Differential Effect of N-(Phosphonacetyl)-L-aspartate on 1-ß-o- Arabinofuranosylcytosine Metabolism and Cytotoxicity in Human Leukemia and Normal Bone Marrow Progenitors1

The effect of A/-[phosphonacetyl]-L-aspartate (PALA) on the metabolism and cytotoxicity of 1-/S-o-arabinofuranosylcytosine (ara-C) was studied in the human promyelocytic leukemic cell line, HL-60, and in normal human bone marrow. HL-60 cells exposed to 0.1 mw PALA for 12 hr accumulated 58.7 pmol ara-C per 106 cells after a 45-min exposure to 1 /XMara-C, compared to 27.8 pmol ara-C per 106 cells in untreated control cells. This PALA concentration and exposure interval was associated with a greater than 2-fold increase in both the 45min generation and 4-hr retention of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate compared to untreated control HL-60 cells. Exposure of HL-60 cells to PALA followed by ara-C produced greater than additive effects on the inhibition of DMA synthesis, the inhibition of cell growth, and clonogenicity. In contrast, exposure of normal human bone marrow to the same PALA-ara-C schedule was not associated with a synergistic inhibition of colony-forming units in soft agar. If these pertur bations also occur in vivo, an improvement in the therapeutic index of ara-C in patients with acute leukemia might result.