Antimetabolite Enzymes

l-Asparaginase is an enzyme that behaves as an antimetabolite. Its physiological role is the hydrolysis of the amino acid l-asparagine to aspartic acid and ammonia (Fig. 2.46). Normal tissues can synthesize l-asparagine in amounts sufficient for protein synthesis, but some types of lymphoid malignancies take it from plasma. Treatment of these patients with l-asparaginase leads to the hydrolysis of circulating l-asparagine and prevents its uptake into the tumor cells, leading to interruption of protein synthesis and cell death. l-Asparaginase is normally used for the treatment of acute lymphocytic leukemia in combination with other agents, such as MTX, doxorubicin, cytarabine, and vincristine.

l-Asparaginase has been modified by covalent attachment of polyethylene-glycol (PEG) compounds such as monomethoxypolyethyleneglycolsuccinimidyl units. This PEG-modified enzyme is known as pegaspargase (see Section 3 of Chapter 11), and it is employed for the treatment of acute lymphocytic leukemia in patients that have developed hypersensitivity to the native form of l-asparaginase.63

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