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

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

Research output: Contribution to journalArticle

Abstract

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
Volume5
Issue number1
DOIs
StatePublished - Feb 2002
Externally publishedYes

Fingerprint

gemcitabine
Deoxycytidine Kinase
Deoxycytidine
Cytarabine
Non-Small Cell Lung Carcinoma
Enzymes
Phosphorylation
Ribonucleotide Reductases
Diphosphates
Cytostatic Agents
Pancreatic Neoplasms
Drug Resistance
Urinary Bladder Neoplasms
Pharmaceutical Preparations
Cell Death
Up-Regulation
Down-Regulation

Keywords

  • 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

Cite this

Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). / Bergman, Andries M.; Pinedo, Herbert M.; Peters, Godefridus J.

In: Drug Resistance Updates, Vol. 5, No. 1, 02.2002, p. 19-33.

Research output: Contribution to journalArticle

Bergman, Andries M. ; Pinedo, Herbert M. ; Peters, Godefridus J. / Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). In: Drug Resistance Updates. 2002 ; Vol. 5, No. 1. pp. 19-33.
@article{468d2bdcf34741e8b627b172e55c3e54,
title = "Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine)",
abstract = "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{\circledR}), 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.",
keywords = "5′-nucleotidase, Apoptosis, Deoxycytidine deaminase, Deoxycytidine kinase, Drug accumulation, Drug resistance, Gemcitabine, Membrane transport, Ribonucleotide reductase, Thymidine kinase 2, Thymidylate synthase",
author = "Bergman, {Andries M.} and Pinedo, {Herbert M.} and Peters, {Godefridus J.}",
year = "2002",
month = "2",
doi = "10.1016/S1368-7646(02)00002-X",
language = "English (US)",
volume = "5",
pages = "19--33",
journal = "Drug Resistance Updates",
issn = "1368-7646",
publisher = "Churchill Livingstone",
number = "1",

}

TY - JOUR

T1 - Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine)

AU - Bergman, Andries M.

AU - Pinedo, Herbert M.

AU - Peters, Godefridus J.

PY - 2002/2

Y1 - 2002/2

N2 - 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.

AB - 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.

KW - 5′-nucleotidase

KW - Apoptosis

KW - Deoxycytidine deaminase

KW - Deoxycytidine kinase

KW - Drug accumulation

KW - Drug resistance

KW - Gemcitabine

KW - Membrane transport

KW - Ribonucleotide reductase

KW - Thymidine kinase 2

KW - Thymidylate synthase

UR - http://www.scopus.com/inward/record.url?scp=0036462584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036462584&partnerID=8YFLogxK

U2 - 10.1016/S1368-7646(02)00002-X

DO - 10.1016/S1368-7646(02)00002-X

M3 - Article

VL - 5

SP - 19

EP - 33

JO - Drug Resistance Updates

JF - Drug Resistance Updates

SN - 1368-7646

IS - 1

ER -