A Glutaminase-Free Asparaginase From Vibrio Succinogenes Lacking Immunosuppression And Toxicity

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Doctor of Philosophy (Ph.D.)


Microbial asparaginases, from Escherichia coli and Erwinia carotovora are now used clinically in the treatment of acute lymphoblastic leukemia. While these enzymes have potent antileukemic activity, they cause a wide range of host toxicity and pronounced immunosuppression. The toxic and immunosuppressive effects of microbial asparaginases may be explained by the fact that these enzymes in addition to degrading L-asparagine also deamidate L-glutamine (glutaminase activity). We have isolated a glutaminase-free asparaginase from V. succinogenes which has potent antilymphoma activity and lacks the immunosuppressive properties of other microbial asparaginases. Our experiments have established that V. succinogenes asparaginase does not suppress the humoral or cell-mediated immunological response to the T-dependent antigen, SRBC, even at dosages 5-fold higher than the levels of the E. coli enzyme that are capable of completely abrogating these responses.In other studies we have compared the hepatotoxic effects of E. coli asparaginase to the glutaminase-free asparaginase from V. succinogenes. Liver sections obtained from E. coli asparaginase treated mice shown a diffuse microlipid accumulation which correlated with a 50% increase in extractable lipid (p < .001). V. succinogenes asparaginase treated animals were found to have histologically normal livers and levels of total extractable lipid were identical to controls. Antithrombin III (AT III) levels, a sensitive index of hepatocellular function were significantly decreased in the serum of E. coli asparaginase treated mice (p < .01). V. succinogenes asparaginase treatment did not result in depleted levels of AT III. The data suggest that the glutaminase-free asparaginase from V. succinogenes is not hepatotoxic and hence it may prove to be a safer, more effective treatment for the leukemia patient.


Health Sciences, Oncology

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