title: Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin.
abstract: Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.
authors.affiliation: Centro Universitário do Distrito Federal, UDF, SEP/SUL EQ704/904 Conj.A, Brasilia/DF, CEP 70390-045, Brazil.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Carvalho Rodrigues
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Neife A G
authors.initials: NA
authors.lastname: dos Santos
authors.affiliation: Universidade Federal do Vale do Jequitinhona e Mucuri, UFVJM, Campus do Mucuri, Teófilo Otoni/MG, Rua do Cruzeiro, nº 01 - Jardim, São Paulo, CEP 39803-371, Brazil.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: da Silva Faria
authors.affiliation: Universidade Federal do Vale do Jequitinhona e Mucuri, UFVJM, Campus do Mucuri, Teófilo Otoni/MG, Rua do Cruzeiro, nº 01 - Jardim, São Paulo, CEP 39803-371, Brazil.
authors.forename: Jairo Lisboa
authors.initials: JL
authors.lastname: Rodrigues
authors.affiliation: Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto - USP, Avenida do Café s/n, 14040-901, Ribeirão Preto, SP, Brazil.
authors.forename: Angela
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto - USP, Avenida do Café s/n, 14040-901, Ribeirão Preto, SP, Brazil.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Baffa
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Lusania M Greggi
authors.initials: LM
authors.lastname: Antunes
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Barbosa
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Princess Alexandra Hospital, Brisbane, QLD, 4102, Australia.
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil. Electronic address: acsantos@fcfrp.usp.br.
authors.forename: Antonio Cardozo
authors.initials: AC
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000077261:Carvedilol; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D002945:Cisplatin
keywords: Biodistribution; Carvedilol; Cisplatin; Genotoxicity; Nephroprotection