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The Effects of Immunization of L-Asparaginase on Antitumor and Enzymatic Activity

Drug Evaluation Branch, Drug Research and Development [A. I. G., J. P. G., M. R. G.], and Laboratory of Toxicology, Experimental Therapeutics [D. A. C., E. R. H., H. A. M.], Chemotherapy, National Cancer Institute, Bethesda, Maryland 20014

BALB/c mice were immunized with Escherichia coli L-asparaginase and tested for the presence of hemagglutination antibody (HA) to the enzyme. Mice were then grouped according to whether they were immune to L-asparaginase (HA titer, >4) or were non-HA responders (negative HA titer). In vivo antitumor activity of L-asparaginase against P-1798 (an L-asparaginase-sensitive lymphoma) was tested in both groups, as well as in control mice (never before exposed to L-asparaginase). L-Asparaginase was inactive against the tumor in immune mice but was equally active in non-HA responders and control animals. Another experiment compared L-asparaginase derived from E. coli with enzyme derived from Erwinia carotovora (which does not cross-react immunologically with E. coli L-asparaginase). Mice immune to E. coli L-asparaginase received about the same benefit from the antitumor activity of E. carotovora L-asparaginase as did control mice. In separate studies, blood samples from immune, non-HA responder, and control mice were tested by in vitro assays for levels of L-asparaginase and L-asparagine at various time intervals up to 120 hr following a single i.v. injection of L-asparaginase. Most immune mice cleared the plasma of enzyme 30 min after injection and consequently had a rapid return to the circulation of L-asparagine. In non-HA responders and control animals, L-asparaginase was detectable for over 48 hr after injection, and L-asparagine remained absent from the circulation. These studies relate the presence of humoral antibody to L-asparaginase with loss of antitumor and enzymatic activity and suggest that, in immunized animals without detectable HA, the antitumor and enzymatic activity of L-asparaginase is intact.

¹ Deceased (May 7, 1971).

Received 2/ 4/72. Accepted 10/20/72.