cells from cisplatin induced ototoxicity in vitro and in vivo. Biochem. Biophys. Res. Commun. 2020; 533:1442–1448.
• 99- Mei H, Zhao L, Li W, Zheng Z Tang D, Lu, X,. et al. Inhibition of ferroptosis protects House Ear Institute-Organ of Corti 1 cells and cochlear hair cells from cisplatin-induced ototoxicity. J. Cell. Mol. Med. 2020; 24: 12065–12081.
• 100- Borse V, Al Aameri RFH, Sheehan K , Sheth S, Kaur T, Mukherjea D., et al. Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity. Cell Death Dis. 2017; 8: e2921.
• 101- Kim HJ. Oh GS. Lee JH, Lyu AR. Ji HM, Lee SH. et al. Cisplatin ototoxicity involves cytokines and STAT6 signaling network. Cell Res. 2011; 21: 944–95697.
• 102- Vlajkovic SM, Housley GD, Thorne PR. Adenosine and the auditory system. Curr Neuropharmacol. 2009; 7:246–56.
• 103- Ghosh S, et al., The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss. Front Cell Neurosci, 2018 12: p. 271.92.
• 104- Benkafadar N, Menardo J, Bourien J, Nouvian R, François F, Decaudin D., et al., Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy. EMBO Molecular Medicine. 2017; 9: 7–26.
• 105- Roy S, Ryals MM, Van den Bruele AB, Fitzgerald TS, Cunningham LL. Sound preconditioning therapy inhibits ototoxic hearing loss in mice. J Clin Invest, 2013; 123: 4945–9.
• 106- Paksoy M, Ayduran E, Sanlı A, Eken M, Aydın S, Oktay ZA. The protective effects of intratympanic dexamethasone and vitamin E on cisplatin-induced ototoxicity are demonstrated in rats. Med Oncol. 2011; 28; 615-21.
• 107- Hill GW, Morest DK, Parham K. Cisplatin-induced ototoxicity: effect of intratympanic dexamethasone injections. Otol Neurotol. 2008; 29: 1005–11.
• 108- Marshak T, Steiner M, Kaminer M, Levy L, Shupak A. Prevention of Cisplatin-Induced Hearing Loss by Intratympanic Dexamethasone: A Randomized Controlled Study. Otolaryngol Head Neck Surg, 2014; 150: 983–90.
• 109- Fernandez R, Harrop-Jones A, Wang X, Dellamary L, LeBel C, Piu F. The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Cisplatin-Induced Hearing Loss. Audiol Neurootol. 2016; 21: 22–9.
• 110- Sooriyaarachchi M, Gailer J, Dolgova NV, PickeringIJ, George GN. Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate. J Inorg Biochem, 2016; 162: 96–101.
• 111- Sooriyaarachchi M, George GN, Pickering IJ, Narendran A, Gailer J. Tuning the metabolism of the anticancer drug cisplatin with chemoprotective agents to improve its safety and efficacy. Metallomics 2016; 8: 1170–1176.
• 112- Rolland , Meyer F, Guitton MJ, Bussières R, Philippon D, Bairati I., et al., A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity in patients with head and neck cancer. J Otolaryngol Head Neck Surg. 2019; 48: 4.
• 113- van As JW, van den Berg H, van Dalen EC. Medical interventions for the prevention of platinum‐induced hearing loss in children with cancer. Cochrane Database Syst Rev. 2019; 5:CD009219.
• 114- Freyer DA, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B.,et al., Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017; 18: 63–74.
• 115- Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ., et al. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. 2018; 378: 2376–2385.
• 116- FDA Approves Sodium Thiosulfate to Reduce the Risk of Ototoxicity Associated with Cisplatin in Pediatric Patients with Localized, Non-Metastatic Solid Tumors. Available online: https://www.fda.gov/drugs/resources-information-approveddrugs/fda-approves-sodium-thiosulfate- reduce risk-ototoxicity-associated-cisplatin-pediatric-patients (accessed on 21 October 2022).
• 117- Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014; 141: 150–9.
• 118- Riga MG, Chelis L, Kakolyris S, Papadopoulos S, Stathakidou S, Chamalidou E., et al. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol. 2013; 36:1–6.
• 119- Yoo J, Hamilton SJ, Angel D, Fung K, Franklin J., Parnes LS, et al. Cisplatin otoprotection using transtympanic L-N-acetylcysteine: a pilot randomized study in head and neck cancer patients. Laryngoscope. 2014; 124: E87–94.
• 120 - Visacri MB, Quintanilha JCF, de Sousa VS, Amaral LS, de F. L. Ambrósio R, Calonga L., et al. Can acetylcysteine ameliorate cisplatin‐induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double‐blind, placebo‐controlled trial involving patients with head and neck cancer. Cancer Medicine. 2019; 8: 2020–2030.
• 121- Yıldırım M, İnançlı HM, Samancı B, Oktay MF, Enöz M, Topçu İ. Preventing cisplatin induced ototoxicity by N-acetylcysteine and salicylate. Kulak Burun Bogaz Ihtis Derg. 2010;20 :173-183.
• 122- Crabb SJ, Martin K, Abab J, Ratcliffe I, Thornton R, Lineton B., et al. COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised c ontrolled trial to establish if aspirin reduces cisplatin induced hearing-loss. Eur J Cancer. 2017; 87: 75-83.
• 123- Landier W. Ototoxicity and Cancer Therapy. Cancer 2016; 122; 1647-1658.