Original Article
Kidney International (2007) 72, 1474–1482; doi:10.1038/sj.ki.5002556; published online 26 September 2007
Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity
S-F Ma1, M Nishikawa2, K Hyoudou1, R Takahashi3, M Ikemura1, Y Kobayashi1, F Yamashita1 and M Hashida1
- 1Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
- 2Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
- 3Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
Correspondence: M Nishikawa, Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: makiya@pharm.kyoto-u.ac.jp
Received 8 November 2006; Accepted 5 December 2006; Published online 26 September 2007.
Abstract
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.
Keywords:
renal delivery, catalase, cationization, cisplatin, nephrotoxicity
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