Ma S-F, Nishikawa M, Hyoudou K, Takahashi R, Ikemura M, Kobayashi Y, Yamashita F, Hashida M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Kidney Int. 2007 Dec;72(12):1474-82. doi: 10.1038/sj.ki.5002556. Epub 2007 Sep 26.
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.
顺铂常用于治疗实体瘤；然而，其由活性氧介导的肾毒性作用限制了它的使用。我们测试了阳离子化过氧化氢酶（一种过氧化氢酶衍生物）抑制顺铂处理小鼠肾毒性的能力。免疫组织化学分析表明，该过氧化氢酶衍生物在肾脏中的富集效率高于天然过氧化氢酶。重复静脉注射阳离子化过氧化氢酶可显著降低顺铂诱导的血清肌酐、血尿素氮、亚硝酸盐/硝酸盐水平、乳酸脱氢酶活性以及肾脏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有效减轻了顺铂诱导的近端肾小管坏死，但对顺铂诱导的皮下肿瘤生长抑制没有显著影响。重复给药过氧化氢酶，尤其是阳离子化过氧化氢酶，可显著提高顺铂处理的荷瘤小鼠的存活率，预防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。
