MCF-7 growth inhibition by ultraviolet radiation and 5-fluorouracil: the importance of treatment sequence

Effective treatment of certain cancers with 5-fluorouracil (5-FU) and irrad iation is well established; however, the most effective combination of thes e agents remains controversial. Although 5-FU has been identified as a radi osensitizer, the mechanism of action remains unknown, To assess the effect of combination, 5-FU and ultraviolet (UV), we constructed a new in vitro mo del with MCF-7 human breast cancer cells that measures growth inhibition an d morphologic changes in nuclear argyrophilic nucleolar organizer regions ( AgNORs). Cells were incubated in media containing 0, 50, 100 and 500 ng/ml 5-FU for 48 h, they were also exposed to UV irradiation of 90 J/m(2) at the beginning, middle, or end of the incubation period. The cells were incubat ed for an additional 48 h with 5-FU free media. A combined treatment with 5 -FU and UV radiation demonstrated an additive inhibitory effect. The strong est growth inhibition was observed when UV exposure was at the beginning of the 5-FU treatment at 5-FU concentrations of 100 and 500 ng/ml. To elucida te the activity of 5-FU radiosensitization, we investigated the aggregation Pof AgNOR, which we previously established to reflect rRNA inhibition. A c ombined treatment with 5-FU and UV radiation accelerated the rate of AgNOR aggregation at 5-FU concentrations of 50 and 100 ng/ml. The timing of UV ir radiation did not affect the rate of AgNOR aggregation. A combined treatmen t with 5-FU and UV radiation showed an additive inhibitory effect on MCF-7 cell growth that might be explained, in part, by rRNA inhibition. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.