{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:33:09Z","timestamp":1791916389810,"version":"4.3.4"},"reference-count":109,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2012,10,8]],"date-time":"2012-10-08T00:00:00Z","timestamp":1349654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Anatomical Record"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cisplatin, carboplatin, nedaplatin, and oxaliplatin are widely used in contemporary oncology; however, their ototoxic and neurotoxic side effects are quite different as discussed in this review. Cisplatin is considered the most ototoxic, but despite its reputation, the magnitude of hair cell loss that occurs with a single, large drug bolus is limited and confined to the base of the cochlea. For all of these platinum compounds, a major factor limiting damage is drug uptake from stria vascularis into the cochlear fluids. Disrupting the blood\u2013labyrinth barrier with diuretics or noise exposure enhances drug uptake and significantly increases the amount of damage. Combined treatment with ethacrynic acid (a loop diuretic) and cisplatin results in rapid apoptotic hair cell death characterized by upregulation of initiator caspase\u20108 and membrane death receptor, TRADD, followed by downstream executioners, caspase\u20103 and caspase\u20106. Unlike cisplatin, nedaplatin and oxaliplatin are highly neurotoxic when applied to cochlear cultures preferentially damaging auditory nerve fibers at low concentrations and hair cells at high concentrations. Carboplatin, considered far less ototoxic than cisplatin, is paradoxically highly toxic to chinchilla inner hair cells and type I spiral ganglion neurons; however, at high doses it also damages outer hair cells. Hair cell death from cisplatin and carboplatin is characterized in its early stages by upregulation of p53; blocking p53 expression with pifithrin\u2010\u03b1 prevents hair cell death. Major differences in the toxicity of these four platinum compounds may arise from several different metal transporters that selectively regulate the influx, efflux, and sequestration of these drugs. Anat Rec, 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ar.22577","type":"journal-article","created":{"date-parts":[[2012,10,9]],"date-time":"2012-10-09T00:09:30Z","timestamp":1349741370000},"page":"1851-1867","source":"Crossref","is-referenced-by-count":131,"title":["Review: Ototoxic Characteristics of Platinum Antitumor Drugs"],"prefix":"10.1002","volume":"295","author":[{"given":"Dalian","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Allman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Salvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,10,8]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"105","article-title":"Intravenous nedaplatin and intraarterial cisplatin with transcatheter arterial embolization for patients with locally advanced uterine cervical cancer","volume":"21","author":"Adachi S","year":"2001","journal-title":"Int J Clin Pharmacol Res"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-199304000-00004"},{"key":"e_1_2_7_4_1","first-page":"88","article-title":"Carboplatin versus cisplatin in ovarian cancer","volume":"22","author":"Alberts DS","year":"1995","journal-title":"Semin Oncol"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21699"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/14992020903160892"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-0311"},{"key":"e_1_2_7_8_1","first-page":"1663","article-title":"Cisplatin and platinum drugs at the molecular level","volume":"10","author":"Boulikas T","year":"2003","journal-title":"Oncol Rep"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(96)00152-9"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(00)00059-9"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.1.199"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)01983-6"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.annonc.a010500"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090610"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(96)00075-5"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2006.12.017"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(02)00634-2"},{"key":"e_1_2_7_18_1","first-page":"39","volume-title":"Hearing loss: classification, causes and treatment","author":"Ding D","year":"2011"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2011.08.002"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2006.07.015"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420038736.ch13"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1672-2930(08)50018-3"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb08640.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000276451"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.3109\/00206098109072701"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.3109\/03005368209081455"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707405"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.7585"},{"key":"e_1_2_7_29_1","first-page":"198","article-title":"Protection against cisplatin ototoxicity in a Sprague\u2010Dawley rat animal model","volume":"26","author":"Giordano P","year":"2006","journal-title":"Acta Otorhinolaryngol Ital"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(90)90046-R"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1992.10.5.795"},{"key":"e_1_2_7_32_1","first-page":"15","article-title":"Safety of oxaliplatin in the treatment of colorectal cancer","volume":"14","author":"Haller DG","year":"2000","journal-title":"Oncology (Williston Park)"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1159\/000227253"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016480902856604"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djn418"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.aud.0000191942.36672.f3"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/MAO.0b013e31818599d5"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2010.10.011"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.3109\/00206099709071981"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0748"},{"key":"e_1_2_7_41_1","first-page":"1327","article-title":"Ototoxicity of cis\u2010diammine glycolato platinum, 254\u2010S","volume":"19","author":"Horiuchi M","year":"1992","journal-title":"Gan To Kagaku