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The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia

Summary

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 μM 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 μM 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 (<1.5 pmol/106 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.

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Correspondence to Adrian L. Harris.

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Harris, A.L., Grahame-Smith, D.G. The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia. Cancer Chemother. Pharmacol. 9, 30–35 (1982). https://doi.org/10.1007/BF00296758

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Keywords

  • Cancer Research
  • Linear Relationship
  • Method Sampling
  • Myeloid Leukaemia
  • Cell Pellet