Tubulin colchicine affecting

The alkaloid colchicine binds tightly to tubulin and this characteristic has been used (Fig. 6.1) to isolate a tubulin-like fraction from H. diminuta, with properties similar to tubulin from other organisms. Furthermore, colchicine affects the qualitative distribution of [3H]proline-incorporated protein in this worm, with label accumulating in the parenchyma (195). This suggests that colchicine inhibits translocation in the tegument and provides evidence that microtubules within the internuncial processes facilitate movement of cell products from tegumentary cytons (Chapter 2) to the body surface for subsequent release. 

The role of microtubules in secretion is more clearly defined. Colchicine and vinblastine inhibit secretion, even in cytochalasin-B-treated cells, and D2O (which promotes tubulin assembly) enhances secretion in cytochalasin-treated cells. Microtubules may also be necessary for the translocation of phagocytic vesicles from the neutrophil periphery into the central region of the cytoplasm. Drugs affecting microtubule assembly may inhibit particle-induced oxidase activation or else increase oxidase activation in response to soluble agents such as fMet-Leu-Phe. 

Mechanism of action Colchicine binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area. Furthermore, colchicine blocks cell division by binding to mitotic spindles. Colchicine also inhibits the synthesis and release of the leukotrienes (see Figure 39.14). 

Although many alkaloids exert their toxic effects by affecting the nervous system, there are other alkaloids that show toxicity in completely different ways. Colchicine binds to tubulin and inhibits its polymerization, and thus inhibits the formation of microtubules in cells. 

Colchicine has a narrow therapeutic index (i.e., the amount of drug that produces the desirable therapeutic effect is not much lower than the amount that produces an adverse effect). Its therapeutic effect depends on inhibiting tubulin synthesis in neutrophils, but it can also prevent tubulin synthesis (and, thus, cell division and other cellular processes) in other cells. Fortunately, neutrophils concentrate colchicine, so they are affected at lower intakes than other cell types. Neutrophils lack the transport protein P-glycoprotein, a member of the ABC cassette family (which includes the CFTR channel). In most other cell types, P-glycoprotein exports chemicals such as colchicine, thus preventing their accumulation. 

So much attention has been paid to podophyllotoxin and its derivatives, that the details cannot be considered here. Etoposide (VP-16), and teniposide (VM-26), 22, are used clinically in the treatment of human cancers and their action has been compared with that of podophyllotoxin, (Fig. 9). It suffices to say that, although podophyllotoxin is closely related to VP-16 and VM-26, uniquely they affect cells by entirely different modes of action.Podophyllotoxin behaves like colchicine, 24, and 3-peltatin, 23, in binding to tubulin, although colchicine and podophyllotoxin occupy adjacent sites rather than the same site.VP-16 and VM-26 are inactive in the inhibition of microtubule formation but inhibit DNA synthesis. 

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