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Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland (E.H.); Departments of Pharmaceutical Sciences (B.W.D.) and Chemistry (B.W.D., D.P.C.), University of Pittsburgh, Pittsburgh, Pennsylvania; School of Biological Sciences (J.H.M.) and School of Chemical and Physical Sciences (P.T.N.), Victoria University of Wellington, Wellington, New Zealand; SAIC-Frederick Inc., National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland (M.K.J.); Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences (M.C., A.K.G.) and Department of Chemistry (A.K.G.), Purdue University, West Lafayette, Indiana; Department of Chemistry and Skaggs Institute of Chemical Biology, Scripps Research Institute, La Jolla, California (K.C.N.); Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California (K.C.N.); Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (I.P.); and Department of Chemistry, Princeton University, Princeton, New Jersey (E.J.S.)

Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide.

Address correspondence to: Dr. E. Hamel, Building 469, Room 104, National Cancer Institute at Frederick, Frederick MD 21702. E-mail: hamele{at}mail.nih.gov