Microtubule stabilizing antimitotic agents

Manetti F, Forli S, Maccari L, et al. 3D QSAR studies of the interaction between (3-tubulin and microtubule stabilizing antimitotic agents (MSAA). A combined pharmacophore generation and pseudoreceptor modeling approach applied to taxanes and epothilones. II Farmaco 2003 58 357-361... 

The determination of the mechanism of action of Taxol proved to be very important in the clinical development of this cytotoxic agent. Initial studies demonstrated that it was a mitotic spindle inhibitor. However, subsequent studies demonstrated that the mechanism was unique because it stabilized microtubules and prevented their depolymerization back to tubulin, an effect opposite that of other antimitotic agents as colchicine, vincristine, vinblastine, and podophyllotoxin. ... 

Hood KA, West LM, Rouwe B, Northcote PT, Berridge MV, Wakefield SJ, Miller JH. Peloruside A, a novel antimitotic agent with pacfitaxel-like microtubule-stabilizing activity. Cancer Res. 2002 62 3356-3360. 

The force which propels secretory granules along the microtubules is less clear. It is known that the micro tubular system exists in at least two states the fully polymerized form represented by intact microtubules, and the disintegrated form represented by a pool of depolymer-ized globular proteins (tubulin) in the cytoplasm. In order for microtubules to function properly, a dynamic state of equilibrium must exist between the fully-formed tubules and the tubule constituent pool. Thus, colchicine and other antimitotic agents bind to specific sites on the microtubular subunits. It has been proposed that they exert their effect by inactivating the free subunits and thereby shift the equilibrium between the associated and dissociated states of the microtubules so that eventually no intact microtubules remain and secretion is inhibited. Similarly, stabilization of microtubules in the polymerized form with D2O also inhibits cellular secretion of insulin. From this, one can hypothesize that if the secretory vesicles were somehow attached to the microtubules, possibly by way of microfilaments, a constant cycle of depolymerization near the cell periphery, with a repolymerization at the central area of the cell, would advance the secretory vesicle from the cell center to the cell web. In addition, if tubulin actually contains an actin-like contractile protein, then this contractile property may well contribute to the intracellular movement of secretory materials. 

The antimitotic mechanism of taxol differs from the antimicrotubule agents such as colchicine and the vinca alkaloids discussed earlier. Rather than causing disassembly of the microtubules, taxol actually enhances tubulin polymerization. This upsets the normal dynamic equilibrium between soluble tubules, which are dimers, and the microtubule polymers. The stabilization of the latter inhibits mitosis in the latter part of Phase G2 and M. Although sharing much of the toxicology of many of the anticancer drugs, taxol promises to be an important addition to the cancer armamentarium. 

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