Evaluation of the therapeutic potential of carvedilol as a nephroprotector during cisplatin chemotherapy: studies of efficiency and interference in the antitumor activity

• Grant number: 10/11586-8
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2010
• End date: March 31, 2013
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Antonio Cardozo dos Santos
• Grantee: Antonio Cardozo dos Santos
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Fernando Barbosa Júnior ; Lusânia Maria Greggi Antunes

Abstract

Cisplatin is one of the most effective anticancer agents; however its clinical use is highly limited mainly due to its nephrotoxic potential. Many studies have demonstrated that the cisplatin nephrotoxicity is directly related to the accumulation of reactive oxygen species and to the apoptotic cell death. The antioxidant adjuvant therapy has been suggested as a strategy to protect healthy tissues against the toxicity induced by cisplatin and the efficacy of several antioxidants has been demonstrated in different experimental models. However, most of these compounds which were promising as cytoprotectors have not been tested in tumor bearing experimental models and there is not a consensus about the impact of the antioxidant therapy on the anticancer activity of cisplatin. Besides that, there are no sufficient data about the effect of many of these compounds on human health; many of them are model drugs, potentially toxic, and therefore, cannot be used in humans, others may have pro-oxidative activity under certain conditions and may aggravate the oxidative damage to tissues. In our previous studies, performed with healthy rats, we have demonstrated that carvedilol efficiently protects against the mitochondriopathy induced by cisplatin (Carvalho Rodrigues et al. 2010) mainly due to its potent antioxidant capacity, and that this effect is not associated to the formation of complexes with cisplatin (Chemico-Biological Interactions, under review). It is noteworthy that carvedilol is a safe drug, already clinically employed as antihypertensive and well tolerated by patients. All together, these features make carvedilol very promising as a nephroprotective agent in cisplatin chemotherapy. Therefore, the present study aims to complement our previous findings, evaluating this time the nephroprotective capacity of carvedilol as well as its influence in the antitumor activity of cisplatin, using a classical tumor-bearing experimental model (Sarcoma 180 in mice). The present investigation will provide the necessary data for a future use of carvedilol with this new therapeutic application (nephroprotection). (AU)