Cell division, microtubule activity

Paclitaxel is a well-established antiproliferative agent with a microtubule-targeting pharmacologic activity (37,42,43). As an anticancer agent, paclitaxel causes polymerization and stabilization of microtubules (43-45). The stabilization of microtubule dynamics by paclitaxel can interrupt many cellular processes, including cell division, migration, activation, maintenance of cytoskeletal framework, and intracellular as well as transmembrane protein transport (42,46,47). 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

One of the major features in the sequence of cell division is the formation of the mitotic spindle and the subsequent separation of chromosomes into their respective daughter cells. An important element of the spindle is the highly conserved, helical molecule tubulin. In addition to spindle formation and the segregation of chromosomes in cell division, alternating helices of a- and -tubulin form the microtubules that form part of the cytoskeleton and have active roles in cell organelle organisation. 

In addition to being an essential component of the mitotic spindle, and being required for the maintenance of cell shape, microtubules are involved in a wide variety of cellular activities, such as cell motility and communication between organelles within the cell. Any disruption of the equilibrium within the microtubule system would be expected to disrupt cell division and normal cellular activities in which microtubules are involved. 

Cytoskeleton. Many cellular activities, such as motility, endocytosis, exocytosis, and cell division, rely on microfilaments and microtubules. A number of alkaloids have been detected which can interfere with the assembly or disassembly of microtubules (Table IV), namely, vincristine, vinblastine, colchicine, maytansine, maytansinine, and taxol. 

Cytoskeleton is defined as the sum of the various filamentous proteins of eukaryotic cells that remain after the cells are extracted with a mild detergent. The cytoskeleton includes actin filaments, two-stranded helical polymers, which form the microfilaments and the actin-binding proteins. Other components are microtubules and intermediate filaments. The cytoskeleton has not only a role in maintaining the shape of cells, it is also actively engaged in cell division, in the organisation and the dynamic movement of ceD organelles and in the movement of cells in chemotaxis. 

Although many other alkaloids have been isolated from C. roseus only vinblastine and vincristine have been developed for clinical use. The antiproliferative activity of the two compounds is related to their specific interaction with tubulin, thus preventing assembly of tubulin into microtubules and arresting cell division (59). However, despite this apparent identical mechanism of action and their clear chemical similarities, vinblastine and vincristine display very different clinical effects. Vinblastine, for example, is used to treat Hodgkin s disease and metastatic testicular tumors, whereas vincristine is used mainly in combination with other anticancer drugs for the treatment of acute lymphocyticleukemia in children. Toxicity profiles are also different, in that vinblastine causes bone-marrow depression, whereas peripheral neuropathy often proves to be dose-limiting in vincristine therapy. 

Paclitaxel acts by enhancing microtubule assembly and stabilizing microtubules (1,2). Microtubules consist of polymers of tubulin in dynamic equilibrium with tubulin heterodimers. Their principal function is the formation of the mitotic spindle during cell division, but they are also active in many interphase functions, such as cellular motility, intracellular transport, and signal transmission. Paclitaxel inhibits the depolymerization of tubulin, and the microtubules formed in the presence of paclitaxel are extremely stable and dysfunctional. This stabilization impairs the essential assembly and disassembly required for dynamic cellular processes, and death of the cell results through disruption of the normal microtubular dynamics required for interphase processes and cell division. In tumor cells, cytotoxicity is represented by the appearance of abnormal microtubular bundles, which accumulate during G2 and mitosis, blocking the cell cycle (3). 

The length of the microtubule cylinder may measure upto 10,000 A, but the diameter is usually 180-250 A. The polymerisation of tubulins to microtubules takes place at 37°C in presence of Mg ions, endogenous cofactors such as GTP and microtubule-associated proteins (MAPs). The depolymerisation of microtubules occurs at temperatures lower than 37°C and in presence of Ca ions. The assembly and disassembly of microtubules proceeds in a nucleated fashion and is associated with a number of cellular functions. The formation of microtubules are required to control various cell activities such as cytoplasmic movement, cell division, cell shape and substrate and vesicle transport etc. Thus, interruption of the microtubulin assembly by a chemotherapeutic agent would result in several cellular dysfunctions leading to death of the parasites. Several drugs are known to bind with tubulin and block its polymerisation into microtubules. This results in gradual disappearance of microtubules from the cells. Consequently cytoplasmic movement and transport of nutrients are disturbed. These abnormal conditions cause death of the cell [59,60]. 

Colchicine exerts a variety of pharmacological effects, but how these occur or how they relate to its activity in gout is not well understood. It has antimitotic effects, arresting cell division in G1 by interfering with microtubule and spindle formation (an effect shared with vinca alkaloids). This... 

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