The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia.
Harris AL., Grahame-Smith DG.
Ara-C phosphorylation and Ara-C deamination was measured in vitro, using intact marrow myeloblasts from 25 patients with previously untreated acute myeloid leukaemia. At Ara-C concentrations above 10 microM there was no longer a linear relationship of phosphorylation to Ara-C concentration. Ara-U production was measured by sampling the incubation medium. This method showed greater Ara-U production than previous methods sampling the cell pellet alone. However, Ara-CTP/Ara-U ratios from intact myeloblasts were much higher than those recorded in studies using lysed myeloblasts. Using 1 microM Ara-C, a concentration representative of in vivo concentrations, deamination and phosphorylation were related to therapeutic response to Ara-C-containing drug regimens. There was no significant correlation of these variables with response, although 5/16 non-responders had low Ara-C phosphorylation (less than 1.5 pmol/10(6) cells/45 min/l pm Ara-C) compared with 0/9 responders. Measuring deaminase activity did not help in selecting non-responders. Even in patients with low phosphorylation increasing Ara-C concentration increased Ara-CTP levels proportionally, but up to 10 times conventional doses may be necessary to exceed endogenous dCTP levels.