Metabolism, Incorporation into DNA, and Interactions with 1-β-d-Arabinofuranosylcytosine of 5-Hydroxymethyl-2′-deoxyuridine in Human Promyelocytic Leukemia Cells (HL-60)¹

5-Hydroxymethyl-2′-deoxyuridine (5HmdUrd) and 1-β-d-arabinofuranosylcytosine (Ara-C) had a dose-dependent synergistic or antagonistic action on growth of human promyelocytic leukemia (HL-60) cells in suspension culture. For instance, in 3-day cultures, the cell number was reduced from 100% (with either 100 nm Ara-C or 10 µm 5HmdUrd alone) to 65% (with 100 nm Ara-C plus 10 µm 5HmdUrd), or from 35% (with 1.0 µm Ara-C alone) to 10% (with 1.0 µm Ara-C plus 10 µm 5HmdUrd), compared to the control cultures without drugs. 1.0 and 10 µm 5HmdUrd potentiated the incorporation of radioactive Ara-C (1.0 µm) into HL-60 cell nucleic acids in 2-day cultures by 56 and 64%, respectively. 5HmdUrd-induced enhancement of Ara-C incorporation is one explanation for the synergism of these two drugs. On the other hand, 10 nm Ara-C partially inhibited the toxicity of 100 µm 5HmdUrd. Radioactive 5HmdUrd was incorporated into DNA, but not RNA, the rate being 5% of that observed with thymidine. [³H]5HmdUrd-derived radioactivity remained stable in DNA for at least 24 h, indicating that the compound was not excised to a significant extent from DNA in these conditions. The incorporation of Ara-C and 5HmdUrd into DNA appeared to take place via different pathways, which is a second explanation for their synergism. Ara-C is the most important drug in the clinical chemotherapy of acute nonlymphoblastic leukemia. Experience with 5HmdUrd in experimental antileukemia chemotherapy has been promising. This novel combination of antileukemic agents merits further evaluation.