In vitro antiproliferative and metabolic activity of eight novel 5-fluorinated uracil nucleosides.

The in vitro growth inhibitory activity of eight novel 5-fluorinated uracil nucleosides was assessed in four human tumour cell lines, one of colon and three of head and neck squamous cell origin. These compounds are ribose or deoxyribose sugars with an acetoxy or an hydroxyl-group at the 6-position in the uracil part of the molecule, and their respective diastereoisomers. Antiproliferative effects were tested in an automated microculture assay based on the reduction of a tetrazolium dye, the MTT assay. Using a continuous drug exposure for four days, all novel nucleosides were more potent inhibitors of cell growth than 5-fluorouracil (5-FU). Most drugs were very active, having an IC50 value at least 10 fold lower than that of 5-FU, and this was consistently found for all cell lines. The 6-acetoxy compounds were generally more active than the compounds with a hydroxyl-group at the 6-position, while diastereoisomerism did not seem to influence the antiproliferative effect. Their capacity to inhibit the incorporation of tritiated deoxyuridine into DNA, which reflects the inhibition of thymidylate synthase, was measured in a short term assay. When tested at a concentration of 10(-6) mol/l, most of the compounds were found to block this incorporation more efficiently than 5-FU.