ENZYMES
The enzyme L-asparaginase (Elspar) is derived from the bacteria Escherichia coli and Erwinia carotovora. It cat-alyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Glutamine also can undergo hydrolysis by this enzyme, and during therapy, the plasma levels of both amino acid substrates fall to zero. Tumor cells sensitive to L-asparaginase are deficient in the enzyme asparagine synthetase and therefore cannot synthesize asparagine. Depletion of exogenous asparagine and glutamine inhibits protein synthesis in cells lacking asparagine synthetase, which leads to inhibition of nucleic acid synthesis and cell death.
The half-life of L-asparaginase in human plasma
is 6 to 30 hours. The drug remains primarily in the intravas-cular space, so
its volume of distribution is only slightly greater than that of the plasma.
Metabolism and dispo-sition are thought to occur through serum proteases, the
reticuloendothelial system, and especially in patients with prior exposure to
the drug, binding by antibodies. The drug is not excreted in urine, and very
little appears in the CSF.
The major indication for L-asparaginase is in the
treatment of acute lymphoblastic leukemia; complete remission rates of 50 to
60% are possible. Lack of cross-resistance and bone marrow toxicity make the
enzyme particularly useful in combination chemotherapy. L-Asparaginase also can be
used in the treatment of cer-tain types of lymphoma. It has no role in the
treatment of nonlymphocytic leukemias or other types of cancer.
Since it is a foreign
protein, L-asparaginase may pro-duce hypersensitivity reactions, including
urticarial skin rashes and severe anaphylactic reactions. One-third of patients
have nausea, anorexia, weight loss, and mild fever. Almost all patients develop
elevated serum transaminases and other biochemical indices of hepatic
dysfunction. Severe hepatic toxicity occurs in fewer than 5% of cases. Patients
receiving L-asparaginase may develop symptoms of CNS toxicity, including
drowsi-ness, confusion, impaired mentation, and even coma. Pancreatitis occurs
in 5 to 10% of cases. Hyperglycemia, possibly due to inhibition of insulin
synthesis, also may occur. L-Asparaginase
differs from most cytotoxic drugs in
its lack of toxicity to bone marrow, gastrointestinal tract, and hair
follicles.
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