Expanding Targets for a Metabolic Therapy of Cancer: LAsparaginase

The antitumour enzyme L-asparaginase (L-Asparagine amidohydrolase, EC 3.5.1.1, ASNase) catalyzes the deamination of L-asparagine to L-Asp and ammonia and has been used for many years in the treatment of acute lymphoblastic leukaemia, Natural Killer cells tumors, subtypes of myeloid leukaemias and T-cell lymphomas. Recently, ovarian carcinomas and other solid tumours have been proposed as additional targets for ASNase, due to its potential role for its glutaminase activity. The increasing attention devoted to the antitumor activity of ASNase prompted us to analyze recent patents specifically concerning this enzyme. An overview of metabolic pathways affected by Asn and Gln depletion along with potential targets of ASNase is discussed. In particular, attention has been paid to novel ASNases, especially the Helicobacter pylori one, and those with amino acid substitutions aimed at improving enzymatic activity of the classical Escherichia coli enzyme. An effort has also been made to include modifications, such as natural glycosylation or synthetic conjugation with other molecules, introduced for therapeutic purposes. Finally, available patent information on biotechnological protocols and strategies applied to production of ASNase as well as to its administration and delivery in organisms has been analyzed.

Keywords: Acute lymphoblastic leukaemia, ALL, amino acid metabolism, amino acid transporters, ASNase, asparagine, asparagine synthetase, cancer, cancer therapy, erwinase, glutaminase, glutamine, glutamine synthetase, immune response, L-Asparaginase, metabolic therapy, mTOR, oncaspar, pegylation, sideeffects.