L-asparagine requirement and the effect of L-asparaginase on the normal and leukemic human bone marrow.

The bone marrow of patients with acute lymphocytic leukemia, acute myelogenous leukemia, and metastatic cancer (normal marrow) was evaluated for l-asparagine dependence with the use of the in vitro test of Sobin and Kidd. All of the marrows including the normal ones showed l-asparagine dependence. There was a direct correlation between the concentration of l-asparaginase and depression of cell function as measured by the in vitro test. It was demonstrated that the enzyme itself and not contaminating materials was responsible for this effect. The above results are consistent with the fact that l-asparaginase treatment produces an initial antileukemic effect in the majority of patients with acute leukemia. However, the in vitro test was not useful in predicting remission. Asparagine synthetase activity was determined in normal and acute leukemic marrow. The activity prior to l-asparaginase treatment was invariably low and in approximately one-half of the bone marrows no activity could be demonstrated. Again, there was no correlation between asparagine synthetase activity and the production of remission with l-asparaginase. The major limitation of l-asparaginase treatment in acute leukemia is the rapid development of clinical resistance. In preliminary studies of serial determination of the in vitro test and asparagine synthetase activity of the bone marrow during l-asparaginase treatment, a decreasing l-asparagine requirement and increasing asparagine synthetase activity were observed. The decreasing l-asparagine requirement presumably results from an increase in asparagine synthetase activity. This would explain the rapid development of resistance in acute leukemia and also the lack of functional impairment of the normal bone marrow. The significance of these findings as well as other possible mechanisms of clinical resistance to l-asparaginase are discussed.