Watanabe H, Kanno H
Department of Otolaryngology, Fukushima Medical College.
Nihon Jibiinkoka Gakkai Kaiho. 1998 Aug;101(8):967-78. doi: 10.3950/jibiinkoka.101.8_967.
Cisplatin (CDDP) is an antitumor agent against several types of neoplasms. It has, however, various side effects such as nephrotoxicity and ototoxicity. Several efforts have been made to prevent these toxic side effects. On the other hand, deferoxiamine mesilate (DFO), an iron-chelating agent, has been used for iron-overloaded patients. Since the 1980s, many authors have reported DFO-associated hearing impairment. Some experimental data suggest that DFO itself was responsible for ototoxicity. In addition, it has also been recognized that DFO can act as a free radical scavenger. Experimental trials using DFO are also expected to prevent CDDP-induced toxicity because its generation mechanism is thought to be associated with free radical formation. The present study was planned to investigate whether DFO, which might be an ototoxic agent, had a protective effect against various CDDP-induced toxicities including ototoxicity. Fisher rats were used in this study and were divided into four groups: 1) Group I, a vehicle control, 2) Group II, animals receiving 100 mg of DFO per kg, 3) Group III, animals administered 0.9 mg of CDDP per kg alone and 4) Group IV, animals receiving 100 mg of DFO per kg 60 min before 0.9 mg of CDDP per kg for 10 days. First, the protective effect of DFO against CDDP-induced ototoxicity was studied. The auditory threshold was determined by using the compound action potential (CAP) from the round window membrane. CAPs were recorded on the 5th day after completion of drug administration. Then CAPs recording, cochlear sensory epithelia were observed over all the turns of the cochlea by scanning electron microscopy. There were no significant differences in CAP thresholds between Group I and IV, though the thresholds in Group III were significantly higher at 16 kHz and 20 kHz than those in Group IV. The rate of missing outer hair cells in Group IV was significantly lower than that in Group III. The results clearly demonstrated that DFO had a protective effect against CDDP-induced ototoxicity. Second, the protective effect of DFO against CDDP-induced nephrotoxicity was studied. Renal function was evaluated by measuring blood urea nitrogen (BUN) and serum creatinine (Cr) levels. Both BUN and Cr levels in Group IV were significantly lower than those in Group III. The data suggested that DFO preadministration prevented CDDP-induced nephrotoxicity. Third, the influence of DFO on the antitumor activity of CDDP was investigated in rats inoculated with squamous cell carcinoma cells (SCC-131) subcutaneously. The influence of drugs was determined by measuring the tumor growth rate. There was no difference in the tumor growth rate between Group III and IV. The result revealed that DFO had no influence on CDDP antitumor activity. In conclusion, the above results demonstrating that DFO preadministration can prevent both CDDP-induced ototoxicity and nephrotoxicity without attenuation of CDDP antitumor activity, suggest the usefulness of CDDP antitumor chemotherapy.
顺铂（CDDP）是一种针对多种肿瘤的抗肿瘤药物。然而，它有多种副作用，如肾毒性和耳毒性。人们已经做出了多种努力来预防这些毒性副作用。另一方面，去铁胺甲磺酸盐（DFO），一种铁螯合剂，已被用于治疗铁过载患者。自20世纪80年代以来，许多作者报告了DFO相关的听力损害。一些实验数据表明，DFO本身是耳毒性的原因。此外，人们还认识到DFO可以作为自由基清除剂。使用DFO的实验性试验也有望预防CDDP诱导的毒性，因为其产生机制被认为与自由基形成有关。本研究旨在调查可能是耳毒性药物的DFO是否对包括耳毒性在内的各种CDDP诱导的毒性具有保护作用。本研究使用Fisher大鼠，并将其分为四组：1）第一组，溶剂对照组；2）第二组，每千克体重接受100毫克DFO的动物；3）第三组，单独每千克体重给予0.9毫克CDDP的动物；4）第四组，在每千克体重给予0.9毫克CDDP前60分钟接受每千克体重100毫克DFO的动物，持续10天。首先，研究了DFO对CDDP诱导的耳毒性的保护作用。通过使用圆窗膜的复合动作电位（CAP）来测定听觉阈值。在给药完成后的第5天记录CAP。然后在记录CAP后，通过扫描电子显微镜观察耳蜗所有螺旋的耳蜗感觉上皮。第一组和第四组之间的CAP阈值没有显著差异，尽管第三组在16千赫和20千赫处的阈值显著高于第四组。第四组中缺失外毛细胞的比例显著低于第三组。结果清楚地表明，DFO对CDDP诱导的耳毒性具有保护作用。其次，研究了DFO对CDDP诱导的肾毒性的保护作用。通过测量血尿素氮（BUN）和血清肌酐（Cr）水平来评估肾功能。第四组的BUN和Cr水平均显著低于第三组。数据表明，预先给予DFO可预防CDDP诱导的肾毒性。第三，在皮下接种鳞状细胞癌细胞（SCC - 131）的大鼠中研究了DFO对CDDP抗肿瘤活性的影响。通过测量肿瘤生长速率来确定药物的影响。第三组和第四组之间的肿瘤生长速率没有差异。结果表明，DFO对CDDP的抗肿瘤活性没有影响。总之，上述结果表明预先给予DFO可以预防CDDP诱导的耳毒性和肾毒性，而不会减弱CDDP的抗肿瘤活性，提示了CDDP抗肿瘤化疗的有效性。
