Schweitzer V G
Department of Otolaryngology-HNS, Henry Ford Hospital, Detroit, MI 48202.
Laryngoscope. 1993 Apr;103(4 Pt 2):1-52.
Cis-diamminedichloroplatinum II (cisplatin), a divalent platinum compound and potent cell-cycle nonspecific chemotherapeutic agent, produces a dose-limiting, permanent, high-frequency sensori-neural hearing loss and peripheral neuropathy, and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. The exact mechanism(s) of ototoxicity and/or nephrotoxicity are still unknown. Continued aggressive high-dose cisplatin chemotherapy necessitates the investigation of ways to decrease the dose-limiting side effects that inhibit the administration of cisplatin at therapeutic and tumoricidal doses. This multifaceted project investigates two categories of potential inhibitors of cisplatin toxicity that, when coadministered with a known tumoricidal and ototoxic dose of cisplatin, will decrease or inhibit the ototoxicity: 1. phosphonic acid antibiotics (fosfomycin; 1,2 epoxypropylphosphonic acid); 2. nonglucocorticoid 21-aminosteroids, which are free oxygen radical scavengers (LAZAROIDS: U74006F and U78517F). This project also investigates the role of pigmentation as a variable affecting the evaluation of platinum-induced ototoxicity in the guinea pig animal model. Identification of an optimal animal model for future cisplatin toxicity research should be based on previously established species-specific differences in total drug dose, systemic toxicity, and morphological and functional evidence of cochlear toxicity, as affected by differences in pigmentation and drug tolerance. Cytocochleography, brainstem auditory evoked response (BSER), scanning and transmission electron microscopy of organ of Corti and the stria vascularis, double-blind light microscopy of renal, small intestine, and peripheral nerve tissue, and gamma-emission analysis of 195Mplatinum localization in inner ear neuroepithelium and the stria vascularis are used in the global evaluation of the ototoxic effects of cisplatin in both the adult albino and pigmented guinea pig.
顺式二氯二氨合铂（II）（顺铂）是一种二价铂化合物，也是一种有效的细胞周期非特异性化疗药物，会导致剂量限制性、永久性、高频感音神经性听力损失和周围神经病变，以及与剂量相关的累积性肾功能不全，并伴有肾小管坏死和间质性肾炎。尽管目前在给药前采用了高渗盐水、水化预处理和甘露醇利尿等方法，但仍存在剂量限制性和永久性耳蜗（神经）毒性的风险。耳毒性和/或肾毒性的确切机制仍然未知。持续进行积极的高剂量顺铂化疗需要研究如何减少剂量限制性副作用，这些副作用会抑制在治疗剂量和杀肿瘤剂量下使用顺铂。这个多方面的项目研究了两类顺铂毒性的潜在抑制剂，当它们与已知的杀肿瘤和耳毒性剂量的顺铂联合使用时，将减少或抑制耳毒性：1. 膦酸类抗生素（磷霉素；1,2-环氧丙基膦酸）；2. 非糖皮质激素类21-氨基类固醇，它们是自由基清除剂（拉扎罗类：U74006F和U78517F）。该项目还研究了色素沉着作为一个变量在豚鼠动物模型中对铂诱导的耳毒性评估的影响。未来顺铂毒性研究的最佳动物模型的确定应基于先前确定的物种特异性差异，包括总药物剂量、全身毒性以及耳蜗毒性的形态和功能证据，这些差异受色素沉着和药物耐受性的影响。细胞耳蜗电图、脑干听觉诱发电位（BSER）、柯蒂氏器和血管纹的扫描及透射电子显微镜检查、肾脏、小肠和周围神经组织的双盲光学显微镜检查，以及内耳神经上皮和血管纹中195铂定位的γ发射分析，用于全面评估顺铂对成年白化豚鼠和有色豚鼠的耳毒性作用。
