Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity

T. Spasokoukotskaja, M. Sasvâri-Székely, G. Keszler, F. Albertioni, S. Eriksson, M. Staub

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Deoxycytidine kinase (dCK), one of the rate-limiting enzymes in the intracellular metabolism of many antileukaemic drugs, was shown to be stimulated after treatment of human tonsillar lymphocytes by 2-chloro-2'- deoxyadenosine (cladribine, CdA) (Sasvari-Szekely, et al., Biochem Pharmacol 1998, 56, 1175-1179). Here we present a comparative study of different normal and malignant cells in respect to the activation of dCK by CdA. G-phase lymphocytes showed a higher sensitivity for dCK stimulation than S-phase cells. Normal and leukaemic peripheral blood mononuclear cells, as well as the promyelocytic cell line HL60 responded to CdA treatment by a 2-5-fold increase in activity of dCK. However, no significant stimulation was detected either in CCRF-CEM T-lymphoblastoid cells, or in K562 myeloid cells. Thymidine kinase (TK) activity was not stimulated in any cases. Treatment of these cells with several other analogues beside CdA, such as 2-chloro-2'- arabino-fluoro-2'-deoxyadenosine (CAFdA), 2-fluoro-1-β-D-arabinosyladenine (Fludarabine, FaraA) and 1-β-D-arabinosylcytosine (cytarabine, araC) gave similar results to CdA treatment. Enhancement of dCK activity could also be achieved with the topoisomerase II inhibitor, etoposide. In contrast, 2- chloro-riboadenosine (CrA) had no effect on the dCK at concentrations of 10 μM or less, while dCyd and 5-aza-dCyd caused slight inhibition. These results indicate that treatment of cells with several inhibitors of DNA synthesis potentiates the dCK activity. The drugs widely differ in their stimulatory effect on dCK, and there are also 'responsive' and 'non- responsive' cells with respect to dCK activation. Thus, enhancement of the dCK activity by specific drugs in 'responsive' cells might give a rationale for combination chemotherapy.

Original languageEnglish
Pages (from-to)1862-1867
Number of pages6
JournalEuropean Journal of Cancer
Volume35
Issue number13
DOIs
Publication statusPublished - Dec 1 1999

Keywords

  • Chemotherapy
  • Deoxycytidine kinase
  • Human
  • Lymphocyte
  • Nucleoside analogues
  • Thymidine kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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