PURINE AND PYRIMIDINE METABOLISM IN HUMAN GLIOMAS - RELATION TO CHROMOSOMAL-ABERRATIONS

Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occa sionally an excess of chromosome 7 and a loss of sex chromosome are ob served. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losse s or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromoso mes 19 and 20. To understand the meaning of these chromosome imbalance s, the relationships between chromosome abnormalities and metabolic di sturbances were studied. The losses or deletions observed affected pri ncipally chromosomes carrying genes encoding enzymes involved in purin e metabolism. The activities of ten enzymes were measured: adenosine k inase, adenine phosphoribosyltransferase, adenylate kinase, methylthio adenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adeny losuccinate lyase, inosine monophosphate dehydrogenase, adenosine deam inase, nucleoside phosphorylase and adenosine monophosphate deaminase. In parallel, 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 glia l tumours with low or high malignancy, six xenografted tumours at diff erent passages, four portions of normal brain tissue and four non-glia l brain neoplasms. As suggested by cytogenetic data, the enzymatic res ults showed a relatively low activity of purine metabolism in glial tu mours when compared with normal brain and non-glial brain neoplasms. C onsidering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage a nd de novo pathways changes in gliomas, and even more in grafted tumou rs, in favour of de novo synthesis. The relation between chromosomes a nd metabolic imbalances does not correspond to a simple gene dosage ef fect in these tumours. These data suggest that the decrease of adenosi ne metabolism occurs before chromosomal aberrations appear, since it i s observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progressio n.