Antitumor effectiveness and toxicity of cisplatin-loaded long-circulating and pH-sensitive liposomes against Ehrlich ascitic tumor.
Cisplatin (CDDP) is one of the most active cytotoxic agents commonly used in the treatment of peritoneal carcinomatosis. The disadvantages of its clinical use are systemic side-effects, such as nephrotoxicity and myelotoxicity. Long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP) were developed by our research group aiming to promote the release of CDDP near the tumor as well as decreasing toxicity. The aim of this study was to evaluate the antitumor efficacy and toxicity of SpHL-CDDP after intraperitoneal administration in initial or disseminated tumor-bearing mice, at a dose of 12 mg/kg. The survival was monitored and blood samples were collected for biochemical and hematological analysis. Kidneys, liver and spleen were removed for histopathological examination. Tumor cells were evaluated for cellular viability and cell cycle. The survival of animals treated with SpHL-CDDP was higher than those treated with free CDDP. The cell death caused by treatment with SpHL-CDDP occurred through induction of apoptosis, with a cell cycle arrest at the G0/G1 phase. The treatment of mice presenting initial cancer with both formulations provoked a suppression of granulocytes. Mice treated with free CDDP also showed a decrease in platelet count, which suggests a high myelotoxicity. In an advanced cancer model, SpHL-CDDP treatment allowed an improvement of the immune response. Mice affected by cancer at an early stage and treated with free CDDP or SpHL-CDDP showed a lower urea/creatinine index compared with the saline control group. These findings indicate that both treatments were able to reduce the renal damage caused by peritoneal carcinomatosis. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed a discrete morphological alteration, while tubular necrosis was observed for free CDDP-treated mice. Concerning hepatotoxicity, no alteration in clinical chemistry parameters was observed. These findings reveal that SpHL-CDDP can improve the antitumor efficacy and decrease renal and bone marrow toxicity.
Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou/FIOCRUZ,Brazil.
Laís
L
de Carvalho Maroni
Amanda Cardoso
AC
de Oliveira Silveira
Elaine Amaral
EA
Leite
Marília Martins
MM
Melo
Ana Flávia
AF
de Carvalho Ribeiro
Geovani Dantas
GD
Cassali
Cristina Maria
CM
de Souza
Elaine Maria
EM
Souza-Fagundes
Iramaya Rodrigues
IR
Caldas
Márcio Sobreira Silva
MS
Araújo
Olindo Assis
OA
Martins-Filho
Mônica Cristina
MC
de Oliveira
Andréa
A
Teixeira-Carvalho
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D017209:Apoptosis; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006651:Histocytochemistry; D006863:Hydrogen-Ion Concentration; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000473:pathology; D051379:Mice; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D002945:Cisplatin