In a significant number of patients with acute leukemia, particularly lymphocytic, the malignant cells are dependent on an exogenous source of asparagine for survival. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase. This is a unique approach to therapy based on a metabolic defect in asparagine synthesis of some malignant cells. ELSPAR, derived from Escherichia coli, is effective in inducing remissions in some patients with acute lymphocytic leukemia.
Asparagine Dependence Test
An asparagine dependence test has been utilized during the investigational studies. In this test leukemic cells obtained from some marrow cultures could be shown to require asparagine in vitro, suggesting sensitivity to asparaginase therapy in vivo. However, present data indicate that the correlation between asparagine dependence in such tests and the final response to therapy is sufficiently poor that the test is not recommended as a basis for selection of patients for treatment.
Pharmacokinetics and Metabolism
In a study in patients with metastatic cancer and leukemia, initial plasma levels of L-asparaginase following intravenous administration were correlated to dose. Daily administration resulted in a cumulative increase in plasma levels. Plasma half-life varied from 8 to 30 hours; it did not appear to be influenced by dosage, either single or repetitive, and could not be correlated with age, sex, surface area, renal or hepatic function, diagnosis or extent of disease. Apparent volume of distribution was approximately 70-80% of estimated plasma volume. There was some slow movement of asparaginase from vascular to extravascular, extracellular space. L-asparaginase was detected in the lymph. Cerebrospinal fluid levels were less than 1% of concurrent plasma levels. Only trace amounts appeared in the urine.
In a study in which patients with leukemia and metastatic cancer received intramuscular L-asparaginase, peak plasma levels of asparaginase were reached 14 to 24 hours after dosing. Plasma half-life was 39 to 49 hours. No asparaginase was detected in the urine.