Potentiation of 1-β- d-arabinofuranosylcytosine in hepatoma cells by 2′-deoxyadenosine or 2′-deoxyguanosine

A 2-hr pretreatment with 2′-deoxyadenosine (AdR), 2′-deoxyguanosine (GdR), or thymidine (TdR) synergized the growth-inhibitory effect of subsequent arabinosylcytosine (Ara-C) treatment in rat hepatoma cell lines N 1S 1 and 3924A and in the rat fibroblast line BF5. In addition, the sequence of 100 μM AdR or GdR for 2 hr followed by 15 μM Ara-C for 6 hr resulted in reduction of N 1S 1 and 3924A colony formation to 13 per cent of control values, representing synergistic killing when compared with treatment by any of these agents alone. Measurements in N 1S 1 hepatoma cells showed that AdR caused increased dATP (221 per cent) and decreased dCTP and dTTP (23 and 41 per cent respectively) in comparison with untreated controls. GdR caused increases in dGTP (351 per cent control) and dATP (191 per cent control) and decreased dCTP (36 per cent control) and dTTP (37 per cent control). Pretreatment with AdR (but not GdR) caused increased cellular Ara-CTP concentration. Pretreatment with AdR (100 μM) for 2hr increased the incorporation of [ 3H]Ara-C into DNA by 2-fold, and 2-hr pretreatment with GdR (100 μm) increased [ 3H]Ara-C incorporation into DNA 3-fold. AdR also increased incorporation of [ 3H]Ara-C into RNA, but GdR did not have this effect. In all three cell lines, AdR treatment decreased the concentrations of cellular UTP and CTP. Of the three deoxynucleosides, AdR, GdR and TdR, the most potent synergism with Ara-C was given by GdR. It was concluded that for all three nucleosides the potentiation was primarily a consequence of decreased cellular pools of dCTP.