PUBLICATION

Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU

Authors
Benyumov, A., Gurvich, V.J., Lis, L.G., Williams, B.W., and Kirstein, M.N.
ID
ZDB-PUB-110207-11
Date
2011
Source
ChemMedChem   6(3): 457-464 (Journal)
Registered Authors
Benyumov, Alexey O.
Keywords
cancer, dFdU, gemcitabine, teratogenicity, zebrafish
MeSH Terms
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols/chemistry
  • Antineoplastic Combined Chemotherapy Protocols/metabolism
  • Antineoplastic Combined Chemotherapy Protocols/toxicity*
  • Cell Line, Tumor
  • Combinatorial Chemistry Techniques
  • Deoxycytidine/analogs & derivatives*
  • Deoxycytidine/chemistry
  • Deoxycytidine/metabolism
  • Deoxycytidine/toxicity
  • Deoxyuridine/chemistry
  • Deoxyuridine/toxicity
  • Embryo, Nonmammalian
  • Embryonic Development/drug effects
  • Floxuridine/analogs & derivatives*
  • Floxuridine/chemistry
  • Floxuridine/toxicity
  • Humans
  • Tumor Stem Cell Assay
  • Zebrafish/embryology
PubMed
21280228 Full text @ ChemMedChem.
Abstract
Recent evidence has shown that the gemcitabine metabolite, dFdU, is pharmacologically active. Though less potent, dFdU has a longer half-life and could potentiate or antagonize the activity of gemcitabine. Hence, studies were undertaken to evaluate the combined effects. Following chemical synthesis, an improved purification procedure for dFdU was developed (80 % yield; >99 % purity). Zebrafish phenotype-based embryo screens revealed no acute toxicity after gemcitabine or dFdU treatment. Only gemcitabine affected zebrafish development in a dose-dependent manner. Synergy or antagonism for the combination was not observed. Antitumor effects for dFdU were dose dependent. Antagonism was tumor cell-line dependent and did not depend on formation of the intracellular active metabolite of gemcitabine, suggesting that the drug-metabolite interaction occurs later. These studies highlight a platform for testing the pharmacologic activity for anticancer agent and metabolite combinations. Such analyses are expected to provide insight into the beneficial or harmful effect(s) of metabolites towards parent drug activity.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping