Microtubules paclitaxel

Fig. 3 a Model for the binding of cyclostreptin at the proposed initial MSA binding site at pore type I. Taken from [21]. b Scheme of the route of paclitaxel to its lumenal site in the microtubules. Paclitaxel binds to the external site at the pores of the microtubules, being later transported to its lumenal site while the external site gets blocked. In the presence of cyclostreptin the external site gets irreversibly blocked thus, paclitaxel cannot reach the lumenal site... 

Fig. 9 Insight of the outer (a) and (b) inner surface of a high resolution microtubule model, showing two different types of pores, I and II (see text). Green beads, polar residues yellow beads, hydrophobic residues red beads, acid residues blue beads, basic residues white beads, paclitaxel bound at its site grey beads, nucleotide. Detail of a pore type I viewed from above (c). Ribbon representation of two neighbour P-tubulin subunits as seen from the plus end of the microtubule, paclitaxel, GDP and the four residues forming a putative taxoid binding site are shown in Van der Waals representation. Taken from [22]...

Paclitaxel belongs to the family of cytoskeletal drugs which target tubulin. Treatment leads to abnormality of the mitotic spindle assembly, chromosome segregation, and consequently defects of cell division. By stabilizing the microtubule polymer and preventing the disassembly of microtubules, paclitaxel arrests cell cycle in the GO/Gl and G2/M phases and induces apoptosis [134]. 

Taxanes (paclitaxel, docetaxel) are derivatives of yew tree bark (Taxus brevifolia). They stabilize microtubules in the polymerized state leading to nonfunctional microtubular bundles in the cell. Inhibition occurs during G2- and M-phases. Taxanes are also radiosensitizers. Unwanted effects include bone marrow suppression and cumulative neurotoxicity. 

Certain drugs bind to microtubules and thus interfere with their assembly or disassembly. These include colchicine (used for treatment of acute gouty arthritis), vinblastine (a vinca alkaloid used for treating certain types of cancer), paclitaxel (Taxol) (effective against ovarian cancer), and griseoflilvin (an antifungal agent). 

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

The answer is c. (Hardman, pp 1260—1262.) Paclitaxel is a large structural molecule that contains a 15 membered taxane ring system. This anti cancer agent is an alkaloid derived from the bark of the Pacific yew tree. Its chemotherapeutic action is related to the microtubules in the cell. Paclitaxel promotes microtubule assembly from dimers and causes microtubule stabilization by preventing depolymerization. As a consequence of these actions, the microtubules form disorganized bundles, which decreases... 

Other anticancer agents have distinct mechanisms paclitaxel and its relatives target microtubules as do the vinca alkaloids. Antiestrogens and antiandrogens target estrogen and androgen receptors. 

Paclitaxel, from the bark of the pacific yew (Taxus brevifolia), inhibits disassembly of microtubules and induces atypical ones. Docetaxel is a semisynthetic derivative. 

Podophyllotoxin (38) Podophyllum peltatum L.), colchicine (9) Colchicum autumnale L.), vinblastine (4), and vincristine (5) Catharan-thus roseus (L.) G. Don] are standard microtubule-destabilizing agents used in cancer research. Paclitaxel (21), from Taxus brevifolia Nutt., acts as a promoter of stabilization of microtubules and causes mitotic arrest in an unusual fashion. ... 

Wild-type p53 will downregulate the levels of microtubule associated protein 4 (MAIM) so that, when p53 function is absent, the high levels of MAP-4 will stabilize microtubules and sensitize cells to paclitaxel therapy. 

The taxanes, paclitaxel and docetaxel, act by promoting the assembly of microtubules. The taxanes induce cell cycle arrest in the most radiosensitive phase, G2/M thereby promoting radiosensitivity. In vitro studies have also demonstrated apoptosis in cell culture lines with paclitaxel (32). Paclitaxel dose-dependent synergy is also seen in squamous carcinoma cell lines (33). Much literature has been published reg arding the use of taxanes when combined with radiotherapy. 

Although the precise mechanism of action of paclitaxel in enhancing radiation effects is not clear, one of the proposed mechanisms is its effect on the cell cycle. Its effects on the microtubules result in an M-phase arrest (55). Experiments done on synchronously dividing Chinese hamster cells have shown that cells in M and G2 are most sensitive to the effects of radiation (56). 

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