Mechanism of Action and Resistance
  • Andries M. Bergman
  • Godefridus J. Peters
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Gemcitabine (2′,2′-difluorodeoxycytidine, Gemzar®) is a deoxycytidine analog with pronounced antitumor activity against a variety of solid tumors, such as non-small cell lung carcinoma and pancreatic and bladder cancer. In this chapter, we summarize the role of the key enzymes in its metabolic activation and deactivation pathways, the role of the various targets, the associated mechanisms of acquired and inherent resistance, and the changes in DNA caused by exposure to this drug. Extensive research has revealed a complex mechanism of action of this relatively new drug. Gemcitabine requires phosphorylation to mono-, di-, and triphosphates (dFdCTP) to be active; this mechanism results in a unique pattern of self-potentiation of the drug, ultimately resulting (when incorporated into the DNA) in a masked chain termination. Similar to the structurally and functionally related deoxycytidine analog 1-β-D-arabinofuranosylcytosine (ara-C), the first, crucial step in phosphorylation is catalyzed by deoxycytidine kinase (dCK). However, unlike ara-C, gemcitabine has multiple intracellular targets; up- or downregulation of these targets may confer resistance to this drug. Resistance is associated with altered activities of enzymes (e.g., dCK) involved in the metabolism of the drug, of target enzymes (e.g., ribo-nucleotide reductase), and of enzymes involved in programmed cell death. Strong correlations with gemcitabine sensitivity have been observed for dCK activity and dFdCTP pools; microarray analyses have suggested a potentially important role for ribonucleotide reductase.

Key Words

Deoxycytidine kinase DNA repair gemcitabine masked chain termination ribonucleotide reductase self-potentiation thymidine kinase 2 


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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Andries M. Bergman
    • 1
  • Godefridus J. Peters
    • 1
  1. 1.Department of Medical OncologyVU University Medical CenterAmsterdamThe Netherlands

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