I t is clear that asparaginase will have to be combined with other drugs if it is to significantly affect survival of patients with ALL, in spite of the 50% remissions achieved, since these remissions are of such short duration. We have investigated the combination of asparaginase with the glutamine antagonists, azaserine and azotomycin, in ALL. The former has not shown a synergistic effect even at doses of 300 mg/m2 every fourth day, and the latter, at doses as low as 10 mg/m2 every fourth day, produces intolerable nausea and vomiting. Thus, to date, these combinations do not appear promising in the clinical situation despite successful animal experiments, and they lend some support to recent laboratory data showing that asparaginase may not act only via a direct biochemical effect on asparagine but rather by some other mechanism such as a broad effect on amino acid uptake. Asparaginase was also added to intermittent courses of high-dose combination chemotherapy with other drugs known to be effective in the treatment of AML. Overall remission rate was 38% in adults and 91% in children. Despite the fact that the drug was administered with 1000 mg/m* of prednisolone, there was a 9/29 (37%) incidence of anaphylaxis in this group of patients and asparaginase had to be dropped from the treatment regimen in ten others because of organ-specific toxicity (pancreas and liver). Thus, asparaginase therapy was tolerated in only 10/29 (34%) of patients. Because of this extremely high toxicity without any evidence of therapeutic effect, it is felt at the moment that asparaginase has no place in the treatment of AML.
SPARACINASE HAS BEEN SHOWN TO PRODUCE
A remissions in 5040% of patients with acute lymphatic leukemia (ALL),lJ*JeJ* with a median duration of remission of about 60 days. This high induction rate is encouraging, but the transient nature of the remissions makes it essential to combine asparaginase with other drugs for effective therapy. In animal tumor systems it has been clearly demonstrated that tumors which lack asparagine synthetase, the enzyme which catalyzes the reaction Laspartate + Lglutamine + Lasparagine + Lglutamate, are dependent on an exogenous source of asparagine and are responsive to asparaginase therapy.1' Compounds which alter glutamine metabolism have shown additive and sometimes syn-