GROWTH-INHIBITORY ACTION OF BREFELDIN-A WITH TAXOL AND TIAZOFURIN IN HUMAN BREAST-CARCINOMA CELLS

Brefeldin A (NSC 89671), a macrocyclic lactone, blocks cellular protei n transport by disturbing the association and dissociation of the Golg i apparatus with a 110-kD protein which is regulated by GTP. Brefeldin also induces retrograde transport from the Golgi membrane to the endo plasmic reticulum, which is mediated by microtubules which also requir e GTP for their biosynthesis. The anti-cancer action of taxol is exert ed by enhancing tubulin polymerization in microtubule assembly; tiazof urin (2-beta-D-ribofuranosylthiazole-A-carboxamide, NSC 286193) acts t hrough decreasing cellular GTP concentrations. Therefore, we tested th e hypothesis that taxol (paclitaxel, NSC 125975) or tiazofurin might p rovide synergism with brefeldin. In human breast carcinoma MDA-MB-435 cells in the growth inhibition assays for brefeldin, taxol and tiazofu rin, the IC(50)s were 41 nM, 6 nM and 13 mu M, respectively. When bref eldin and taxol were given simultaneously, addition (brefeldin 10 nM w ith taxol 2 to 8 nM) or synergism (brefeldin 30 nM with taxol 2 to 8 n M) was observed. When brefeldin and tiazofurin were given simultaneous ly, or tiazofurin was followed 12 h later by brefeldin, addition was o bserved. The protocols yielding synergism and addition should be of va lue in the design of clinical trials for breast carcinoma.