Review: Ototoxic Characteristics of Platinum Antitumor Drugs

被引:103
作者
Ding, Dalian [1 ]
Allman, Brian L. [1 ]
Salvi, Richard [1 ]
机构
[1] SUNY Buffalo, Ctr Hearing & Deafness, Buffalo, NY 14214 USA
来源
ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY | 2012年 / 295卷 / 11期
关键词
cisplatin; oxaliplatin; carboplatin; apoptosis; ethacrynic acid; caspase-8; TRADD; copper transporter; HAIR CELL LOSS; CISPLATIN PLUS CYCLOPHOSPHAMIDE; ORGANIC CATION TRANSPORTERS; COPPER TRANSPORTER; PROTEOMIC ANALYSIS; INDUCED APOPTOSIS; STRIA VASCULARIS; OXIDATIVE STRESS; ETHACRYNIC-ACID; SENSORY CELLS;
D O I
10.1002/ar.22577
中图分类号
R602 [外科病理学、解剖学]; R32 [人体形态学];
学科分类号
100101 ;
摘要
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 bloodlabyrinth 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-8 and membrane death receptor, TRADD, followed by downstream executioners, caspase-3 and caspase-6. 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-a 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. (C) 2012 Wiley Periodicals, Inc.
引用
收藏
页码:1851 / 1867
页数:17
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