DISCODERMOLIDE, A CYTOTOXIC MARINE AGENT THAT STABILIZES MICROTUBULESMORE POTENTLY THAN TAXOL

Computer-assisted structure analysis indicated (+)-discodermolide, a p olyhydroxylated alkatetraene lactone marine natural product, was an an timitotic compound, and we confirmed this prediction. Previous work ha d shown an accumulation of discodermolide-treated cells in the G(2)/M portion of the cell cycle, and we have now found that discodermolide a rrests Burkitt lymphoma cells in mitosis. Discodermolide-treated breas t carcinoma cells displayed spectacular rearrangement of the microtubu le cytoskeleton, including extensive microtubule bundling. Microtubule rearrangement that occurred with 10 nM discodermolide required 1 mu M taxol. Discodermolide had equally impressive effects on tubulin assem bly in vitro. Near-total polymerization occurred at 0 degrees C with t ubulin plus microtubule-associated proteins (MAPs) under conditions in which taxol at an identical concentration was inactive. Without MAPs and/or without GTP, tubulin assembly was also more vigorous with disco dermolide than with taxol under every reaction condition examined. Dis codermolide-induced polymer differed from taxol-induced polymer in tha t it was completely stable at 0 degrees C in the presence of high conc entrations of Ca2+. In a quantitative assay designed to select for age nts more effective than taxol in inducing assembly, discodermolide had an EC(50) value of 3.2 mu M versus 23 mu M for taxol.