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Antimetabolic Activity of 1-p-Toluenesulfonylcytosine and 5-Bromo-1-methansulfonyluracil in Human Tumor Cells

In the present study, we evaluated the antiproliferative and antimetabolic potential of newly syntethised N-sulfonylcyclourea derivatives of nucleobases uracil and cytosine. The investigations were performed in vitro on colon carcinoma (CaCo2) and cervical carcinoma (HeLa) cells. The reduction of tumor cells proliferative capacity was followed by tetrazolium dye assay. Biosynthetic activity of the tumor cells enzymes involved in de novo DNA, RNA and protein synthesis and also de novo and salavage pyrimidine and purine synthesis were determined via sensitive radioassays. The enzymes studied were thymidine and uridine kinases, thymidine and uridine phosphorylases, thymidylate synthetase, RNA polymerases, DNA polymerase, ribonucleotid reductase, orotate fosforibosyl transpherase, carbamyl phosphate synthetase and aspartate transcarbamylase. The enzyme activity in treated cells was calculated relative to untreated control cells. The results of assays of antiproliferative effects of 1-p-toluensulfonylcytosine and 5-bromo-1-methansulfonyluracil showed a growth inhibitory activity against the human cancer cell lines with a 50% inhibitory concentration (IC50) of 5x10-6 M. The determined antimetabolic activity of 1-p-toluensulfonylcytosine and 5-bromo-1-methansulfonyluracil on HeLa and CaCo2 cells indicated the most pronounced inhibitory effects of the investigated compounds in both examined cell lines. Within 24 hours of cell tretment, protein syntethis decreased for 30-70%, DNA synthesis for 50-80% and RNA synthesis for 20-45% depending on type of tumor cells and applied compounds. The 5-bromo-1-methansulfonyluracil inhibited DNA polymerase (27%), thymidine kinase (68%), thymidilate synthetase (43%) and ribonucleotid reductase (46%) in CaCo2 cells and DNA polymerase (63%), RNA polymerase (20%), uridine kinase (24%), thymidine kinase (23%) and ribonucleotid reductase (38%) in HeLa cells. De novo biosynthesis of pyrimidine and purine was affected for 20%. The 1-p-toluensulfonylcytosine was able to inhibit RNA polymerase (32%), orotate phosphoribosyl transpherase (39%), uridine kinase (44%) de novo pyrimidine (28%) and purine (61%) synthesis in HeLa and CaCo2 cells. The ribonucleotid reductase was inhibited for 47% in both examined cell lines. On the basis of present results it can be concluded that antitumor activity of 1-p-toluensulfonylcytosine and 5-bromo-1-methansulfonyluracil is clossely associated with their inhibitory activity on, for tumor cells metabolism, very important enzyme.

Antimetabolic activity; nucleo base derivatives; human tumor cells

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