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Inhibition of tubulin

Inhibition of Tubulin Addition and Cell Proliferation bt Vinblastine and Related Compounds... [Pg.208]

The for vinblastine estimated for inhibition of tubulin addition was 0.18 lM, and vinblastine inhibited the growth of B16 melanoma cells completely at a concentration of 4 nM (3). [Pg.208]

Vinflumine (Javlor ) is a second-generation Vinca alkaloid. It is more active than the nonfluorinated parent compound (vinorelbine) in several cancers (Figure 8.7). Vinflumine is currently in Phase III clinical trials as a chemotherapeutic agent against a variety of cancers (metastasic breast cancer, small cell lung cancer, and bladder cancer). This drug inhibits mitotic assembly, via inhibition of tubulin polymerization in microtubules, a major element of the cytoskeleton. Effects of fluorine substimtion on tubulin affinity or on metabolism are not responsible for the increased efficiency and decreased toxicity. The synthesis of vinflumine is reported in Chapter 4. ... [Pg.284]

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... [Pg.1175]

Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in non-small cell lung cancer, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH. [Pg.1177]

Compound AM ID (jiM) Tubulin Polymerization % Inhibition of Tubulin at 100 pM 0/ to Protein-Linked DNA Breaks IC50 (jiAO for Maximal DNA Breaks... [Pg.85]

ITP = Inhibition of tubulin polymerization. b ICB = Inhibition of colchicine binding. [Pg.92]

The mode of action of benzimidazole anthelmintics has proved the subject of much debate. Although they were first thought to inhibit the fumarate-reductase enzyme system of helminths, it now seems likely that their mode of action is the inhibition of tubulin polymerization which leads to a number of degenerative processes. This is consistent with their somewhat slower mode of action than most other anthelmintics which generally cause rapid paralysis of the helminths followed by expulsion. [Pg.202]

Fig. 26. Comparison of tubulin binding affinities of naturual colchicinoids with thio congeners. 1C30 values (p.M) of inhibition of tubulin polymerization are given. Fig. 26. Comparison of tubulin binding affinities of naturual colchicinoids with thio congeners. 1C30 values (p.M) of inhibition of tubulin polymerization are given.
Vincristine, a vinca-alkaloid, prevents proliferation of tumor cells through the inhibition of tubulin polymerization. Vincristine is used as an anticancer agent for leukemia and lymphoma (Himes etal, 1976 Owellen etal., 1976). Clinical use of vincristine is often limited by its adverse effects, which include painful peripheral neuropathy (i.e., neuropathic pain) (Casey et al., 1973 Sandler et al., 1969). Elucidation of the detailed mechanism of neuropathic pain caused by vincristine is needed to improve quality-of-life for patients, and to make vincristine more tolerable for cancer treatment. [Pg.180]

A series of small peptides were prepared in order to identify the minimal unit that could mimic the effect of the N-terminal cap domain. The structure of the most efficient (I19L, Fig. 35) was studied by NMR and molecular modeling [142]. The concentration dependence of inhibition of tubulin polymerization suggested that the peptides bind stoichiometrically to unpolymerized tubulin rather than to assembled MT. It is well known that the stability of the tubulin/stathmin complex decreases upon phosphorylation of stathmin [8]. In agreement with this, phosphorylated I19L was found to be fourfold less efficient than its unphosphorylated form. [Pg.136]

Welwistatin also inhibits cell proliferation with reversible depletion of cellular microtubules in ovarian carcinoma cells and A-10 vascular smooth muscle cells by inhibiting the polymerization of tubulin, but it does not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP [8]. Due to the cytotoxicity associated with the inhibition of tubulin polymerization, which is the main mechanism of action of antitumor drugs such as vincristine and vinblastine, and because P-gp-overexpressing cells show virtually no resistance to welwistatin due to its MDR reversal properties, this natural product could be a good candidate in the chemotherapy of drug-resistant tumors. [Pg.66]

Several groups have used this reaction in recent years to prepare biologically active molecules. Benzothiophene derivatives 93, prepared from Gewald products 92 in three steps via a palladium-mediated aromatization reaction, (Scheme 21) were tested for their antiproliferative activity and inhibition of tubulin polymerization [55]. Several compounds showed inhibitory effects against murine leukemia (L1210), murine mammary carcinoma (FM3A) and human T-lymphoblastoid (Molt/4 and GEM) cells. For most of the compounds, there was a positive... [Pg.253]

Fig. 15 Antiproliferative activity and inhibition of tubulin polymerization of thiophene 94 and combretastatin A-4... Fig. 15 Antiproliferative activity and inhibition of tubulin polymerization of thiophene 94 and combretastatin A-4...
Bai R, Pettit GR, Hamel E. Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem. Pharmacol. 1990 39 1941-1949. [Pg.1477]

Figure 19.11. Structure of discodermolide. The circled biophore is responsible for the inhibition of tubulin polymerization. Figure 19.11. Structure of discodermolide. The circled biophore is responsible for the inhibition of tubulin polymerization.
The Combretastatin A-4 analogues, containing a variety of heterocyclic moieties, such as imidazoles, thiazoles and tetrazoles, not only display efficient inhibition of tubulin polymerization but also exert potent cellular growth inhibition in different cancer lines including MDR cancer cells. It is worthy to note that some of Combretastatin A-4 analogues, such as imidazole-based Combretastatin A-4 exhibited oral availability leading to solid tumor regression in vivo tumor models. [Pg.96]


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See also in sourсe #XX -- [ Pg.142 ]




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