Fukaya H, Kanno H
Department of Otolaryngology, Fukushima Medical University School of Medicine.
Nihon Jibiinkoka Gakkai Kaiho. 1999 Jul;102(7):907-17. doi: 10.3950/jibiinkoka.102.907.
Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of solid malignant tumors. Its clinical use, however, is limited because of various side effects including sensorineural hearing loss. Several agents have been proposed to reduce these side effects. GBE has recently been reported to scavenge superoxide and hydroxyl radicals, resulting in a reduction of lipid peroxidation. GBE is expected to protect against CDDP-induced toxicity because its generative mechanism is thought to be associated with free-radical formation. The purpose of the present study was to evaluate GBE's efficacy as a protective agent against cisplatin-induced ototoxicity. Fisher rats were used in this study and were divided into three treatment groups: 1) animals administered 1.0 mg of CDDP per kg for 10 days (Group I), 2) animals receiving 100 mg of GBE per kg 90 min before administration 1.0 mg of CDDP per kg (Group II) and 3) a vehicle control (Group III). First, the protective effect of GBE on CDDP-induced ototoxicity was investigated. The auditory threshold was evaluated by means of the compound action potential (CAP) recording. After CAP recordings, cochlear sensory epithelia were observed throughout the cochlea by scanning electron microscopy. In Group II, the elevation of CAP thresholds at 12 kHz, 16 kHz, 20 kHz and the missing rate for the outer hair cells were significantly reduced as compared to those in Group I. These data suggest that GBE is effective for otoprotection against CDDP. Second, the protective effect of GBE on CDDP-induced nephrotoxicity was evaluated. Nephrotoxicity was evaluated by means of measurement of serum BUN and creatinine and histopathological examination of the kidney. These were significant differences in serum BUN and creatinine levels between Group I and Group II. Third, the influence of GBE against the antitumor effect of CDDP was researched in the rats inoculated subcutaneously with SCC-158 squamous cell carcinoma cells. There was no difference in tumor growth rate (TGR) between Group I and Group II. The result suggested that the combined administration had no influence on the antitumor activity of CDDP. In conclusion, the co-administration of CDDP with GBE is beneficial to ameliorate CDDP-induced toxicity without attenuation of CDDP antitumor activity.
顺铂（CDDP）是治疗实体恶性肿瘤的一种有效抗肿瘤药物。然而，由于包括感音神经性听力损失在内的各种副作用，其临床应用受到限制。已经提出了几种药物来减少这些副作用。最近有报道称GBE可清除超氧阴离子和羟基自由基，从而减少脂质过氧化。GBE有望预防顺铂诱导的毒性，因为其产生机制被认为与自由基形成有关。本研究的目的是评估GBE作为预防顺铂诱导耳毒性的保护剂的疗效。本研究使用Fisher大鼠，并将其分为三个治疗组：1）每千克体重给予1.0 mg顺铂，持续10天的动物（第一组），2）在每千克体重给予1.0 mg顺铂前90分钟接受每千克体重100 mg GBE的动物（第二组），以及3）溶剂对照组（第三组）。首先，研究了GBE对顺铂诱导耳毒性的保护作用。通过复合动作电位（CAP）记录评估听觉阈值。在CAP记录后，通过扫描电子显微镜观察整个耳蜗的耳蜗感觉上皮。与第一组相比，第二组中12 kHz、16 kHz、20 kHz处CAP阈值的升高以及外毛细胞的缺失率显著降低。这些数据表明GBE对预防顺铂引起的耳毒性有效。其次，评估了GBE对顺铂诱导肾毒性的保护作用。通过测量血清尿素氮和肌酐以及对肾脏进行组织病理学检查来评估肾毒性。第一组和第二组之间血清尿素氮和肌酐水平存在显著差异。第三，在皮下接种SCC - 158鳞状细胞癌细胞的大鼠中研究了GBE对顺铂抗肿瘤作用的影响。第一组和第二组之间肿瘤生长率（TGR）没有差异。结果表明联合给药对顺铂的抗肿瘤活性没有影响。总之，顺铂与GBE联合给药有利于改善顺铂诱导的毒性，而不会减弱顺铂的抗肿瘤活性。
