Decreased resistance to gemcitabine (2',2'-difluorodeoxycitidine) of cytosine arabinoside-resistant myeloblastic murine and rat leukemia cell lines: Role of altered activity and substrate specificity of deoxycytidine kinase

Andries M. Bergman, Herbert M. Pinedo, Ans P M Jongsma, Marjoleine Brouwer, Veronique W T Ruiz Van Haperen, Gijsbert Veerman, Albert Leyva, Steffan Eriksson, Godefridus J. Peters

Research output: Contribution to journalArticlepeer-review

Abstract

We determined the potential activity of 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) in 1-β-d-arabinofuranosylcytidine (ara-C)-sensitive and-resistant leukemia cell lines. Both drugs are phosphorylated by deoxycytidine kinase (dCK); the triphosphates, dFdCTP and ara-CTP, respectively, are incorporated into DNA. In the murine leukemia cell line L1210, induction of resistance to ara-C resulted in the 2200-fold resistant subline L4A6. The Brown Norway rat myelocytic leukemia ara-C-sensitive cell line (BCLO) was >300-fold more sensitive to ara-C than its variant Bara-C. In L1210 cells, gemcitabine was 8-fold more active than ara-C; in L4A6, BCLO, and Bara-C cells, gemcitabine was 16-, 28-, and more than 3-fold more active than ara-C, respectively. A partial explanation for these differences may be the higher dCK activity in the parental cell lines L1210 and BCLO with gemcitabine compared to ara-C as a substrate. DCK activity was not or hardly detectable in the resistant L4A6 and Bara-C cell. In the rat leukemia cell lines, deoxycytidine (dCyd) phosphorylation activity showed an aberrant pattern, since the activity with dCyd was 1.5-fold higher in the Bara-C cell line compared with BCLO, possibly due to thymidine kinase 2. The wild-type L1210 cells accumulated at least 3-fold more ara-CTP and dFdCTP than the rat leukemia cell line BCLO. The ara-C-resistant variants L4A6 and Bara-C did not accumulate dFdCTP or ara-CTP. In conclusion, gemcitabine was more active than ara-C in all leukemia cell lines tested. The sensitivity of the wild-type cell lines correlates with the accumulation of dFdCTP and ara-CTP, but is independent of dCK. However, both resistant variants had decreased dCK activities, but were relatively more sensitive to dFdC than to ara-C. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)397-406
Number of pages10
JournalBiochemical Pharmacology
Volume57
Issue number4
DOIs
StatePublished - Feb 15 1999
Externally publishedYes

Keywords

  • ara-C
  • Cytogenetic alterations
  • Deoxycytidine kinase activity
  • Drug accumulation
  • Drug resistance
  • Gemcitabine
  • Thymidine kinase activity

ASJC Scopus subject areas

  • Pharmacology

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