Kaltenbach J A, Church M W, Blakley B W, McCaslin D L, Burgio D L
Department of Otolaryngology-Head and Neck Surgery, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Otolaryngol Head Neck Surg. 1997 Nov;117(5):493-500. doi: 10.1016/S0194-59989770020-2.
The purpose of this investigation was to study the ameliorating effects of four agents on cisplatin-induced ototoxicity. Hamsters were given a series of five cisplatin injections either alone or in combination with sodium thiosulfate (STS), diethyldihydrothiocarbamate (DDTC), and S-2(3-aminopropylamino) ethylphosphorothioic acid (WR-2721), or fosfomycin. Ototoxicity was assessed anatomically by quantifying the extent of cochlear damage with the scanning electron microscope and physiologically with measures of the auditory brain stem response. When administered alone, cisplatin induced widespread loss of outer hair cells (OHCs) along much of the cochlea in the hamster, especially in the basal and middle turns, with an average survival of only 56% of the OHC population. In contrast, inner hair cells resisted cisplatin ototoxicity in the hamster. Thus the ameliorative effects of the different test agents were assessed by counting the number of surviving OHCs in each treatment group and comparing with cisplatin-treated controls. STS provided the most effective protection against the ototoxic effects of cisplatin, yielding 91% survival of OHCs. DDTC also reduced the ototoxic effects of cisplatin, yielding 68% survival of OHCs. Cotreatment with WR-2721 and fosfomycin yielded 45% and 52% OHC survival, respectively, and thus did not provide any chemoprotection. The results closely paralleled those based on auditory brain stem response recordings in that the magnitude of threshold shift was proportional to the amount of OHC loss; also, the amount of threshold shift at each frequency was in good agreement with the pattern of hair cell loss along the cochlear spiral. Thus both histologic and physiologic results suggest that STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy.
本研究的目的是探讨四种药物对顺铂所致耳毒性的改善作用。给仓鼠单独注射一系列五次顺铂，或同时联合注射硫代硫酸钠（STS）、二乙基二氢硫代氨基甲酸盐（DDTC）、S-2(3-氨丙基氨基)乙基硫代磷酸（WR-2721）或磷霉素。通过扫描电子显微镜定量耳蜗损伤程度进行解剖学耳毒性评估，以及通过听性脑干反应测量进行生理学评估。单独给予顺铂时，可导致仓鼠耳蜗大部分区域外毛细胞（OHC）广泛缺失，尤其是在基部和中部螺旋，OHC平均存活率仅为56%。相比之下，仓鼠的内毛细胞对顺铂耳毒性具有抵抗力。因此，通过计算每个治疗组中存活的OHC数量并与顺铂治疗的对照组进行比较，来评估不同测试药物的改善效果。STS对顺铂的耳毒性提供了最有效的保护，OHC存活率达91%。DDTC也降低了顺铂的耳毒性，OHC存活率为68%。与WR-2721和磷霉素联合治疗分别使OHC存活率达45%和52%，因此未提供任何化学保护作用。结果与基于听性脑干反应记录的结果非常相似，即阈值偏移的幅度与OHC损失量成正比；此外，每个频率的阈值偏移量与沿耳蜗螺旋的毛细胞损失模式高度一致。因此，组织学和生理学结果均表明，STS和DDTC有望改善顺铂化疗的耳毒性作用。
