Differential effect of N-(phosphonacetyl)-L-aspartate on 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity in human leukemia and normal bone marrow progenitors.
The effect of N-[phosphonacetyl]-L-aspartate (PALA) on the metabolism and cytotoxicity of 1-beta-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 10(6) cells after a 45-min exposure to 1 microM ara-C, compared to 27.8 pmol ara-C per 10(6) 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-beta-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 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 result.
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003561:Cytarabine / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D009943:Organophosphorus Compounds; D003561:Cytarabine; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid