IN-VITRO ANTITUMOR-ACTIVITY OF CIS-5-FLUORO-5,6-DIHYDRO-6-ALKOXY-URACIL AND TRANS-5-FLUORO-5,6-DIHYDRO-6-ALKOXY-URACIL - EFFECTS ON THYMIDYLATE SYNTHESIS

A class of new 5-fluorouracil (FU) analogues, the 5-fluoro-5,6-dihydro -6-alkoxy-uracils was synthesised with a modification at the 6-positio n of the pyrimidine ring. At this position the analogues have a hydrox y or alkoxy group of different chain lengths either in the cis- or tra ns-configuration. The antiproliferative effect of these compounds was tested on five cell lines of different origin. Generally, the analogue s with a cis-configuration had a higher activity than those with a tra ns-configuration. The growth inhibitory effect of the compounds decrea sed with increasing alkoxy chain length, but the compound with a hydro xy group had the lowest growth inhibitory effect. One analogue, cis-5- F-5,6-dihydro-6-methoxy-uracil had a higher antiproliferative effect t han FU in one of the cell lines. Effects on thymidylate synthase (TS), the possible target of these analogues, were evaluated by thymidine r escue of growth inhibition and incorporation of tritiated deoxyuridine (H-3-UdR) into DNA. In solid tumour cell lines addition of TdR revers ed the antiproliferative effect. Inhibition of TS in intact cells was determined by measuring H-3-UdR incorporation in two cell lines. The e ffect of cis-5-F-5,6-dihydro-6-methoxy-uracil on incorporation of H-3- UdR was 2- to 5-fold stronger than that of FU in both cell lines. All other compounds produced a higher H-3-UdR incorporation than FU both a t equimolar and equi-toxic concentration. Concluding from these result s we regard cis-5-F-5,6-dihydro-6-methoxy-uracil as the most promising FU analogue of this series, because of its higher antiproliferative a ctivity than FU and marked inhibition of TS in intact cells.