Gene dosage and expression, and enzyme activity of thymidine kinase and thymidylate synthase in xenografted colorectal adenocarcinomas

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Abstract
Cytogenetic studies performed on human colorectal tumors have revealed 2 specific patterns of chromosomal anomalies. The major pattern, known as the monosomic type (MT), is characterized by the loss or deletion of chromosomes 18, 17 (short arm 17p) and, less frequently, Ip, 4, 15, 5 (long arm 5q) and 21. The other one, known as the trisomic type (TT), is characterized by the gain of several chromosomes: 7, 12, X, 5 and 8. Losses of chromosome 18 and of the 17p arm never coexist in TT tumors. It was observed that many chromosome losses or deletions involved genes encoding for enzymes of the de novo pathways of nucleotide synthesis. In contrast, gains involved genes encoding for enzymes of the salvage pathways of the same metabolism. This led to the hypothesis that chromosome imbalances corresponded to those of nucleotide synthesis in tumor cells. Such an interrelation was confirmed by the dosage of thymidylate synthase (TS) and thymidine kinase (TK) activities in a series of colorectal grafted tumors. This study has been expanded to a larger series of xenografted tumors (23 cases) in which both TS and TK activities were studied, in parallel with an analysis of mRNA, by Northern blotting. The amount of mRNA was found to correlate with the number of gene copies calculated from cytogenetic data, indicating a direct gene-dosage effect. It also correlated with enzyme activities, but less strongly. This suggests the existence of an efficient post-transcriptional regulation, in particular for TS, whose level of expression varies over a wide range. Such variations may explain the diversity of responses to chemotherapy.