THE ROLE OF GLUTAMINE AND GLUCOSE ANALOGS IN METABOLIC INHIBITION OF HUMAN MYELOID-LEUKEMIA IN-VITRO

1. Glutamine analogues alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleace tic acid (acivicin) and 6-diazo-5-oxo-L-norleucine (DON) have been sho wn to possess cytotoxic activity against a wide variety of animal and human xenografted solid tumours, however their potential in man has be en limited by toxicity. 2. We have analysed the effects of acivicin an d DON on glutamine utilization to determine whether the reason for the disappointing therapeutic profile is solely due to the inefficient in hibition of glutamine metabolism. 3. Human myeloid leukaemic cells tre ated with acivicin inhibited ribonucleotide biosynthesis but not energ y production via glutaminolysis and had little effect on viability, wh ereas treatment with DON inhibited both ribonucleotide biosynthesis an d glutamine oxidation and resulted in reduced viability. 4. Treatment of the myeloid leukaemic cells with the glucose analogue 2-deoxy-D-glu cose in addition to DON potentiated the inhibition of de novo nucleoti de biosynthesis, glutaminolysis and glycolysis, and caused a further r eduction in cell viability. 5. These results provide further support f or the essential role of glutamine in cellular metabolism, and indicat e that use of the glutamine analogue DON in the treatment of acute mye loid leukaemia may be more clinically effective if used in combination with 2-deoxy-D-glucose.