Gemcitabine is frequently used in the treatment of patients with solid
tumors.
Gemcitabine is taken up into the cell via human
nucleoside transporters (hNTs) and is intracellularly phosphorylated by
deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active
triphosphate metabolite
2',2'-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into
DNA and inhibits
DNA synthesis. In addition,
gemcitabine is extensively deaminated to
2',2'-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative
nucleoside transporter type 1 were associated with a significantly longer overall survival duration after
gemcitabine treatment in patients with
pancreatic cancer. Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of
gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of
gemcitabine at a fixed dose rate (FDR) of 10 mg/m2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of
gemcitabine in patients with
pancreatic cancer. In the current review, we discuss the molecular pharmacology of
nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of
gemcitabine, which is the basis for clinical studies on FDR administration, and the results of FDR
gemcitabine administration in patients. These findings might aid optimal clinical application of
gemcitabine in the future.