Antimitotic drugs, microtubules

A new antitumor drug, taxol, has been isolated from the bark of Taxus brevifolia, the Pacific yew tree. Like vinblastine and colchicine, taxol inhibits cell replication by acting on microtubules. Unlike these other antimitotic drugs, however, taxol stimulates microtubule polymerization and stabilizes microtubules. 

Vinblastine (6.73) is an antimitotic drug that prevents polymerization of tubulin (Figure 6.26). When incubated with tubulin, vinblastine complexes in a 1 1 ratio with tubulin proteins. By blocking polymerization, vinblastine prevents microtubule formation and therefore mitosis. In contrast, paclitaxel (Taxol, 6.74) and epothilone B (6.75) stabilize aggregated tubulin. As a result, in the presence of paclitaxel and epothilone B, cells form static bundles of microtubules that are nonfunctional. Vinblastine and paclitaxel are both approved for clinical use against cancer. Ixabepilone (6.76), an analogue of epothilone B (6.75), has been approved by the FDA for treatment of certain forms of breast cancer. The European Medicines Agency (EMEA) did not approve ixabepilone out of concern over severe side effects.27... 

Antimitotic drugs that target microtubules (MT) or its constituent protein tubulin are one of the most successful classes of anticancer agents discovered so far. MT are long, filamentous, tube-shaped protein polymers that are essential in all eukaryotic cells. Antimitotic agents are compounds that arrest cells in mitosis, which results in the slowing or blocking of mitosis and induction of apoptotic cell death. 

The best known drugs acting as antimitotics are the vinca alkaloids, vincristine (7.90) and vinblastine (7.91). They are very complex indole derivatives that nevertheless have been synthesized. Both are quite effective in various leukemias and in Hodgkin s lymphoma, but show considerable neurotoxicity. Vinblastine and vincristine bind specifically to the microtubular protein tubulin in dimeric form, precipitating depolymerization of the microtubules and functionally acting as a mitotic poison. Vinorelbine (7.92) is a semisynthetic vinca alkaloid functionally identical to vinblastine. 

Many compounds that perturb the cellular cytoskeleton affect phagocytosis and macropinocytosis. Binding to actin filaments by the natural product cytochalasin D blocks both of these uptake mechanisms. Disruption of microtubules by the antimitotic agents colchicine and nocodazole inhibits macropinocytosis and affects some mechanisms of phagocytosis. The diuretic drug amiloride, which is an inhibitor of Na+/H+ antiporters, selectively blocks macropinocytosis. By activating protein kinase C, phorbol esters represent a class of small molecules that promote macropinocytosis. 

Various drugs, Including colchicine and taxol, disrupt microtubule dynamics and have an antimitotic effect. Some of these drugs are useful In the treatment of certain cancers. 

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. 

Taxol (42) is highly cytotoxic and has broad antitumor activity. This alkaloid acts by a mechanism different than any other antitumor drug. At concentrations completely inhibitory to cell division, taxol had no significant effects on DNA, RNA, or protein synthesis, but HeLa cells were blocked in late G2 and/or M phase. In contrast to other antimitotic agents such as colchicine, maytansine, vincristine, or podophyllotoxin, taxol (42) was found to promote assembly of calf-brain microtubules, and the microtubules so produced were resistant to depolymerization by cold or CaCl2. 

Taxol is a complex diterpene from the yew tree, especially the Pacific yew—Taxus brevifolia (Taxaceae). Taxol and its derivatives are used as prescription drugs for cervical and breast tumours (Lenaz and De Furia 1993). It has an antimitotic effect, associated with an interaction of taxol with the tubulin-microtubule system (Hamburger and Hostettmann 1991). 

Discodermolide (36) is a cytotoxic polyketide isolated in low yield from the Caribbean sponge Discodermia dissoluta 44), The recent discovery that discodermolide shares the same microtubule-stabilising mechanism of antimitotic action as the clinically important anticancer drug, Taxol (paclitaxel), and retains activity against Taxol -resistant cancer cells has stimulated considerable interest (45,46). Due to the scarce supply of the natural material, the development of an efficient total synthesis (47-52) of (+)-discodermolide is needed to provide useful quantities for further testing, as well as enabling access to structurally simplified analogues. 

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