Protective effects of a glutathione disulfide mimetic (NOV-002) against cisplatin induced kidney toxicity.
NOV-002 is a glutathione disulfide (GSSG) mimetic with chemoprotective activity. Previous and ongoing clinical studies demonstrate a significantly improved 1-year survival and decreased tumor progression rates in non-small cell lung (NSCLC) and ovarian cancer patients when NOV-002 was included in cisplatin containing regimens. In order to understand this chemoprotective property, we employed as an animal model of kidney toxicity, 8-week-old Bl6 mice that were treated with a single nephrotoxic dose of cisplatin (15 mg/kg, ip) and sacrificed on Day 5. One group of animals was treated with NOV-002 (15 mg/kg, im) daily. NOV-002-treated mice had significantly lower levels of plasma creatinine compared to mice treated with cisplatin alone (4.7 vs 2.9 mg/dL, respectively). Moreover, NOV-002 protected the kidneys from cisplatin mediated proximal tubule damage, including dilation of tubules and the presence of protein casts. Since cisplatin-induced nephrotoxicity can be mediated by a glutathione-platinum conjugate catalyzed by gamma-glutamyl-transpeptidase (GGT) and glutathione is an endogenous substrate of GGT, the protective effect of NOV-002 in the kidney may be attributed to its ability to act as a competitive substrate for the enzyme.
Jenderny
Sara
S
Departments of Pharmaceutical and Biomedical Sciences, Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.
Lin
He
H
Garrett
Tracy
T
Tew
Kenneth D
KD
Townsend
Danyelle M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000494:pharmacology* / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D004338:Drug Combinations; D005260:Female; D019803:Glutathione Disulfide / Q000494:pharmacology* / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000970:Antineoplastic Agents; D004338:Drug Combinations; C529375:NOV 002; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D002945:Cisplatin; D019803:Glutathione Disulfide