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dc.contributor.authorTsume, Yasuhiro
dc.contributor.authorBorrás Bermejo, Blanca
dc.contributor.authorAmidon, Gordon L.
dc.description.abstractDipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.ca_ES
dc.description.sponsorshipThis work was supported by grants NIGMD-2R01GM037188.ca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofPharmaceuticals, 2014, vol. 7, p. 169-191ca_ES
dc.rightscc-by (c) Tsume et al., 2016ca_ES
dc.subjectGemcitabine prodrugca_ES
dc.subjectFloxuridine prodrugca_ES
dc.subjectMouse in situ perfusionca_ES
dc.titleThe dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogsca_ES

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