The role of glutamine and glucose analogues in metabolic inhibition of human myeloid leukaemia in vitro.
1. Glutamine analogues L-[alpha S,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) and 6-diazo-5-oxo-L-norleucine (DON) have been shown to possess cytotoxic activity against a wide variety of animal and human xenografted solid tumours, however their potential in man has been limited by toxicity. 2. We have analysed the effects of acivicin and DON on glutamine utilization to determine whether the reason for the disappointing therapeutic profile is solely due to the inefficient inhibition of glutamine metabolism. 3. Human myeloid leukaemic cells treated with acivicin inhibited ribonucleotide biosynthesis but not energy production via glutaminolysis and had little effect on viability, whereas treatment with DON inhibited both ribonucleotide biosynthesis and glutamine oxidation and resulted in reduced viability. 4. Treatment of the myeloid leukaemic cells with the glucose analogue 2-deoxy-D-glucose in addition to DON potentiated the inhibition of de novo nucleotide biosynthesis, glutaminolysis and glycolysis, and caused a further reduction in cell viability. 5. These results provide further support for the essential role of glutamine in cellular metabolism, and indicate that use of the glutamine analogue DON in the treatment of acute myeloid leukaemia may be more clinically effective if used in combination with 2-deoxy-D-glucose.
Griffiths
M
M
University Department of Microbiology, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia.
Keast
D
D
Patrick
G
G
Crawford
M
M
Palmer
T N
TN
D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003847:Deoxyglucose / Q000627:therapeutic use; D003980:Diazooxonorleucine / Q000627:therapeutic use*; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D007555:Isoxazoles; D003980:Diazooxonorleucine; D003847:Deoxyglucose; C006303:acivicin