Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase.
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.
Kiriyama
Y
Y
Department of Pediatrics, Kobe City General Hospital, Japan.
Kubota
M
M
Takimoto
T
T
Kitoh
T
T
Tanizawa
A
A
Akiyama
Y
Y
Mikawa
H
H
D000596:Amino Acids / Q000378:metabolism; D001215:Asparaginase / Q000494:pharmacology*; D001217:Aspartate-Ammonia Ligase / Q000032:analysis / Q000502:physiology*; D006801:Humans; D006822:Hybrid Cells; D008025:Ligases / Q000502:physiology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000596:Amino Acids; D001215:Asparaginase; D008025:Ligases; D001217:Aspartate-Ammonia Ligase