The cytotoxic interaction of combined 5-fluorouracil (5-FU) with different nucleoside analogues was investigated in vitro on a colon (WiDr) and a breast (MCF-7) cancer cell line. Azidothymidine (AZT), 3'-deoxy-2', 3'-didehydrothymidine (D4T), 5-iododeoxyuridine (IdUrd) and 2',3'-dideoxycytidine (DDC) were tested at different concentrations (5-600 microM) as modulators of 5-FU. The experimental endpoints were cellular viability and cell cycle distribution. The combination of 5-FU and AZT or D4T yielded supra-additive cytotoxic effects in both cell lines at all concentrations. On WiDr, IdUrd at high concentrations of 50 and 100 microM showed a supra-additive effect whereas at low concentrations (5, 10 and 20 microM) the effect was antagonistic. 5-FU combined with IdUrd produced a synergistic effect on MCF-7 cells at all concentrations. DDC antagonised the toxic effect of 5-FU on the WiDr cell line. In WiDr cells, a significant increase in the overall S-phase was observed 48 and 72 hours after exposure to D4T, AZT and DDC at the low concentration of 10 microM. On the contrary, this accumulation in S-phase was not present in MCF-7 cells. The combined effect of 5-FU and nucleoside analogues in vitro is dependent on the type and concentration of nucleosides and the cell-line tested. AZT, D4T and IdUrd are more likely to be subjected to more intensive in vitro and in vivo research as far as modulation of 5-FU toxicity is concerned.