Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine in the Presence of Ganciclovir or Foscarnet

Abstract

Comparisons were made between the intracellular phosphorylation of 3′-Azido-3′-deoxythymidine (AZT) alone and in combination with ganciclovir (GCV) or foscarnet (PFA) in lymphocytes, uninfected fibroblasts and CMV-infected fibroblasts. The effects of AZT and the combinations of AZT with GCV or PFA on cellular dNTP pools were also examined. The phosphorylation of AZT was not altered by the presence of GCV or PFA in lymphocytes, and neither AZT nor the combinations of AZT with GCV or PFA changed the levels of cellular dNTP pools in these cells. AZT was phosphorylated to a greater extent in lymphocytes when compared to fibroblasts, but the proportion of AZT di- and triphosphates was greater in fibroblasts. The infection of fibroblasts with CMV enhanced AZT phosphorylation and increased the levels of cellular dNTP pools. GCV caused a specific reduction in AZT phosphorylation in CMV-infected fibroblasts, with a seven-fold drop in AZT triphosphate compared to AZT alone. GCV did not affect AZT phosphorylation in uninfected fibroblasts, nor did GCV reduce the dTTP pool compared to AZT alone. The effects of GCV upon AZT phosphorylation in CMV-infected cells may shed light on the antagonistic effects of GCV upon the anti-HIV activity of AZT, and are of importance for the development of effective combination therapies for the treatment of AIDS patients infected with CMV.