Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine)

Andries M. Bergman, Herbert M. Pinedo, Godefridus J. Peters

Research output: Contribution to journalArticlepeer-review

277 Scopus citations


The inherent or induced resistance of tumors to cytostatic agents is a major clinical problem. In this review, we summarize the pre-clinical mechanisms of acquired and inherent resistance to the fluorinated deoxycytidine analog gemcitabine (2′,2′-difluorodeoxycytidine. dFdC, Gemzar®), which has proven activity in non-small cell lung carcinoma, pancreatic and bladder cancer. Extensive research has been performed to elucidate the complex mechanism of action of this relatively new drug. Gemcitabine requires phosphorylation to mono-, di- and triphosphates to be active. Similar to the structurally and functionally related deoxycytidine analog ara-C, the first, crucial step in phosphorylation is catalyzed by deoxycytidine kinase (dCK). However, in contrast to ara-C, gemcitabine has multiple intracellular targets; up- or down-regulation of these targets may confer resistance to this drug. Resistance is associated with altered activities of enzymes involved in the metabolism of the drug, of target enzymes, and of enzymes involved in programmed cell death. However, the only strong correlations with gemcitabine sensitivity are dCK activity and dFdCTP pools, with a potential important role for ribonucleotide reductase.

Original languageEnglish (US)
Pages (from-to)19-33
Number of pages15
JournalDrug Resistance Updates
Issue number1
StatePublished - Feb 2002
Externally publishedYes


  • 5′-nucleotidase
  • Apoptosis
  • Deoxycytidine deaminase
  • Deoxycytidine kinase
  • Drug accumulation
  • Drug resistance
  • Gemcitabine
  • Membrane transport
  • Ribonucleotide reductase
  • Thymidine kinase 2
  • Thymidylate synthase

ASJC Scopus subject areas

  • Cancer Research
  • Infectious Diseases
  • Oncology
  • Pharmaceutical Science


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