L-Asparaginase is one of the key drugs used to treat children with acute lymphoblastic leukemia (ALL). However, some children fail to achieve therapeutic levels of L-asparaginase after receiving the drug. The mechanisms underlying such therapeutic failure are not well defined. But now, Vaskar Saha and colleagues, at the Paterson Institute for Cancer Research, United Kingdom, have found that leukemic cells from some patients with ALL express two proteins capable of degrading ASNase, one of the commercially available sources of L-asparaginase. Importantly, expression of one of these proteins, AEP, is predominantly observed in individuals with high-risk forms of ALL. By modifying one amino acid of ASNase, the authors were able to render it resistant to cleavage by AEP; however, the modified drug was not as active. The authors hope that this description of a potential mechanism to explain why some children fail to achieve therapeutic levels of L-asparaginase after receiving ASNase will enable optimization of L-asparaginase therapy to the benefit of children with ALL.
TITLE: A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase
Paterson Institute for Cancer Research, Manchester, United Kingdom.
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