Differential effect of N-(phosphonacetyl)-L-aspartate on 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity in human leukemia and normal bone marrow progenitors.

Abstract

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.

• Authors: S Grant, F Rauscher 3rd, E Cadman
• Journal: Cancer research (Cancer Res) Vol. 42 Issue 10 Pg. 4007-13 (Oct 1982) ISSN: 0008-5472 [Print] United States
• PMID: 6955007 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• Organophosphorus Compounds
• Cytarabine
• Aspartic Acid
• sparfosic acid
• Phosphonoacetic Acid

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Aspartic Acid (analogs & derivatives, metabolism, pharmacology)
• Bone Marrow (drug effects, metabolism)
• Cell Line
• Cells, Cultured
• Cytarabine (metabolism)
• DNA Replication (drug effects)
• Hematopoietic Stem Cells (drug effects, metabolism)
• Humans
• Leukemia, Myeloid, Acute (metabolism)
• Organophosphorus Compounds (pharmacology)
• Phosphonoacetic Acid (analogs & derivatives, metabolism, pharmacology)