Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase

Leukemia. 1989 Apr;3(4):294-7.

Abstract

A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Asparaginase / pharmacology*
  • Aspartate-Ammonia Ligase / analysis
  • Aspartate-Ammonia Ligase / physiology*
  • Humans
  • Hybrid Cells
  • Ligases / physiology*
  • Lymphoma, Large B-Cell, Diffuse / enzymology*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Tumor Cells, Cultured / drug effects

Substances

  • Amino Acids
  • Asparaginase
  • Ligases
  • Aspartate-Ammonia Ligase