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Eleutherobin, a Novel Cytotoxic Agent That Induces Tubulin Polymerization, Is Similar to Paclitaxel (Taxol®)¹

Oncology Drug Discovery [B. H. L., J. M. C., L. A. C., A. M. C., C. R. F.] and Experimental Pathology [A. J. W.], Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, and Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093 [P. R. J., T. L., W. F.]

Eleutherobin is a novel natural product isolated from a marine soft coral that is extremely potent for inducing tubulin polymerization in vitro and is cytotoxic for cancer cells with an IC₅₀ similar to that of paclitaxel. This compound is cross-resistant along with other multidrug-resistant agents against P-glycoprotein-expressing cells and is cross-resistant with paclitaxel against a cell line that has altered tubulin. In mechanistic studies, eleutherobin shares with paclitaxel the ability to induce tubulin polymerization in vitro and is most likely cytotoxic by virtue of this mechanism. Human colon carcinoma cells exposed to eleutherobin contain multiple micronuclei and microtubule bundles, and they arrest in mitosis, depending on concentration, cell line, and length of exposure. These morphological abnormalities appearing in cultured cells are indistinguishable from those induced by paclitaxel. Electron microscopy reveals that eleutherobin induces homogeneous populations of long, rigid microtubules similar to those formed by paclitaxel. Thus, eleutherobin is a new chemotype with a mechanism of action similar to that of paclitaxel and, as such, has promising potential as a new anticancer agent.

¹ This work was supported in part through a National Cooperative Drug Discovery Group (NCDDG) under NIH Grant CA 55056.

² Present address: Bayer Pharmaceuticals, 400 Morgan Lane, West Haven, CT 06516.

³ To whom requests for reprints should be addressed, at Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543.

Received 10/30/97. Accepted 1/26/98.

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