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Substrate-specific Deoxycytidine Kinase Deficiency in 1-ß-D-Arabinofuranosylcytosine-resistant Leukemic Cells

Department of Hematology, Leiden University Medical Center, 2300 RC Leiden [D. J. R., L. P. C., M. W. A-H., M. G. D. K., P. M. t. R., R. W.], and Institute of Applied Radiology and Immunology, 2280 HV, Rijswijk [G. J. A. A.], The Netherlands

In this study we describe the establishment of a leukemic cell line (BNML-CL/ara-C), originating from the 1-ß-D-arabinofuranosylcytosine (ara-C)-resistant brown Norway rat myelocytic leukemia model (BNML/ara-C), that retains the in vivo generated ara-C resistance. Its biological and biochemical characteristics have been compared with a cell line, derived from the ara-C-sensitive BNML model (BNML-CL/O). Resistance to ara-C was attributed to a decrease in phosphorylation of ara-C. Deoxycytidine (dCyd) kinase activity in crude cell extracts with dCyd as substrate showed similar enzyme activities in both cell lines, whereas with ara-C as substrate no dCyd kinase activity was detectable in the ara-C-resistant cell line. Two isoenzymes of dCyd kinase with different substrate specificities have been described (Cheng, Y. C., Domin, B., and Lee, L. S. Biochim. Biophys. Acta, 481: 481–492, 1977), cytoplasmic (dCyd kinase I, substrates: dCyd and ara-C) and mitochondrial (dCyd kinase II, substrates: dCyd and thymidine). In the ara-C-sensitive BNML model, thymidine induced a reduction of dCyd kinase activity when dCyd was used as substrate. However, thymidine did not affect kinase activity with ara-C was used as substrate. In the BNML-CL/ara-C, thymidine even induces a dCyd kinase inhibition of 85% with dCyd as substrate. It is likely that the ara-C-specific dCyd kinase deficiency in BNML-CL/ara-C cells was due to a selective loss of dCyd kinase I, whereas dCyd kinase II activity remained intact.

¹ To whom requests for reprints should be addressed, at Department of Hematology, Building 1: C2-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Received 3/23/90. Accepted 7/12/90.

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