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Phase I Evaluation of Succinylated Acinetobacter Glutaminase-Asparaginase in Adults¹

Developmental Chemotherapy Service [R. P. W., C. W. Y.], the Laboratories of Experimental Enzyme Therapy [J. R.], Pharmacology [T-C. C., F. S. P.], and Clinical Pharmacology [C. G.], and the Departments of Pathology [S. S. S.] and Pediatrics [C. T.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients.

Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 ± 9 hr. 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 central nervous system, ranging from encephalopathy to coma, occurred in a doserelated manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia.

SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.

¹ Supported in part by Grants CA-08748, CA-15860, CA-05826, and CA-18856 from the National Cancer Institute, NIH, Bethesda, Md.

² Recipient of National Research Service Award CA-09207. To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, N. Y. 10021.

Received 4/17/80. Accepted 9/10/80.