Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations

Abstract

3Clinique Neurologique, H6pital de la Salptriere, 47 boulevard de l'Hopital, 75 651 Paris cedex 13, France. SmaryChromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imblances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in punne metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nuckoside phosphorylase and adenosine monophosphate deaminase. In paralkle, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-gal brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of puine metabolism in ghal tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only T'S had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balanc between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalancs does not correspond to a simple gene dosage effect in these tumours.These data suggest that the dcrease of adenosine metabolism ocus before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.

A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity

“…ADSL has been reported to be elevated in some malignancies such as colorectal, breast and prostate cancer, and gliomas. 43–45 …”

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].…”

Genes Associated with Fast Glioma Cell Migration In Vitro and In Vivo

“…Proteins that have been shown to be expressed in glioma biopsy specimens and to promote in vitro migration of glioma cells include laminin-5 (11), galectin-3 encoded by LGALS3 (5), and insulin-like growth factor-1 (4,17), all of them being upregulated in fast cells here. Likewise, thymidylate synthase is overexpressed in malignant gliomas as compared to non-neoplastic brain (2), and in a variety of cancer types its activity is related to dissemination (33). Other proteins regulated here have been found in glioma cell lines and/or glioma biopsy specimens and shown to mediate migration of other, non-glial cell types such as T-cells, endothelial cells and carcinoma cells, while functional data on glioma cells are missing so far; these proteins include sialophorin (CD43) (6, 10), ephrin-B1 (16,19), inhibitor of DNA-binding 3 (ID3) (26,43) and met-enkephalin and its precursor preproenkephalin (9,15).…”