Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain.
Dolastatin 10, a cytostatic peptide containing several unique amino acid subunits, was isolated from the marine shell-less mollusk Dolabella auricularia (Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB and Bontems RJ, J Am Chem Soc 109: 6883-6885, 1987). Since our preliminary studies demonstrated that dolastatin 10 inhibited tubulin polymerization and the binding of radiolabeled vinblastine to tubulin, an initial characterization of the properties of dolastatin 10 included a comparison to other antimitotic drugs interfering with vinca alkaloid binding to tubulin (vinblastine, maytansine, rhizoxin, and phomopsin A). Dolastatin 10 inhibited the growth of L1210 murine leukemia cells in culture, with a concordant rise in the mitotic index, and its IC50 value for cell growth was 0.5 nM. Comparable values for the other drugs were 0.5 nM for maytansine, 1 nM for rhizoxin, 20 nM for vinblastine, and 7 microM for phomopsin A. IC50 values were also obtained for the polymerization of purified tubulin in glutamate: 1.2 microM for dolastatin 10, 1.4 microM for phomopsin A, 1.5 microM for vinblastine, 3.5 microM for maytansine, and 6.8 microM for rhizoxin. Dolastatin 10 and vinblastine were comparable in their effects on microtubule assembly dependent on microtubule-associated proteins. Preliminary studies indicated that dolastatin 10, like vinblastine, causes formation of a cold-stable tubulin aggregate at higher drug concentrations. We confirmed that rhizoxin, phomopsin A, and maytansine also inhibit the binding of radiolabeled vinblastine and vincristine to tubulin. Dolastatin 10 and phomopsin A were the strongest inhibitors of these reactions, and rhizoxin the weakest. Dolastatin 10, phomopsin A, maytansine, vinblastine, and rhizoxin all inhibited tubulin-dependent GTP hydrolysis. The greatest inhibition of hydrolysis was observed with dolastatin 10 and phomopsin A, and the least inhibition with rhizoxin.
Bai
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Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Pettit
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GR
Hamel
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D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001388:Aziridines / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides; D003959:Diamines / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006160:Guanosine Triphosphate / Q000378:metabolism; D051379:Mice; D008940:Mitotic Index / Q000187:drug effects; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014748:Vinca Alkaloids / Q000378:metabolism* / Q000494:pharmacology; D014750:Vincristine / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D001388:Aziridines; D047630:Depsipeptides; D003959:Diamines; D009842:Oligopeptides; D009943:Organophosphorus Compounds; D013844:Thiazoles; D014404:Tubulin; D014748:Vinca Alkaloids; D014750:Vincristine; C032227:dolastatin 1; D006160:Guanosine Triphosphate; C064571:DIAM 3; C064570:dolastatin 10