Tubulin mutations

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to 6-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy. 

Giannakakou, P., Gussio, R., Nogales, E., Downing, K. H., Zaharevitz, D., Bollbuck, B., Poy, G., Sackett, D., Nicolaou, K. C., and Fojo, T. (2000). A common pharmacophore for epothilone and taxanes molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc. Natl. Acad. Sci. USA 97, 2904-2909. 

In 2000, Giannakakou et al. [86] proposed another common pharmacophore for taxanes and epothilones, based on biological activity and resistance data related to (3-tubulin mutations. In particular, the study focused on (3276Thr->Ile, (3284Arg->Gln and (3272Phe->Val mutations, affecting both paclitaxel and epothilones ability to induce tubulin polymerization and inhibition of cell proliferation [113]. To identify patterns of epothilone to be superposed to taxanes, the authors sampled 100... 

In summary, all tubulin mutations identified to date in epothilone-resistant cells are found in regions of the tubulin structure, which are predicted to be important for... 

Epothilones retain significant activity against paclitaxel-selected cell lines that harbor a distinct set of tubulin mutations, and again this could perhaps translate into clinical utility in the treatment of Taxol-resistant tumors. However, any such predictions must be treated with great caution, as the clinical significance of individual resistance mechanisms identified in vitro has not been established. 

In cultured tumor cells, resistance to taxanes is associated in some lines with increased expression of the mdr-1 gene and its product, the P-glycoprotein other resistant cells have P-tubulin mutations, and these latter cells may display heightened sensitivity to vinca alkaloids. Other cell lines display an increase in survivin, an antiapoptotic factor or aurora kinase, an enzyme that promotes completion of mitosis. The basis of clinical drug resistance is not known. Cell death occurs by apoptosis, but the effectiveness of paclitaxel against experimental tumors does not depend on an intact p53 gene product. 

BMS-247550 (INN Ixabepilone) (34c) is a semisynthetic analogue of Epothilone B developed by Bristol-Myers Squibb currently in phase II/IH clinical trials. Like Epothilone B, BMS-247550 is a stabilising tubulin antagonist with broad anti-tumour activity [115].The drug is active towards Taxol sensitive and insensitive cell lines, including A2780Tax ovarian carcinoma cells with defined B-tubulin mutations (F — V or... 

The basis of clinical drug resistance is not known. Resistance to taxanes in some tumor cells is due to increased expression of the P-glycoprotein other resistant cells have /3-tubulin mutations and may display heightened sensitivity to vinca alkaloids. Cell death occurs by apoptosis. 

Giannakakou P, Gussio R, Nc es E. A common pharmacophore for epothilone and taxanes Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci USA 2000 97 2904-2909. 

A third approach to the taxol pharmacophore was developed by Giannakakou et al 503), who compared the effects of taxol and various epothilone analogs on the polymerization of native tubulin and of modified tubulins carrying / -tubulin mutations near the taxol-binding... 

Giannakakou P, Gussio R, Nogales E, Downing KH, Zaharevitz D, Bollbuck B, Poy G, Sackett D, Nicolaou KC, Fojo T (2000) A Common Pharmacophore for Epothilone and Taxanes Molecular Basis for Drug Resistance Conferred by Tubulin Mutations in Human Cancer Cells. Proc Natl Acad Sci U.S.A. 97 2904... 

In contrast to taxol, epothilones also potently inhibit the growth of multidrug-resistant cancer cells, including variants whose taxol resistance is mediated by specific tubulin mutations. In addition, epothilones possess more favorable biopharmaceutical properties than taxol, for example, improved water solubility, which offered a prospect for better tolerated clinical formulation vehicles than those required for taxol. ... 

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