The effect of N-[phosphonacetyl]-l-aspartate (PALA) on the metabolism and cytotoxicity of 1-β-d-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 mm PALA for 12 hr accumulated 58.7 pmol ara-C per 106 cells after a 45-min exposure to 1 µm ara-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 45-min generation and 4-hr retention of 1-β-d-arabinofuranosyl-cytosine 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 DNA 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 perturbations also occur in vivo, an improvement in the therapeutic index of ara-C in patients with acute leukemia might results.

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Supported by Grants CA-24187, CA-27130, and CA-08341 from the National Cancer Institute; Grants CH-145 and CA-5-61659 from the American Cancer Society; and the Cele Butwin Foundation for Cancer Research and the Zinberg Foundation for Research. Presented in part at the 72nd Annual Meeting of the American Association for Cancer Research, Washington, D. C., April 27 to 30, 1981 (19).

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