Ryoho"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.063172"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-2977(00)00081-4"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(01)00306-9"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(98)00137-3"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/29.6.299"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(97)00214-1"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr8002479"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2011.08.007"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1177\/000348948109000208"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(93)90021-R"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.1981.00790460006003"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/00365520510015601"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.052381"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(97)00154-8"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780453"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019130"},{"key":"e_1_2_7_58_1","first-page":"1","article-title":"Vestibular destruction by slow infusion of gentamicin into semicircular canals","volume":"552","author":"Li M","year":"2004","journal-title":"Acta Otolaryngol"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-011-9244-0"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199808030-00034"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199810000-00006"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.128.9.1026"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1177\/014556131008900607"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2306"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-10-04054.2003"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2004.07.016"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.3950\/jibiinkoka.87.202"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1544-10.2010"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200508010-00010"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410140310"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200059004-00003"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10162-007-0106-7"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/hyq196"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1159\/000013846"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.08.9599"},{"key":"e_1_2_7_76_1","first-page":"119","article-title":"Induction of p53\u2010mediated apoptosis and recovery of chemosensitivity through p53 transduction in human glioblastoma cells by cisplatin","volume":"28","author":"Park CM","year":"2006","journal-title":"Int J Oncol"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2006.01.001"},{"key":"e_1_2_7_78_1","first-page":"1249","article-title":"Sequence variations of mitochondrial DNA and individual sensitivity to the ototoxic effect of cisplatin","volume":"23","author":"Peters U","year":"2003","journal-title":"Anticancer Res"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012259625746"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2009.12.003"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2007.12.002"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1995.tb00167.x"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(01)00309-4"},{"key":"e_1_2_7_84_1","first-page":"ORL\u2010125","article-title":"Potentiation of kanamycin ototoxicity by a history of noise exposure","volume":"86","author":"Ryan AF","year":"1978","journal-title":"Otolaryngology"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-0709(82)80065-3"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1288\/00005537-198509010-00001"},{"key":"e_1_2_7_87_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0030-6665(20)30770-2","article-title":"Ototoxicity of loop diuretics","volume":"26","author":"Rybak LP","year":"1993","journal-title":"Otolaryngol Clin North Am"},{"key":"e_1_2_7_88_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0385-8146(89)80003-3","article-title":"Ototoxicity of carboplatin in guinea pigs","volume":"16","author":"Saito T","year":"1989","journal-title":"Auris Nasus Larynx"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0137"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(02)04090-8"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.2170\/physiolsci.RP010806"},{"key":"e_1_2_7_92_1","first-page":"521","article-title":"Effect of high\u2010dose cisplatin on auditory brainstem responses and otoacoustic emissions in laboratory animals","volume":"21","author":"Sockalingam R","year":"2000","journal-title":"Am J Otol"},{"key":"e_1_2_7_93_1","first-page":"63","article-title":"Comparison of the effects of furosemide and ethacrynic acid upon the cochlear function in the guinea pig","volume":"14","author":"Syka J","year":"1981","journal-title":"Scand Audiol Suppl"},{"key":"e_1_2_7_94_1","first-page":"97","article-title":"Induction of selective inner hair cell damage by carboplatin","volume":"8","author":"Takeno S","year":"1994","journal-title":"Scanning Microsc"},{"key":"e_1_2_7_95_1","doi-asserted-by":"publisher","DOI":"10.3109\/00206099209072917"},{"key":"e_1_2_7_96_1","first-page":"219","article-title":"Phase II study of carboplatin and cyclophosphamide combination chemotherapy for the treatment of advanced ovarian cancer","volume":"11","author":"Teeling M","year":"1990","journal-title":"Eur J Gynaecol Oncol"},{"key":"e_1_2_7_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(83)90078-3"},{"key":"e_1_2_7_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(96)00040-8"},{"key":"e_1_2_7_99_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-005-0648-6"},{"key":"e_1_2_7_100_1","doi-asserted-by":"publisher","DOI":"10.2174\/157015909789152155"},{"key":"e_1_2_7_101_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0022215100123771"},{"key":"e_1_2_7_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(03)00176-X"},{"key":"e_1_2_7_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5955(97)00020-8"},{"key":"e_1_2_7_104_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10162-009-0160-4"},{"key":"e_1_2_7_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2007.03.004"},{"key":"e_1_2_7_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.11.016"},{"key":"e_1_2_7_107_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-010-9221-z"},{"key":"e_1_2_7_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00286-0"},{"key":"e_1_2_7_109_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0769"},{"key":"e_1_2_7_110_1","doi-asserted-by":"publisher","DOI":"10.3109\/16513860903335795"}],"container-title":["The Anatomical Record"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Far.22577","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/anatomypubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ar.22577","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:31:04Z","timestamp":1759941064000},"score":1,"resource":{"primary":{"URL":"https:\/\/anatomypubs.onlinelibrary.wiley.com\/doi\/10.1002\/ar.22577"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,8]]},"references-count":109,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2012,11]]}},"alternative-id":["10.1002\/ar.22577"],"URL":"https:\/\/doi.org\/10.1002\/ar.22577","archive":["Portico"],"relation":{},"ISSN":["1932-8486","1932-8494"],"issn-type":[{"value":"1932-8486","type":"print"},{"value":"1932-8494","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,10,8]]}}}