Purine metabolism in relation to leukemia and lymphoid cell differentiation

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells

“…Important differences between TP and PNP involve their function: TP overexpression in tumor sites has clearly been related with angiogenesis [2], while PNP is involved in immune function [33,34]. In addition, PNP is hardly overexpressed in cancer [33,34,35], making it less likely to be an angiogenic enzyme. It might be possible that other products than the sugars are involved in angiogenesis as well, such as β-Aminoiso-butyric acid, which is another downstream metabolite of thymine [19].…”

De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo

“…These new findings are consistent with prior studies reporting constitutive differences in purine enzyme activities in T-lineage ALL compared with B-lineage ALL. 20,21 Therefore, T-lineage ALL may be more dependent on the de novo pathway for purine synthesis (especially adenine) compared with B-lineage ALL, a finding consistent with previous in vitro data in cell lines 9 and with recent evidence [22][23][24] that methylthioadenosine phosphorylase (an adenine salvage gene) is more frequently deleted in T-lineage than in B-lineage ALL, because of its close genomic proximity to the tumor suppressors P16 INK4A /P15 INK4B . In addition, hypoxanthine inhibits DNPS by feedback mechanisms, 25,26 and the lower intracellular hypoxanthine plus inosine concentrations in T-lineage ALL compared with B-lineage ALL suggest that lower purine recycling and salvage activity may be compensated for by increased DNPS in T-lineage ALL.…”

Terminal Differentiation of Cord Blood Lymphocytes Induced by Thymosin Fraction 5 and Thymosin Alpha1

“…Moreover, low levels of the membrane enzyme ecto-5'-nucleotidase (5'NT) are consistently found in CBL and are similar to the values found in leukaemic cells from chronic Iymphocytic leukaemia [7,10], Some thymic factors, among them thymosin fraction 5 (TMS-F5), can induce several differentiation changes in immature T cells of murine or human origin [17], Several of the TMS-F5 component peptides have been purified to homogeneity and sequeneed. Among them, thymosin alpha, (TMS-a,) seemed to induce the differentiation of early T precursors at high concentrations and of more mature T-cell subsets at low concentrations [16,17], Different stages of T-cell differentiation can be characterized by specific patterns of the purine degradative enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'NT, with a fall of ADA and a rise in PNP and 5'NT during maturation [2,8,14], Since TMS-F5 and TMS-a, induced changes in purine enzyme pattern and in surface phenotypic markers of normal human thymocytes and leukaemie cells [5,6,9], the effects of TMS-F5 and TMS-Oj on the purine enzymes and phenotypic markers of cord blood lymphocytes, whose T cells are more mature than thymocytes, have been studied.…”