Retained Sensitivity to Cytotoxic Pyrimidine Nucleoside Analogs in Thymidine Kinase 2 Deficient Human Fibroblasts

Abstract

Thymidine kinase 2 (TK2) is a mitochondrial deoxyribonucleoside kinase that phosphorylates several nucleoside analogs used in anti-viral and anti-cancer therapy. A fibroblast cell line with decreased TK2 activity was investigated in order to obtain insights in the effects of TK2 deficiency on nucleotide metabolism. The role of TK2 for the sensitivity against cytotoxic nucleoside analogs was also investigated. The TK2 deficient cells retained their sensitivity against all pyrimidine nucleoside analogs tested. This study suggests that nucleoside analog phosphorylation mediated by TK2 may be less important, compared to other deoxyribonucleoside kinases, for the cytotoxic effects of these compounds.

Keywords:

• Nucleoside kinase
• nucleoside analog
• mitochondrial DNA

Acknowledgments

This work was supported by grants from the Swedish Research Council (A.K. grant 521-2004-6284) and the Medical Faculty of the Karolinska Institute (A.K., M.J.) and the “Geconcerteerde Onderzoeksacties” (05/15) of the K. U. Leuven (J.B.).