Microtubule stabilizing

Taxol s journey to the clinic was slow and arduous. Initial difficulties with aqueous solubility and lack of knowledge regarding its mechanism, of action delayed its development until 1979 when, in another seminal paper in the field, S.B.Horwitz and her collaborators disclosed their findings on the interaction of taxol with microtubules.4 Taxol s unique biological action, which includes promotion of microtubule formation and microtubule stabilization, stimulated a renewed interest in taxol as a potential drug candidate. The problem of procuring adequate supplies of taxol became even... 

Bergstralh DT, Ting JP (2006) Microtubule stabilizing agents their molecular signaling consequences and the potential for enhancement by drug combination. Cancer Treat Rev 32 166-179... 

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... 

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

Chemical Synthesis and Biological Studies of the Epothilones - Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. 

This group or complex of proteins may be isolated from cold-staUe microtubules. Their ability to stabilize microtubules appears to be diminished by the comUned action of calcium ion and calmodulin (Job et al., 1983). The role in controlling or affecting microtubule stability at physiological temperatures remains to be established... 

Mooberry, S.L., RandaU-Hlubek, D.A., Leal, R.M., et al. (2004) Microtubule-stabilizing agents based on designed lauhmatide analogues. Proc. Natl. Acad. Sci. U. S. A., 101, 8803-8808. 

Goodin S. (2008) Ixabepilone A novel microtubule-stabilizing agent for the treatment of metastatic breast cancer. Am J Health Syst Pharm 65 2017-2026. 

Epothilones A-E (3, 17, 48-50, Fig. 12) were isolated by Hofle and Reichen-bach and co-workers from the myxobacterium Sorangium cellulosum [80, 81]. After initial selection for their antifungal activity, the epothilones were soon shown to possess significant cytotoxicity against mammalian cells, epothilone B being the most active one [82]. Their mode of action was shown to be microtubule stabilization in a fashion very similar to that of... 

Molnar 1, Schupp T, Ono M, et al. (2000) The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium ceUulosum So ce90. Chem. Biol. 7 97-109. 

Epothilones are naturally occurring cytotoxic macrolides, which were initially isolated from a mycobacterium. Their antitumor activity is similar to that of the clinically established taxoids (Taxol, Taxotere), by interrupting the dynamic mechanism of microtubule assembly/disassembly via microtubule stabilization. In contrast to taxoids, epothilones are remarkably efficient against multidrug resistant cells. 

The first epithilone, a highly potent microtubule stabilizer, in advanced clinical development (Phase II) is ZK-EPO (ZK-219447), while fludelone is still in preclinical trials (cf. Chapter 4). 

D. C. Myles (2002). Emerging microtubule stabilizing agents for cancer chemotherapy. Annu. Rep. Med. Chem. 37 125. 

Other chemicals, which affect tubulin polymerization or spindle microtubule stability, are podophyllotoxin and the drugs, paclitaxel, benomyl, griseofulvin, nocodazole, and colecimid. 

This pocket in /(-tubulin, where microtubule-stabilizing drugs from different organisms can bind, also binds the assembly-promoting repeat motifs of tau protein (and other microtubule-associated proteins [MAPs]). It lies above the /(-sheet of the second domain and next to the core helix (Figs. 3 and 4), so that anything that fills it is in contact with the core helix and with the M-loop. When assembled in microtubules, the pocket is located on the inside face. In a-tubulin, the corresponding... 

Kowalski RJ, Giannakakous P et al (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272 2534-2541... 

The first chapter focuses on the total synthesis of macrolide-based microtubules stabilizing agents and on SAR data thereof, which have not been covered in other... 

The third chapter describes a comprehensive study of the mechanisms of activity of microtubules stabilizing drugs. Thermodynamic, kinetic, structural and functional data on microtubules stabilizing drugs are discussed in an interdisciplinary manner to generate a time-resolved picture of the interaction of the drugs with different tubulin forms. 

The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology. 

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