title: Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)).
abstract: Epothilones A and B, natural products with minimal structural analogy to taxoids, have effects similar to those of paclitaxel (Taxol(R)) in cultured cells and on microtubule protein, but differ from paclitaxel in retaining activity in multidrug-resistant cells. We examined interactions of the epothilones with purified tubulin and additional cell lines, including a paclitaxel-resistant ovarian carcinoma line with an altered beta-tubulin. The epothilones, like paclitaxel, induced tubulin to form microtubules at low temperatures and without GTP and/or microtubule-associated proteins. The epothilones are competitive inhibitors of the binding of [3H]paclitaxel to tubulin polymers. The apparent Ki values for epothilones A and B were 1.4 and 0.7 microM by Hanes analysis and 0.6 and 0.4 microM by Dixon analysis. In the paclitaxel-sensitive human cell lines we examined, epothilone B had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel. A multidrug-resistant colon carcinoma line and the paclitaxel-resistant ovarian line retained sensitivity to the epothilones. With Potorous tridactylis kidney epithelial (PtK2) cells examined by indirect immunofluorescence, microtubule bundles appeared more rapidly following epothilone B treatment, and there were different proportions of various mitotic aberrations following treatment with different drugs.
authors.affiliation: Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment, Diagnosis and Centers, NCI, Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kowalski
authors.forename: P
authors.initials: P
authors.lastname: Giannakakou
authors.forename: E
authors.initials: E
authors.lastname: Hamel
mesh_terms: D018432:Drug Resistance, Multiple; D034261:Epothilones; D004852:Epoxy Compounds / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008940:Mitotic Index; D017239:Paclitaxel / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D034261:Epothilones; D004852:Epoxy Compounds; D008869:Microtubule-Associated Proteins; D011108:Polymers; D013844:Thiazoles; D014404:Tubulin; C093787:epothilone A; D006160:Guanosine Triphosphate; D017239:Paclitaxel; C093788:epothilone B