Modulation of metabolism and cytotoxicity of cytosine arabinoside with N-(phosphon)-acetyl-L-aspartate in human leukemic blast cells and cell lines.

Abstract

Cytosine arabinoside (Ara-C) activation to cytosine arabinoside triphosphate (Ara-CTP) and subsequent incorporation into DNA is regulated by the pyrimidine nucleotides UTP, CTP and dCTP. Inhibition of the de novo synthesis of these pyrimidine nucleotides by N-(phosphon)-acetyl-L-aspartate (PALA) may enhance the cytotoxicity of Ara-C. We therefore studied the effect of PALA on Ara-C cytotoxicity and on Ara-CTP accumulation and incorporation into DNA on cell lines and patient samples. Fifty micromolar PALA increased the growth inhibitory effect of Ara-C in U937 cells several fold both with pre- and coincubation. Ara-C cytotoxicity was not potentiated by PALA in Hl60 cells. However, coincubation with PALA did not enhance Ara-CTP accumulation both in HL60 and U937 cells, nor affect Ara-C incorporation into DNA. Ara-C cytotoxicity to leukemic blast cells from 11 untreated patients with different types of leukemia was only modulated to a small extent by high PALA concentrations in only two cases. Ara-CTP accumulation in leukemic blast cells varied from non-detectable levels to 200 pmol/10(6) cells. Fifty micromolar PALA enhanced the accumulation of Ara-CTP significantly in only one patient with no apparent effect on UTP and CTP levels. Raising PALA to 500 microM decreased UTP and CTP levels to 50% but had no effect on Ara-CTP levels. In conclusion, modulation by PALA of Ara-C cytotoxicity and metabolism is limited in leukemic cells, both in culture and from patients. This suggests the possibility for selective modulation of other agents by PALA on non-hematological cells.

• Authors: P Noordhuis, K M Kazemier, G J Kasperrs, G J Peters
• Journal: Leukemia research (Leuk Res) Vol. 20 Issue 2 Pg. 127-34 (Feb 1996) ISSN: 0145-2126 [Print] England
• PMID: 8628011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• DNA, Neoplasm
• Cytarabine
• Arabinofuranosylcytosine Triphosphate
• Aspartic Acid
• Cytidine Triphosphate
• sparfosic acid
• Phosphonoacetic Acid
• Uridine Triphosphate

Topics

• Antimetabolites, Antineoplastic (metabolism, pharmacology)
• Arabinofuranosylcytosine Triphosphate (metabolism)
• Aspartic Acid (analogs & derivatives, pharmacology)
• Cytarabine (metabolism, pharmacology)
• Cytidine Triphosphate (metabolism)
• DNA, Neoplasm (drug effects, metabolism)
• Drug Screening Assays, Antitumor
• HL-60 Cells (metabolism)
• Humans
• Leukemia (metabolism, pathology)
• Phosphonoacetic Acid (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured (drug effects, metabolism, pathology)
• Uridine Triphosphate (metabolism)