Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts

Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described...

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Main Authors: Nathalia D. de Moura Sperotto, Rodrigo Braccini Madeira Silva, Marcia Alberton Perelló, Ana Flávia Borsoi, Adilio da Silva Dadda, Candida Deves Roth, Raquel Dal Sasso Freitas, Ana Paula Duarte de Souza, Deise do Nascimento de Freitas, Jaqueline Nascimento Picada, Jayne Torres de Sousa, Débora Dreher Nabinger, Stefani Altenhofen, Carla Denise Bonan, Valnês S. Rodrigues-Junior, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado
Format: Article
Language:English
Published: Elsevier 2021-07-01
Series:Biomedicine & Pharmacotherapy
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Online Access:http://www.sciencedirect.com/science/article/pii/S0753332221004546
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Summary:Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described as a tumor angiogenesis inhibitor. The present study investigated the effects of CPBMF-223 in a xenograft tumor induced by human colorectal carcinoma cells (HCT-116). Additionally, CPBMF-223 capacity to reduce cell migration, its toxicological profile, and pharmacokinetic characteristics, were also evaluated. The intraperitoneal treatment with CPBMF-223 markedly prevented the relative tumor growth with an efficacy similar to that observed for 5-fluorouracil. Interestingly, number of vessels were significantly decreased in the treated groups. Moreover, CPBMF-223 significantly reduced the migration of cell line HCT-116. In the Ames assay and in an acute oral toxicity test, the molecule did not alter any evaluated parameter. Using the zebrafish toxicity model, cardiac and locomotor parameters were slightly changed. Regarding the pharmacokinetics profile, CPBMF-223 showed clearance of 9.42 L/h/kg after intravenous administration, oral bioavailability of 13.5%, and a half-life of 0.75 h. Our findings shed new light on the role of hTP in colorectal cancer induced by HCT-116 cell in mice, pointing out CPBMF-223 as, hopefully, a promising drug candidate.
ISSN:0753-3322