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Increased Activation of 1-ß-D-Arabinofuranosylcytosine by Hydroxyurea in L1210 Cells¹

Section of Medical Oncology, The Evans Memorial Department of Clinical Research [R. P. A.], and Department of Pharmacology and Experimental Therapeutics [C. T. W., R. W. C., R. P. A.], Boston University Medical Center, Boston, Massachusetts 02118

Hydroxyurea (0.1 to 10 mM), incubated with L1210 cells in the presence of 1 µM 1-ß-D-arabinofuranosylcytosine (ara-C), produced a concentration- and time-dependent increase in levels of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). This effect was abolished upon removal of hydroxyurea from cells. The enhancement of ara-CTP by hydroxyurea was observed for concentrations of ara-C ranging from 0.1 to 100 µM. These changes were not associated with alteration in the activity of deoxycytidine kinase, measured in extracts from L1210 cells both with and without deoxycytidine triphosphate. Hydroxyurea did, however, increase the apparent maximum velocity of this enzyme when determined with intact cell preparations, a finding consistent with alteration in endogenous regulation of this enzyme. Four-hr i.v. infusion of hydroxyurea (192 mg/kg/hr) with ara-C (1 mg/kg/hr) into ascites tumor-bearing mice also resulted in increased L1210 cell concentrations of ara-CTP. ara-C levels in plasma and L1210 cells were unaffected by hydroxyurea. Therefore, the enhancement of ara-CTP concentration in vivo, like in vitro, resulted from changes in ara-C conversion in the L1210 cells.

¹ Supported in part by Grant CA 18837 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 1/14/80. Accepted 6/ 6/80.