Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity
Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity
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DOI：
10.1038/sj.ki.5002556
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发表时间：
2007-12-01
影响因子：
19.6
通讯作者：
Hashida, M.
中科院分区：
文献类型：
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作者：
Ma, S-F;Nishikawa, M.;Hashida, M.
顺铂经常用于治疗实体瘤；然而，由于其活性氧介导的作用而产生的肾毒性限制了其使用。我们测试了阳离子化过氧化氢酶（一种过氧化氢酶衍生物）抑制顺铂治疗小鼠肾毒性的能力。免疫组织化学分析表明，过氧化氢酶衍生物比天然过氧化氢酶更有效地集中在肾脏中。重复静脉注射阳离子化过氧化氢酶可显着降低顺铂引起的血清肌酐、血尿素氮、亚硝酸盐/硝酸盐水平、乳酸脱氢酶活性以及肾总谷胱甘肽和丙二醛含量的变化。此外，阳离子化过氧化氢酶可有效减弱顺铂诱导的近端小管坏死，但对顺铂诱导的皮下肿瘤生长抑制没有显着影响。重复剂量的过氧化氢酶，尤其是阳离子化过氧化氢酶，显着增加了顺铂治疗的荷瘤小鼠的存活率，防止了顺铂诱导的急性死亡。我们的研究表明过氧化氢酶及其衍生物可抑制顺铂诱导的肾毒性，从而提高顺铂治疗实体瘤的效率。
Cisplatin is frequently used to treat solid tumors; however, nephrotoxicity due to its reactive oxygen species-mediated effect limits its use. We tested the ability of cationized catalase, a catalase derivative, to inhibit nephrotoxicity in cisplatin-treated mice. Immunohistochemical analysis showed that the catalase derivative concentrated in the kidney more efficiently than native catalase. Repeated intravenous doses of cationized catalase significantly decreased cisplatin-induced changes in serum creatinine, blood urea nitrogen, nitrite/nitrate levels, lactic dehydrogenase activity, and renal total glutathione and malondialdehyde contents. In addition, cationized catalase effectively blunted cisplatin-induced proximal tubule necrosis but had no significant effect on the cisplatin-induced inhibition of subcutaneous tumor growth. Repeated doses of catalase, especially cationized catalase, significantly increased the survival of cisplatin-treated tumor-bearing mice preventing cisplatin-induced acute death. Our studies suggest that catalase and its derivatives inhibit cisplatin-induced nephrotoxicity, thus improving the efficiency of cisplatin to treat solid tumors.