Kinetic analysis of hepatotoxicity associated with antineoplastic asparaginases.

In early studies using high dosages of Escherichia coli asparaginase (10 doses of 1000 ID/kg each) for the treatment of acute lymphoblastic leukemia, hepatotoxicity was a major com plication 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 ID/sq m each) has reduced the incidence of hepatic complication. Hepatic dysfunction in the form of severe life-threatening thromboembolic coagulopathy, however, contin ues 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) £.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 £.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 triglycéridesoccurring 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 aspa raginase 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 hepato toxicity. In contrast, a glutaminase-free asparaginase with potent antilymphoma activity isolated from V. succinogenes is not hep atotoxic even after prolonged treatment. Therefore, it may prove to be a more efficacious antitumor agent in humans.