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Kinetic Analysis of Hepatotoxicity Associated with Antineoplastic Asparaginases¹

Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33101

In early studies using high dosages of Escherichia coli asparaginase (10 doses of 1000 IU/kg each) for the treatment of acute lymphoblastic leukemia, hepatotoxicity was a major complication of therapy. Biochemical evidence of hepatic dysfunction occurred in 75% of patients during the first 2 weeks of treatment. Currently, the use of lower dosages of E. coli asparaginase (three doses of 6000 IU/sq m each) has reduced the incidence of hepatic complication. Hepatic dysfunction in the form of severe life-threatening thromboembolic coagulopathy, however, continues to be associated with the use of this enzyme. Our previous work has established that the fatty degenerative changes and hepatocellular dysfunction associated with short-term (1 week) E. coli asparaginase treatment does not occur in mice treated with a glutaminase-free asparaginase from Vibrio succinogenes. In this report, we examined the hepatotoxic effects of prolonged treatment with E. coli and Erwinia carotovora asparaginases and compared the observed toxicities to those observed with the glutaminase-free asparaginase from V. succinogenes. Using a murine model, our data indicate that the hepatotoxicity of E. coli asparaginase parallels the toxicity observed in humans with a rapid increase in liver lipid levels and decreased plasma levels of albumin, antithrombin III, cholesterol, and triglycerides occurring in the first and second weeks followed by a resumption to normal hepatic function during Weeks 3 and 4. In contrast, prolonged treatment of mice with V. succinogenes asparaginase is not associated with significant hepatotoxicity. Er. carotovora asparaginase treatment is associated with an intermediate level of toxicity as indicated by increased hepatic lipid concentration occurring during the second and fourth weeks of treatment. Hepatic function as determined by plasma lipids and proteins was normal in Er. carotovora asparaginase-treated mice.

Our data suggest that the combined physiological depletion of asparagine and glutamine following administration of E. coli or Er. carotovora asparaginases may result in pronounced hepatotoxicity. In contrast, a glutaminase-free asparaginase with potent antilymphoma activity isolated from V. succinogenes is not hepatotoxic even after prolonged treatment. Therefore, it may prove to be a more efficacious antitumor agent in humans.

¹ This work was supported by a grant from the Woman's Cancer Association of the University of Miami.

² Recipient of a John J. Fomon Memorial Research Fellowship, American Cancer Society, Florida Division, Inc.

³ Visiting student from Yale University School of Medicine, New Haven, Conn.

⁴ To whom requests for reprints should be addressed, at Department of Microbiology and Immunology D4-4, University of Miami School of Medicine, P. O. Box 016960, Miami, Fla. 33101.

Received 7/27/82. Accepted 1/12/83.

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