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Laboratory of Drug Discovery Research and Development,
Developmental Therapeutics Program, Division of Cancer Treatment,
Diagnosis, and Centers, National Cancer Institute, Frederick
Cancer Research and Development Center, Frederick, Maryland 21702 (R.J.K., E.H.),
Medicine Branch, Division of Clinical Sciences,
National Cancer Institute, National Institutes of Health, Bethesda,
Maryland 20892 (P.G.),
Division of Biomedical Marine Research, Harbor
Branch Oceanographic Institution, Fort Pierce, Florida 34946 (S.P.G.,
R.E.L.), and
Department of Environmental and Occupational Health
and Department of Pharmaceutical Sciences, University of Pittsburgh
Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
15238 (B.W.D.)
The lactone-bearing polyhydroxylated alkatetraene (+)-discodermolide,
which was isolated from the sponge Discodermia
dissoluta, induces the polymerization of purified tubulin with
and without microtubule-associated proteins or GTP, and the polymers
formed are stable to cold and calcium. These effects are similar to
those of paclitaxel (Taxol), but discodermolide is more potent. We
confirmed that these properties represent hypernucleation phenomena; we obtained lower tubulin critical concentrations and shorter polymers with discodermolide than paclitaxel under a variety of reaction conditions. Furthermore, we demonstrated that discodermolide is a
competitive inhibitor with [3H]paclitaxel in binding to
tubulin polymer, with an apparent
Ki value of 0.4 µM. Multidrug-resistant human colon and ovarian
carcinoma cells overexpressing P-glycoprotein, which are 900- and
2800-fold resistant to paclitaxel, respectively, relative to the
parental lines, retained significant sensitivity to discodermolide (25- and 89-fold more resistant relative to the parental lines). Ovarian carcinoma cells that are 20-30-fold more resistant to paclitaxel than
the parental line on the basis of expression of altered 
-tubulin polypeptides retained nearly complete sensitivity to discodermolide. The effects of discodermolide on the reorganization of the microtubules of Potorous tridactylis kidney epithelial cells were
examined at different times. Intracellular microtubules were
reorganized into bundles in interphase cells much more rapidly after
discodermolide treatment compared with paclitaxel treatment. A variety
of spindle aberrations were observed after treatment with both drugs.
The proportions of the different types of aberration were different for
the two drugs and changed with the length of drug treatment.
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