Abstract
Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). Wepreviously reported that apparent DAC uptake into cells may be described using a simple compartment model with clearance for facilitated diffusion (PS) and subsequent phosphorylation (CLmet). In the present study, time course of apparent intracellular [3H]-DAC uptake was analyzed numerically, and PS and CLmet values were calculated using the compartment model in human colon cancer HCT116 cells. PS at 0.1μM [3H]-DAC was markedly decreased in the presence of 100μM irinotecan or etoposide, while CLmet was markedly decreased in the presence of 100μM cytarabine or gemcitabine. CLmet at 0.1-10μM [3H]-DAC varied in a concentration-dependent manner and was described by Michaelis-Menten parameters Km,met and Vmax,met. In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters.
Published Version
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