TAMOXIFEN DOWN-REGULATES SIGNAL-TRANSDUCTION AND IS SYNERGISTIC WITH TIAZOFURIN IN HUMAN BREAST-CARCINOMA MDA-MB-435 CELLS

Breast carcinoma is a leading cause of cancer death in women in the US . Tamoxifen (TAM), an antiestrogen, is used as a chemopreventive and c hemotherapeutic compound against human breast carcinoma. Tiazofurin (T R), an oncolytic C-nucleoside, inhibits IMP dehydrogenase activity, de creases cellular GTP pools, and downregulates ras gene expression. MDA -MB-435 cells are estrogen receptor negative human breast carcinoma ce lls that have elevated signal transduction activity. Because TR and TA M decrease signal transduction enzyme activity and inositol 1,4,5-tris phosphate (IP,) concentration via different mechanisms, we tested the hypothesis that the two compounds may be synergistic in human breast c arcinoma cells. In MDA-MB-435 cells in growth inhibition assay, the IC (50)s for TR and TAM were (mean +/- SE) 17 +/- 1.2 and 12 +/- 1.1 mu M ; in clonogenic assays they were 4 +/- 0.3 and 0.7 +/- 0.3 mu M, respe ctively. When TR was added to MDA-MB-435 cells, followed 12 h later by TAM, synergism was observed in growth inhibition and clonogenic assay s and in the reduction of IP3 concentration. The latter may explain, a t least in part, the synergistic action of TR and TAM in these cells. The synergistic action of TR and TAM may have implication in the clini cal treatment of human breast carcinoma.