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Improving the treatment of acute lymphoblastic leukemia

Radadiya, Ashish, Zhu, Wen, Coricello, Adriana, Alcaro, Stefano and Richards, Nigel G. J. 2020. Improving the treatment of acute lymphoblastic leukemia. Biochemistry 59 (35) , pp. 3193-3200. 10.1021/acs.biochem.0c00354

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Abstract

l-Asparaginase (EC 3.5.1.1) was first used as a component of combination drug therapies to treat acute lymphoblastic leukemia (ALL), a cancer of the blood and bone marrow, almost 50 years ago. Administering this enzyme to reduce asparagine levels in the blood is a cornerstone of modern clinical protocols for ALL; indeed, this remains the only successful example of a therapy targeted against a specific metabolic weakness in any form of cancer. Three problems, however, constrain the clinical use of l-asparaginase. First, a type II bacterial variant of l-asparaginase is administered to patients, the majority of whom are children, which produces an immune response thereby limiting the time over which the enzyme can be tolerated. Second, l-asparaginase is subject to proteolytic degradation in the blood. Third, toxic side effects are observed, which may be correlated with the l-glutaminase activity of the enzyme. This Perspective will outline how asparagine depletion negatively impacts the growth of leukemic blasts, discuss the structure and mechanism of l-asparaginase, and briefly describe the clinical use of chemically modified forms of clinically useful l-asparaginases, such as Asparlas, which was recently given FDA approval for use in children (babies to young adults) as part of multidrug treatments for ALL. Finally, we review ongoing efforts to engineer l-asparaginase variants with improved therapeutic properties and briefly detail emerging, alternate strategies for the treatment of forms of ALL that are resistant to asparagine depletion.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 0006-2960
Funders: BBSRC
Date of First Compliant Deposit: 24 August 2020
Date of Acceptance: 12 August 2020
Last Modified: 22 Oct 2020 13:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/134347

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