Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity.
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.
Ma
S-F
SF
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Nishikawa
M
M
Hyoudou
K
K
Takahashi
R
R
Ikemura
M
M
Kobayashi
Y
Y
Yamashita
F
F
Hashida
M
M
D000818:Animals; D021461:Animals, Outbred Strains; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D002374:Catalase / Q000494:pharmacology*; D002412:Cations / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D012878:Skin Neoplasms / Q000188:drug therapy*; D015996:Survival Rate
D000970:Antineoplastic Agents; D000975:Antioxidants; D002412:Cations; D009566:Nitrates; D009573:Nitrites; D008315:Malondialdehyde; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D002945:Cisplatin