title: Combinatorial pharmacologic effects of gemcitabine and its metabolite dFdU.
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.
authors.affiliation: Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota 55414, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Benyumov
authors.forename: Vadim J
authors.initials: VJ
authors.lastname: Gurvich
authors.forename: Lev G
authors.initials: LG
authors.lastname: Lis
authors.forename: Brent W
authors.initials: BW
authors.lastname: Williams
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kirstein
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D003857:Deoxyuridine / Q000737:chemistry / Q000633:toxicity; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D014410:Tumor Stem Cell Assay; D015027:Zebrafish / Q000196:embryology; D000093542:Gemcitabine
chemical_list: D005467:Floxuridine; D003841:Deoxycytidine; D003857:Deoxyuridine; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine