Abstract
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-position of the pyrimidine ring. At this position the analogues have a hydroxy or alkoxy group of different chain lengths either in the cis- or trans-configuration. The antiproliferative effect of these compounds was tested on five cell lines of different origin. Generally, the analogues with a cis-configuration had a higher activity than those with a trans-configuration. The growth inhibitory effect of the compounds decreased with increasing alkoxy chain length, but the compound with a hydroxy group had the lowest growth inhibitory effect. One analogue, cis-5-F-5,6-dihydro-6-methoxy-uracil had a higher antiproliferative effect than FU in one of the cell lines. Effects on thymidylate synthase (TS), the possible target of these analogues, were evaluated by thymidine rescue of growth inhibition and incorporation of tritiated deoxyuridine (3H-UdR) into DNA. In solid tumour cell lines addition of TdR reversed the antiproliferative effect. Inhibition of TS in intact cells was determined by measuring 3H-UdR incorporation in two cell lines. The effect of cis-5-F-5,6-dihydro-6-methoxy-uracil on incorporation of 3H-UdR was 2- to 5-fold stronger than that of FU in both cell lines. All other compounds produced a higher 3H-UdR incorporation than FU both at equimolar and equi-toxic concentration. Concluding from these results 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 activity than FU and marked inhibition of TS in intact cells.
Highlights
Since its introduction as an antineoplastic agent 5fluorouracil (FU) has been used for the treatment of a wide spectrum of solid tumours
The antiproliferative effect of the compounds decreased with increasing chain length of the alkoxy substitution, which was illustrated by the step-like pattern of compounds number 2, 4, 6 and 8 (Figure 2)
The antiproliferative effect of one of the FU analogues tested in this study, 'cis-5-F-5,6-dihydro-6-methoxy-uracil' showed a higher activity than FU in C26-10 (Figure 2)
Summary
Since its introduction as an antineoplastic agent 5fluorouracil (FU) has been used for the treatment of a wide spectrum of solid tumours. Several approaches have been used to increase this therapeutic index, such as combination with other anticancer drugs, biochemical modulation of the FU metabolism (Peters & Van Groeningen, 1991a) and synthesis of more potent analogues (Heidelberger et al, 1983) All these studies are based on thorough research on the mechanism of action of FU, that has been performed during the last three decades (Pinedo & Peters, 1988; Diasio & Harris, 1989; Weckbecker, 1991). These compounds are supposed to generate their activity by a more selective conversion to FU and/or its metabolites in tumour tissues Examples of this group are floxuridine (5-fluoro-2'-deoxyuridine) (Heidelberger et al, 1958), ftorafur (NI-tetrahydrofuran-2-yl-5-fluorouracil) (Blokhina et al, 1972) and doxifluridine (5'-deoxy-5-fluorouridine) (Cook et al, 1979).
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