discodermolide and Burkitt-Lymphoma

Computer-assisted structure analysis indicated (+)-discodermolide, a polyhydroxylated alkatetraene lactone marine natural product, was an antimitotic compound, and we confirmed this prediction. Previous work had shown an accumulation of discodermolide-treated cells in the G2/M portion of the cell cycle, and we have now found that discodermolide arrests Burkitt lymphoma cells in mitosis. Discodermolide-treated breast carcinoma cells displayed spectacular rearrangement of the microtubule cytoskeleton, including extensive microtubule bundling. Microtubule rearrangement that occurred with 10 nM discodermolide required 1 microM taxol. Discodermolide had equally impressive effects on tubulin assembly in vitro. Near-total polymerization occurred at 0 degree C with tubulin 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 discodermolide than with taxol under every reaction condition examined. Discodermolide-induced polymer differed from taxol-induced polymer in that it was completely stable at 0 degree C in the presence of high concentrations of Ca2+. In a quantitative assay designed to select for agents more effective than taxol in inducing assembly, discodermolide had an EC50 value of 3.2 microM versus 23 microM for taxol.

Topics: Alkanes; Animals; Antineoplastic Agents; Breast Neoplasms; Burkitt Lymphoma; Calcium; Carbamates; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Fluorescent Antibody Technique, Indirect; Guanosine Triphosphate; Humans; Kinetics; Lactones; Microscopy, Electron; Microtubule-Associated Proteins; Microtubules; Paclitaxel; Porifera; Pyrones; Time Factors; Tubulin; Tumor Cells, Cultured