SIMULTANEOUS COMBINATION OF MICROTUBULE DEPOLYMERIZING AND STABILIZING AGENTS ACTS AT LOW-DOSES

The combined activity of a stabilizing and a depolymerizing agent was studied on microtubule formation in vitro and on cellular parameters r elated to the cytoskeleton. New compounds in each class of microtubula r drugs, docetaxel, as stabilizing agent, and CI 980, as colchicine an alog, currently in clinical trials, were tested at high and low concen trations. Simultaneous combination of docetaxel and CI 980, both in vi tro and in cell lines, induced microtubule structures resulting from t he association of the effects of the two drugs: short and numerous mic rotubules in vitro, abnormal asters or short bundles in cells depolyme rized in their periphery. Moreover, combining the two drugs at low con centrations inducing neither modification of the microtubular network nor variation in cell polymerized tubulin content showed synergistic e ffects in mitotic cell block and, at lower concentrations, in inhibiti on of proliferation in the KB 3-1 cell line. Similar qualitative resul ts were obtained with paclitaxel and colcemid, used in the place of do cetaxel and CI 980, respectively. At low doses, the taxoid/colchine an alog combination seems to induce some degree of mitotic inhibition, re sulting from a subtle effect on the inhibition of microtubule dynamics .