Effect of cytosine arabinoside on the human immunosystem: toxicity against quiescent human peripheral blood mononuclear cells in vitro.

The toxic and metabolic effects of cytosine arabinoside (Ara-C) were studied in vitro with normal human peripheral blood mononuclear cells. The majority of target cells were T-lymphocytes. Dose-dependent toxicity of clinically relevant Ara-C concentrations was manifested by increased cell loss, inhibition of spontaneous blastic transformation, inhibition of DNA synthesis assessed by 3H-thymidine incorporation, inhibition of protein synthesis assessed by 14C-leucine incorporation, and inhibition of the mitogenic response of T-lymphocytes when challenged with phytohemagglutinin after Ara-C treatment. Cell death among the resting cells was delayed and it was mainly, if not entirely, cell-cycle-independent, since most of the cells stayed in the G0- or G1-phase. The toxicity of Ara-C was effectively reversed by an excess of deoxycytidine. This suggests that the molecular mechanism of Ara-C toxicity against quiescent peripheral blood mononuclear cells is based on its anti-metabolic role in the salvage pathway of biosynthesis of DNA deoxycytidine.