title: Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice.
abstract: Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, 14040-903 Ribeirão Preto, SP, Brazil.
authors: Marcia C
authors: MC
authors: da Silva Faria
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, 14040-903 Ribeirão Preto, SP, Brazil.
authors: Neife A G Dos
authors: NA
authors: Santos
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, 14040-903 Ribeirão Preto, SP, Brazil.
authors: Maria A
authors: MA
authors: Carvalho Rodrigues
authors: Instituto de Ciência e Tecnologia do Mucuri, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Teófilo Otoni, MG, Brazil.
authors: Jairo Lisboa
authors: JL
authors: Rodrigues
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, 14040-903 Ribeirão Preto, SP, Brazil.
authors: Fernando
authors: F
authors: Barbosa Junior
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address: acsantos@fcfrp.usp.br.
authors: Antonio Cardozo Dos
authors: AC
authors: Santos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D012510:Sarcoma 180 / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Antitumor activity; Biodistribution; Cisplatin; Diabetes; Nephrotoxicity; Sarcoma 180