顺铂耳毒性机制及抗氧化药物局部应用的预防作用

Cisplatin Ototoxicity Mechanisms and Prevention with Locally Delivered Antioxidant Drugs

顺铂是临床普遍应用的广谱高效抗肿瘤药物,与多种抗肿瘤药有协同效应、无交叉耐药等特点,为当前联合化疗中最常用的药物之一。然而,顺铂的毒副作用严重困扰着癌症患者,其耳毒性尤为突出。顺铂耳毒性多为双侧、进展性、不可逆性、剂量依赖性听力损伤,往往导致成人、尤其是儿童患者出现语言交流障碍。大量研究证实,顺铂通过诱发活性氧(ROS)升高导致听觉毛细胞发生caspase-3激活的细胞凋亡。哺乳动物听觉毛细胞无自发再生能力,一旦损伤即为永久性。因此,顺铂耳毒性预防的药物研发或治疗策略开发至关重要。目前,越来越多的药物被证实在细胞和动物水平上具有顺铂耳毒性保护作用。然而,绝大部分药物经系统性用药后拮抗顺铂抗肿瘤疗效,无法实现临床上的有效应用。至今仍无有效顺铂耳毒性保护药物被批准上市。耳蜗局部鼓室内用药可部分缓解耳毒性保护候选药物对顺铂抗肿瘤疗效的干扰,但因顺铂需周期性用药,多次鼓室内给予耳毒性保护药物易引起局部创伤和感染。本文总结了具有代表性抗氧化药物预防顺铂耳毒性的基础和临床研究进展,为顺铂耳毒性新药研发提供理论依据。

Cisplatin is a widely used and effective drug for the treatment of various solid tumors.Unfortunately,its severe side-effects have also impacted patients,especially its often bilateral,progressive,irreversible and dose-dependent ototoxicity.Current evidence indicates that cisplatin triggers the production of reactive oxygen species(ROS)in target tissues in the inner ear.A large number of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models.However,many of them interfere with the therapeutic effects of cisplatin,and therefore are not suitable for systemic administration in clinical practice.Until now,none of them has been approved by the FDA.Consequently,local administration strategies,namely intratympanic administration,have been developed to achieve otoprotection,without reducing the antitumoral effects of cisplatin.This review summarizes the clinical and experimental studies of ciaplatin ototoxicity,including details of the molecular mechanisms of action,to gain insight for future drug development in this field.