PHASE-I EVALUATION OF SUCCINYLATED ACINETOBACTER GLUTAMINASE-ASPARAGINASE IN ADULTS

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (12) , 4546-4551
Abstract
Succinylated Acinctobacter gluatminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. The pharmacology and toxicology of SAGA after single-dose and serial daily dose injections in 20 adult patients was studied. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple 1st-order kinetics (half-life during the initial 24 h was 21 .+-. 9 h). A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the CNS ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia nausea and vomiting. Transient antitumor effects were noted in 2 patients with solid tumors and in 2 patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.