Antimitotic agents colchicines

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. 

Rao, V.C., Mehendale, H.M. Effect of antimitotic agent colchicine on carbon tetrachloride toxicity. Arch. Toxicol. 1993 67 392-400... 

Colchicine is an antimitotic agent and is widely employed as an experimental tool in the study of cell division and function. 

Colchicine is an antimitotic agent, highly effective in the treatment of gout, but associated with considerable toxicity. Diarrhea is used as a criterion for adequate dosage. Accidental overdosage occurs relatively often and can be dangerous. For these reasons, NSAIDs (except aspirin) are often used in acute gout instead of colchicine. 

C 9754 Colchicine Antimitotic agent that disrupts microtubules by binding to tubulin and preventing its polymerization induces apoptosis in several normal and tumor cell lines. 

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. ... 

Known antimitotic agents (see Fig. 2) bind to a number of characterized sites on the tubulin protein. The most well characterized sites include the taxol binding site, the vinca alkaloid domain and the colchicine site. 

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. 

Verdier-Pinard P, Lai JY, Yoo HD, Yu JR, Marquez B, Nagle DG, Nambu M, White JD, Ealck JR, Gerwick WH, Day BW, Hamel E. Structure-activity analysis of the interaction of curacin A, the potent colchicine site antimitotic agent, with tubulin and effects of analogs on the growth of mcf-7 breast cancer cells. Mol Pharmacol 1998 53 62-76. 

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 active principle of the autumn crocus (Colchicum autumnale), colchicine (48), is one of the very few drugs that have remained in reputable medical use since ancient times. This drug was the only useful treatment available for the excruciating pain associated with crystallization of uric acid in the joints characteristic of gout until the advent of allopurinol. Although the precise mechanism by which colchicine gives this dramatic relief remains undefined, the antimitotic activity of this agent is... 

In addition, the alkaloid colchicine (from Colchicum autumnale) blocks tubulin polymerization by binding to heterodimeric (3-tubulin between amino acids 239 and 254. Since it inhibits the MT-dependent migration of granulocytes into areas of inflammation and their MT-dependent release of proinflammatory agents, it is used to treat attacks of gout. Its antimitotic effect in the gastrointestinal system induces diarrhoea. Nocodazole competes for the binding site of colchicine and has similar effects on heterodimeric (3-tubulin. 

Other approaches to induce gastrointestinal discomfort have far more serious toxic effects. The chemical colchicine stops cell division (an antimitotic), producing severe nausea, vomiting, and dehydration, which can lead to delirium, neuropathy, and kidney failure. On the other hand, colchicine is used in the treatment of gout and has been studied as an anticancer agent because it stops cell division. Most toxic of all are plants that produce lectins, and the most toxic of these is the chemical ricin produced by castor beans. Only 5 to 6 seeds are necessary to kill a small child. Fortunately, following oral consumption much of the ricin is destroyed in the stomach. Ricin is extremely effective at stopping protein synthesis, so much so that direct exposure to only 0.1 pg/kg can be fatal. 

The natural compound colchicine (1) was extracted from the poisonous meadow saffron Colchicum autumnale L. and was the first antimitotic destabilizing agent to be discovered [9], It consists of three rings a trimethoxyphenyl (TMP, ring A), a... 

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