1. Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts.
- Author
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Sperotto NDM, Silva RBM, Perelló MA, Borsoi AF, da Silva Dadda A, Roth CD, Freitas RDS, de Souza APD, Freitas DDN, Picada JN, de Sousa JT, Nabinger DD, Altenhofen S, Bonan CD, Rodrigues-Junior VS, Bizarro CV, Basso LA, and Machado P
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors therapeutic use, Angiogenesis Inhibitors toxicity, Animals, Antimetabolites, Antineoplastic pharmacology, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents toxicity, Cell Line, Tumor, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors toxicity, Female, Fluorouracil pharmacology, HCT116 Cells, Half-Life, Humans, Male, Mice, Mice, Inbred BALB C, Mutagenicity Tests, Xenograft Model Antitumor Assays, Zebrafish, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms enzymology, Enzyme Inhibitors therapeutic use, Thymidine Phosphorylase antagonists & inhibitors
- Abstract
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., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2021
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