Sunitinib improves chemotherapeutic efficacy and ameliorates cisplatin-induced nephrotoxicity in experimental animals.
OBJECTIVE
Therapeutic inhibition of angiogenesis has a benefit in the treatment of neoplastic diseases. Cisplatin is a widely used anti-cancer agent; however, it has serious side effects on non-tumor cells and causes nephrotoxicity due to its reactive oxygen species-mediated effect. Thus, a combination between cisplatin and angiogenesis inhibitors may be useful in cancer treatment. In the present study, the effect of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, on the antitumor activity as well as the nephrotoxic side effect of cisplatin was examined.


METHODS
The antitumor activity was evaluated both in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo using a mouse model of solid tumor. In addition, the effect of cisplatin and/or sunitinib on the angiogenic marker, VEGF, was examined. Nephrotoxicity was induced in rats by single i.p. injection of cisplatin (6 mg/kg).


RESULTS
Sunitinib significantly potentiated the cytotoxic effect of cisplatin in vitro and in vivo. The nephrotoxicity of cisplatin was evidenced by decrease in the body weight, increase in kidney/body weight ratio and decrease in the percent survival of rats. The toxicity was also confirmed biochemically by measuring some kidney function parameters and oxidative stress markers. Sunitinib significantly decreased cisplatin-induced changes in serum creatinine, blood urea nitrogen, creatinine clearance and micro total protein in urine, renal malondialdehyde levels and reduced glutathione contents. In addition, sunitinib effectively blunted cisplatin-induced proximal and distal tubules necrosis.


CONCLUSIONS
The potential for sunitinib to ameliorate the cisplatin-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with cisplatin.
Suddek
Ghada M
GM
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt. ghmsuddek@yahoo.com
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects*; D004357:Drug Synergism; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000975:Antioxidants; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases; D002945:Cisplatin; D000077210:Sunitinib