5-Hydroxymethyl-2'-deoxyuridine (5HmdUrd) and 1-beta-D-arabinofuranosylcytosine (
Ara-C) had a dose-dependent synergistic or antagonistic action on growth of human promyelocytic leukemic (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 microM 5HmdUrd alone) to 65% (with 100 nM
Ara-C plus 10 microM 5HmdUrd), or from 35% (with 1.0 microM
Ara-C alone) to 10% (with 1.0 microM
Ara-C plus 10 microM 5HmdUrd), compared to the control cultures without drugs. 1.0 and 10 microM 5HmdUrd potentiated the incorporation of radioactive
Ara-C (1.0 microM) 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 microM 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.