Tamoxifen inhibits nitrobenzylthioinosine-sensitive equilibrative uridine transport in human MCF-7 breast cancer cells

Tamoxifen inhibits the binding of [H-3]nitrobenzylthioinosine ([H-3]NBMPR) to human MCF-7 breast cancer cells with an IC50 of 8 mu M Tamoxifen at 30 mu M changed the apparent K-d for [H-3]NBMPR binding from 0.63+/-0.12 to 4.75+/-0.58 nM, with little effect on the B-max (311000+/-76000 and 263000+/-46000 sites per cell for untreated and tamoxifen-treated cells respectively). Corresponding to this decrease in binding of [H-3]NBMPR in the presence of tamoxifen was an inhibition of NBMPR-sensitive equilibrative transport of 50 mu M [H-3]uridine (IC50 7-10 mu M). In the presence of 15 mu M tamoxifen, the apparent K-m for [H-3]uridine transport was increased from 390+/-30 to 1500+/-250 mu M, with no change in V-max (12.0+/-0.1 and 11.3+/-4.3 mu M/s for untreated and tamoxifen-treated cells respectively). The inhibitory effect of tamoxifen on NBMPR-sensitive equilibrative uridine transport was specific, as similar results were also observed in HL-60 leukaemia and EL4 lymphoma cells. Furthermore a similar concentration of tamoxifen had no effect on the NBMPR-insensitive equilibrative transport of uridine in MCF-7, HL-60 and Morris 7777 hepatoma cells, and on the Na+-dependent transport of uridine in murine splenocytes. In this paper we demonstrate that tamoxifen by itself might have some antiproliferative effects through inhibition of DNA synthesis by blocking the nucleoside salvage pathway.