SYNERGISTIC ACTION OF TAXOL WITH TIAZOFURIN AND METHOTREXATE IN HUMANBREAST-CANCER CELLS - SCHEDULE-DEPENDENCE

Taxol (paclitaxel, (NSC 125973)) is an active agent in the treatment o f metastatic carcinoma of the breast; however, positive responses were observed in only about 60% of cases. Therefore, drug combinations whi ch might improve the effectiveness are required. Since tiazofurin (2-b eta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), methotrexate ( MTX) and taxol exert their anticancer action in different phases of th e cell cycle and have different biochemical targets, we tested the hyp othesis that tiazofurin and methotrexate might be synergistic with tax ol. MDA-MB-435 human breast cancer cells were grown in monolayer in fl asks. In the growth inhibition assay for tiazofurin, methotrexate and taxol the IC(50)s were 12.5, 0.5 and 0.016 mu M, respectively, and in the clonogenic assay 4.5, 0.065 and 0.004 mu M. When taxol was given 6 hr before tiazofurin, antagonism was observed and summation was seen when drugs were given simultaneously. Synergism was obtained in both g rowth inhibitory and clonogenic assays when tiazofurin was followed 12 hr later by taxol. Methotrexate and taxol had an antagonistic effect when they were added simultaneously or when taxol was given 6 hr befor e methotrexate; summation was observed when taxol was followed 12 hr l ater by methotrexate. Synergistic action was obtained in the clonogeni c assay when methotrexate was followed 12 hr later by taxol. The proto cols yielding synergism should be of value in the design of taxol-base d clinical trials for breast cancer.