Avaliação da atividade antitumoral e do perfil toxicológico do composto CPBMF-223 em experimentos in vitro e in vivo

Abstract

Human thymidine phosphorylase (hTP) is an enzyme responsible for catalizing the phosphorolysis of thymidine in thymine and 2-deoxy-D-ribose-1-phosphate, being overexpressed in several solid tumors, including glioblastoma and colorectal carcinoma. The present study aimed to investigate the toxicological and pharmacological profiles of CPBMF-223 compound - a potent noncompetitive hTP inhibitor -, in a glioblastoma and colorectal carcinoma animal models. To evaluate the toxicity of CPBMF-223, in vitro assays of cytotoxicity (25 – 1000 μM), genotoxicity (250 – 1000 μM) and mutagenesis (100 – 2000 μg/plate) were performed. In addition, the cardiotoxicity and neurotoxicity effects were assessed in zebrafish larvae (50 – 500 μM), as well as the acute oral toxicity in mice (300 and 2000 mg/kg). The pharmacokinetic profile of the hTP inhibitor was analysed by intravenous (i.v.), intraperitoneal (i.p.), and oral as well as the plasma protein binding capacity. The pharmacological effects of CPBMF-223 (50 mg/kg, 5 days/week) were observed on the tumor growth in the xenographic model induced by human glioblastoma cells (U-87 MG) and human colorectal cancer (HCT-116) in nude mice (female and male). Interestingly, the results showed that CPBMF-223 did not induce cytotoxicity, genotoxicity and mutagenic effects. Moreveover, no significant changes was noted in acute toxicity experiments, with a slightly low toxic profile in the zebrafish model. CPBMF-223 also demonstrated a high bioavailaibity (>100%) in i.p. administration and low plasma protein binding (34%). Notably, the hTP inhibitor was able to reduce the relative tumor volume and the tumor growth rate, in both experimental models. In the glioblastoma model, the inhibition rate was 31% in male mice, and 50% in the colorectal model. For female, the percentage of reduction was 50% in the colorectal model. Interestingly, in both in vivo models, CPBMF-223 was able to decrease the tumors number of blood vesses and did not modify the liver injury enzymes. Collectively, the resuts bring new evidence of the toxicological safety of the CPBMF-223 compound and the antitumor activity performed in in vivo cancer models, pointing out this inhibitor as a promising drug to cancer treatment.