Expanding Targets for a Metabolic Therapy of Cancer: L-Asparaginase

Daniele      Covini; Saverio      Tardito; Ovidio      Bussolati; Laurent      R. Chiarelli; Maria      V. Pasquetto; Rita      Digilio; Giovanna      Valentini; Claudia      Scotti

doi:10.2174/157489212798358001

Abstract

The antitumour enzyme L-asparaginase (L-asparagine amidohydrolase, EC 3.5.1.1, ASNase), which catalyses the deamidation of L-asparagine (Asn) to L-aspartic acid and ammonia, has been used for many years in the treatment of acute lymphoblastic leukaemia. Also NK tumours, subtypes of myeloid leukaemias and T-cell lymphomas respond to ASNase, and ovarian carcinomas and other solid tumours have been proposed as additional targets for ASNase, with a potential role for its glutaminase activity. The increasing attention devoted to the antitumour activity of ASNase prompted us to analyse recent patents specifically concerning this enzyme. Here, we first give an overview of metabolic pathways affected by Asn and Gln depletion and, hence, potential targets of ASNase. We then discuss recent published patents concerning ASNases. In particular, we pay attention to novel ASNases, such as the recently characterised ASNase produced by Helicobacter pylori, and those presenting amino acid substitutions aimed at improving enzymatic activity of the classical Escherichia coli enzyme. We detail modifications, such as natural glycosylation or synthetic conjugation with other molecules, for therapeutic purposes. Finally, we analyse patents concerning biotechnological protocols and strategies applied to production of ASNase as well as to its administration and delivery in organisms.

Keywords: Acute lymphoblastic leukaemia, amino acid metabolism, asparagine, cancer, glutaminase, glutamine, L-asparaginase, myeloid leukaemias, T-cell lymphomas, ovarian carcinomas