PUBLICATION
Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts
- Authors
- Sperotto, N.D.M., Silva, R.B.M., Perelló, M.A., Borsoi, A.F., da Silva Dadda, A., Roth, C.D., Freitas, R.D.S., de Souza, A.P.D., Freitas, D.D.N., Picada, J.N., de Sousa, J.T., Nabinger, D.D., Altenhofen, S., Bonan, C.D., Rodrigues-Junior, V.S., Bizarro, C.V., Basso, L.A., Machado, P.
- ID
- ZDB-PUB-210511-3
- Date
- 2021
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 139: 111672 (Journal)
- Registered Authors
- Bonan, Carla Denise
- Keywords
- Colorectal cancer, Pharmacokinetics, Thymidine phosphorylase inhibitor, Toxicity, Tumor xenograft model
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacokinetics
- Angiogenesis Inhibitors/therapeutic use
- Angiogenesis Inhibitors/toxicity
- Animals
- Antimetabolites, Antineoplastic/pharmacology
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/therapeutic use*
- Antineoplastic Agents/toxicity
- Cell Line, Tumor
- Colorectal Neoplasms/drug therapy*
- Colorectal Neoplasms/enzymology*
- Enzyme Inhibitors/pharmacokinetics
- Enzyme Inhibitors/therapeutic use*
- Enzyme Inhibitors/toxicity
- Female
- Fluorouracil/pharmacology
- HCT116 Cells
- Half-Life
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mutagenicity Tests
- Thymidine Phosphorylase/antagonists & inhibitors*
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 33965731 Full text @ Biomed. Pharmacother.
Citation
Sperotto, N.D.M., Silva, R.B.M., Perelló, M.A., Borsoi, A.F., da Silva Dadda, A., Roth, C.D., Freitas, R.D.S., de Souza, A.P.D., Freitas, D.D.N., Picada, J.N., de Sousa, J.T., Nabinger, D.D., Altenhofen, S., Bonan, C.D., Rodrigues-Junior, V.S., Bizarro, C.V., Basso, L.A., Machado, P. (2021) Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 139:111672.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping