Microtubule stabilizing effects

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

In line with its effects on mbulin polymerization in vitro (i.e., in an excellular context), the prevention of cold-induced depolymerization of micrombules by epothilones has also been demonstrated in cells. Microtubule stabilization in intact cells (as well as cancer cell growth inhibition, vide infra), however, is observed at strikingly lower concentrations than those required for the induction... 

The check the validity of the arguments a series of model calculations based on the reaction mechanism of Fig. 10 were performed [19], details to be published). They are based on a set of coupled differential equations and on the assumption that the phase transition between microtubule growth and shrinkage can be explained by cooperative interactions between tubulin subunits at microtubule ends. Two examples are shown in Fig. 13 where the rate of GTP hydrolysis following the incorporation of tubulin into microtubules was varied. When this rate is fast (Fig. 13 a) one finds pronounced oscillations (this is equivalent to an intermediate stability of microtubules, compare Fig. lib). When the rate of hydrolysis is reduced (Fig. 13 b) the oscillations disappear because microtubules are effectively stabilized, and they remain assembled in a steady state (compare Fig. 11 a). 

M. Karbowski, J. H. Spodnik, M. Teranishi, M. Wozniak, Y. Nishizawa, J. Usiikma, and T. Wakabayashi, Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J. Cell. Sci., 114 (2001)281-91. 

Taxanes (paclitaxel, docetaxel) are derivatives of yew tree bark (Taxus brevifolia). They stabilize microtubules in the polymerized state leading to nonfunctional microtubular bundles in the cell. Inhibition occurs during G2- and M-phases. Taxanes are also radiosensitizers. Unwanted effects include bone marrow suppression and cumulative neurotoxicity. 

Another drug is taxol, which is extracted from the bark of the Pacific yew tree, Taxus brevijolia. Unlike colchicine and the vinca alkaloids, taxol binds tightly to microtubules and stabilizes them against depolymerization by Ca. It also enhances the rate and yield of microtubule assembly, thereby decreasing the amount of soluble tubulin in the cytosol pool. Again, the overall effect of taxol is to arrest dividing cells in mitosis. Taxol is used in cancer chemotherapy. 

Newport-. The way that spindles and microtubules are normally reoriented is by the stabilization of dynamic instability at the plus-end of the microtubule. So if microtubules were to embed in this apically localized complex, they would effectively be capped and this would reorient the spindle. One would expect that this would happen to the centriole prior to mitosis, so that the interphase microtubules would be stabilized at that location as well. Are you saying this doesn t happen If it doesn t happen, perhaps Cdc2 is necessary to activate this apical region for stabilizing plus ends, and this would explain why it rocks about. Are any of these molecules potential candidates for capping microtubules at the plus-end, for instance ... 

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