Mitotic inhibition

Those herbicides that block mitotic entry decrease or prevent the formation of mitotic figures in meristems. Amino acid, protein, RNA, DNA, and ATP synthesis and/or utilization can all attest cell growth (163,166). Although not registered as herbicides, cycloheximide [66-81-9] inhibits mitotic entry by inhibiting protein synthesis (167) hydroxyurea/727-(97-/7 inhibits DNA synthesis (168) and actinomycin D [50-76-0] nh2oix.s RNA synthesis (167). 

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. ... 

Rundle, N. T., Nelson, J., Flory, M. R., Joseph, J., et al. (2006). An ent-kaurene that inhibits mitotic chromosome movement and binds the kinetochore protein Ran-binding protein 2. ACS Chem. Biol, 7,443-450. 

Antineoplastic plant alkaloid cell cycle (M phase)-specific agent inhibits mitotic spindle formation. Tox peripheral neuropathy. Vinblastine, a congener, causes myelosuppression. 

Docetaxel Taxane (Diterpene) Breast, prostate, ovarian, nonsmall cell lung Inhibition mitotic cell-division Acral erythema scleroderma-Uke Neutropenia anemia Dys Br GI symptoms Cross-reaction with paclit el but reactions less frequent Infusion... 

Paclitaxel Taxane (Diterpene) Breast, ovarian, head and neck, lung, bladder, etc. Inhibition mitotic cell division Acral erythema injection site reaction AGEP-Uke EM SJS Neutre nia hypersensitivity pn GI synptoms back pain Dys Incidence 10-16 % without premedication. Risks—atopy, bee sting allergy... 

Colchicine has long been used as the potent chromosome-doubling agent. It induces chromosome doubling by inhibiting mitotic spindle of dividing cells. Mechanism of mitotic poisoning by colchicine has recently been elucidated. Colchicine has direct effect on microtubule assembly. 

Regan, C. M. (1985) Therapeutic levels of sodium valproate inhibits mitotic indices in cells of neural origin. Brain Res., 347, 394-398... 

The influences of herbicides on cell division fall into two classes, ie, dismption of the mitotic sequence and inhibition of mitotic entry from interphase (G, S, G2). If ceU-cycle analyses indicate increases in abnormal mitotic figures, combined with decreases in one or more of the normal mitotic stages, the effect is upon mitosis. Mitotic effects usually involve the microtubules of the spindle apparatus in the form of spindle depolymerization, blocked tubulin synthesis, or inhibited microtubule polymerization (163). Alkaloids such as colchicine [64-86-8J,viahla.stiae [865-21-4] and vincristine [57-22-7] dismpt microtubule function (164). Colchicine prevents microtubule formation and promotes disassembly of those already present. Vinblastine and vincristine also bind to free tubulin molecules, precipitating crystalline tubulin in the cytoplasm. The capacities of these dmgs to interfere with mitotic spindles, blocking cell division, makes them useful in cancer treatment. 

The growth inhibitory mechanism of the thiocarbamate herbicides, eg, EPTC, butylate, cycloate, diaHate, and triaHate, is not well defined. Cell elongation, rather than cell division, appears to be inhibited (183), although mitotic entry may be inhibited by diaHate (184). Thiocarbamates have a greater effect on shoot than toot tissue (163,184). The weU-documented inhibition of Hpid synthesis by thiocarbamates certainly contributes to the observed inhibitions of cell division and elongation. These compounds may also inhibit gibbereUic acid synthesis (185). 

The inhibitors of amino acid synthesis, sulfonylureas, imidazolinones, and glyphosate, were first recognized as general growth inhibitors that prevent mitotic entry (188,189). Whatever the mode of action, herbicides that inhibit amino acid synthesis also cause a rapid inhibition of cell growth, usually through inhibition of mitotic entry. 

DCPA inhibits the growth of grass species by dismpting the mitotic sequence, probably at entry (190). DCPA influences spindle formation and function (181) and causes root-tip swelling (182) and britde shoot tissue (191). It has been reported that DCPA, like colchicine and vinblastine, attests mitosis at prometaphase and is associated with formation of polymorphic nuclei after mitotic arrest (192). Pronamide also inhibits root growth by dismpting the mitotic sequence in a manner similar to the effect of colchicine and the dinitroanilines (193,194). Cinmethylin and bensuhde prevent mitotic entry by unknown mechanisms (194). 

Also nonkinase molecules might be important targets for anticancer drugs. For instance, the activity of the mitotic kinesin Eg5 (KSP, kinesin-5) can be inhibited by small molecules (e.g., monastrol, KSP-IA) resulting in mitotic defects associated with the induction of apoptosis. 

Ngan VK, Bellman K, Hill BT et al (2001) Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine. Mol Pharmacol 60 225-232... 

It is possible to observe effects of organotin(lV) compounds exposure such as inhibition of cleavage of fertilized eggs, interference with the formation of the mitotic spindle, damages affecting chromosome structure, and electron-dense precipitate formation in organelles. 

Colchicine has a long history of successful use and was the treatment of choice for many years. It is used infrequently today because of its low therapeutic index. Colchicine is thought to exert its anti-inflammatory effects by interfering with the function of mitotic spindles in neutrophils by binding of tubulin dimers this inhibits phagocytic activity. 

Paclitaxel -natural taxane inhibits depolymerization of tubulin in mitotic spindle apparatus -bone marrow suppression -nausea and vomiting—mild -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hypersensitivity reactions -peripheral neuropathy -myalgias, arthralgias -mild vesicant... 

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