The role of 5′nucleotidase in therapy-resistance of childhood leukemia

Purine nucleotides become available for a cell by two routes, namely purine de novo synthesis and the purine salvage pathway. 5′Nucleotidase is a purine pathway enzyme and is present in two forms. Cytoplasmic 5′nucleotidase (cyto 5′NT) catalyzes the intracellular degradation of purine nucleotides into their corresponding nucleosides. The plasmamembrane bound form (ecto 5′NT) has its active site facing the external medium. Its function is the extracellular dephosphorylation of nucleotides, to which cells are generally impermeable, into nucleosides and the transport of these nucleosides through the cell membrane. Lymphoblastic 5′NT activity varies between different children with common-ALL. 5′NT positive cases have a higher relapse rate and thus a poorer prognosis than 5′NT negative cases (10). This can be explained by two hypotheses which are not mutually exclusive: 1. 1. Rescue hypothesis. When purine de novo synthesis is blocked by methotrexate (MTX) and/or 6-mercaptopurine (6-MP), the malignant cell has to rely on the purine salvage pathway. This pathway depends on the ecto-5′NT activity. So, leukemic cells might be resistant to MTX and/or 6-MP because of ecto-5′NT activity. 2. 2. Breakdown hypothesis. Leukemic cells are resistant to 6-MP because of the breakdown of the toxic nucleotide form of 6-MP into the nucleoside form by cyto-5′NT.