The use of L-asparaginase for the treatment of solid tumors: data from experimental studies and clinical trials

Abstract

Drug therapy is one of the main strategies of cancer treatment. L-asparaginase, the enzyme that hydrolyzes asparagine, has long been included in the treatment regimens for acute lymphoblastic leukemia and other hematological malignancies more than 50 years ago, but its use for the treatment of solid tumors is still extremely limited. This review analyzes experimental data on the sensitivity of cell lines and xenografts of solid tumors to L-asparaginase, examines the results of clinical trials. Among the mechanisms of the cytotoxic effect of L-asparaginase on tumor cells, such processes as depletion of aspartic and glutamic acids, influence on the internal and external pathways of apoptosis, inhibition of cellular processes through a decrease in the activity of the mTOR protein, and weakening of the expression of the telomerase gene are discussed. Separately, molecular markers are considered, which can be used to suggest the effectiveness of future therapy with L-asparaginase in solid tumors. These markers include 1) expression levels of asparagine synthetase and glutamine synthetase genes, 2) degree of methylation of the ASNS promoter region, 3) PTEN protein activity and 4) autophagy, 5) bone marrow environment of tumor cells, 6) expression of genes associated with asparaginase resistance, such as the 1 opioid receptor gene and the huntingtin-associated protein 1 gene.