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Biochemical and Cytokinetic Modulation of L1210 and HL-60 Cells by Hydroxyurea and Effect on 1-ß-D-Arabinofuranosylcytosine Metabolism and Cytotoxicity¹

Departments of Medicine and Pharmacology, Yale School of Medicine, New Haven, Connecticut 06510

The modulating effect of hydroxyurea (HU) on 1-ß-D-arabinofuranosylcytosine (ara-C) metabolism and cytotoxicity was evaluated in L1210 cells and the human promyelocytic leukemic cells HL-60. A dose- and time-dependent HU exposure was observed which resulted in maximum deoxycytidine 5'-triphosphate reduction, intracellular ara-C accumulation, 1-ß-D-arabinofuranosylcytosine 5'-triphosphate formation, and cytotoxicity as determined by soft agar cloning. For the L1210 cells, a 5-hr pretreatment of 5 mM HU was optimum. The best result obtained with the HL-60 cells was after a 24-hr exposure of 1 mM HU. There was also a maximum incorporation of ara-C into DNA in both cells following these optimal pretreatment conditions. Cytofluorometric analysis demonstrated that this HU treatment resulted in a maximum accumulation of L1210 and HL-60 cells in the pre-S phase of the cell cycle and that after removal of the HU there was a rapid progression of the cell population through S phase. Because cytotoxicity of ara-C is considered to be predominately from the inhibition of DNA polymerase and/or the incorporation into DNA, the cytokinetic and biochemical modulatory effects of HU must both be contributing factors to consider in achieving maximal cell kill from this drug sequence.

¹ Supported by the following grants from the National Cancer Institute: CA-24187; CA-27130; and CA-08341; and by Grant CH-145 from the American Cancer Society.

² Recipient of a Cancer Research Award from the American Cancer Society. To whom requests for reprints should be addressed.

Received 2/ 4/82. Accepted 2/ 2/83.