Mitotic inhibitors

Mitotic inhibitors (antimitotics) interfere with or stop cell division. Examples of mitotic inhibitors include paclitaxel (Taxol) and vincristine (Oncovin). 

Featherstone, C., and Russell, P. (1991). Fission yeast p serine kinase. Nature 349 808-811. 

The vinca alkaloids are isolated from plant Vinca rosea. They are cell cycle specific and mitotic inhibitors. 

Direct-Acting Defense Chemicals — Mitotic Inhibitors and DNA Protectants... 

Colchicine is a poisonous tricyclic tropane alkaloid from the autumn crocus (Colchicum autumnale) and gloriosa lily (Gloriosa superba). This alkaloid is a potent spindle fiber poison, preventing tubulin polymerization.25 Colchicine has been used as an effective anti-inflammatory drug in the treatment of gout and chronic myelocytic leukemia, but therapeutic effects are attainable at toxic or near toxic dosages. For this reason, colchicine and its analogs are primarily used as biochemical tools in the mechanistic study of new mitotic inhibitors. 

Many phytotoxins are mitotic inhibitors. However, the effects are seldom due to direct effects on the mitotic apparatus. Onion (Allium cepa L.) seeds are germinated in the presence of the natural products under a 14-h photoperiod.6 Root tips are prepared according to Armbruster et al.,2 and mitotic analysis is performed with a compound microscrope on 1000 cells per slide (three slides per treatment).6 9137 In addition to the proportions of cells in each stage of mitosis, the number of abnormal mitotic figures should be determined. 

The alkaloid colchicine (FI) isolated from the medicinal plant Colchicum autumnale L. (Liliaceae family) still is used to treat gout and familial Mediterranean fever. FI and thiocolchicine (F2) (SCH3 rather than OCH3 at C-10), which is more stable and more potent but slightly more toxic, are mitotic inhibitors that inhibit polymerization of tubulin (69). Although they show antileukemic activity, they are too toxic to use as anticancer agents, which prompts the synthesis of new, less toxic analogs. 

A group of mitotic inhibitors (vinblastine, vincristine, and vinorelbine) exert their cytotoxic effects by binding to tubulin. This inhibits formation of microtubules, causing metaphase arrest. Their mechanism of action and metabolism are similar, but the antitumor spectrum, dose and clinical toxicities of vinblastine, vincristine, and vinorelbine are very different. Paclitaxel and docetaxel are also mitotic inhibitors. However, they differ from the vinca alkaloids by enhancing microtubule formation. As a result, a stable and nonfunctional microtubule is produced. 

Vincristine, vinblastine, and vinorelbine are natural alkaloids derived from the periwinkle (vinca) plant. They act as mitotic inhibitors, or spindle poisons. Although the alkaloids are very similar structurally, they have different activities and patterns of toxicity (Table 124—12). 

Administration of mitotic inhibitor shortly before tissue sampling might impact the... 

The Vinca alkaloids and some other antimitotic agents thus represent another class of agents that can selectively inhibit tumor blood flow by a mechanism that is distinct from that of TNF or TNF inducers such as FAA and DMXAA. Combretastatin A4, another antimitotic agent, appears to have a vascular basis for its action (81) and is currently a candidate for clinical trial. The mechanism of action of mitotic inhibitors is not well understood, but may result from their effects on vascular endothelial cells (82). 

Carvajal D, Tovar C, Yang H et al (2005) Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res 65 1918-1924... 

In further confirmation, there are antibiotics prominently listed in Appendices E and E of Hoffman (1999) as inhibitors for enzymes involved in DNA and RNA processes. With regard to cancer treatment, however, a search of Medline indicates that most antibiotics are used against bacterial infections incurred during cancer treatment. An exception involves studies at the M.D. Anderson Cancer Center of the University of Texas, located in Houston. These studies utilized actinomycin D and doxorubicin, both said to be known anticancer agents, in conjunction with the mitotic inhibitors vinblastine and Taxol. (The latter two are from plant extracts, and inhibit cell division or mitosis. The first-mentioned is derived from the Madagascar periwinkle [as is another alkaloid called vincristine], the latter from the yew tree of the... 

Vassalli JD, Hamilton J, Reich E. Macrophage plasminogen activator modulation of enzyme production by anti-inflammatory steroids, mitotic inhibitors, and cyclic nucleotides. Cell 1976 8 271-281. 

Colchicine and a synthetic relative, colcemid, have long been used as mitotic inhibitors. In cells exposed to high concentrations of colcemid, cytosolic microtubules depolymer-ize, leaving an MTOC. However, when plant or animal cells are exposed to low concentrations of colcemid, the microtubules remain and the cells become blocked at meta-... 

Many antineoplastic dru are available to treat malignancies. The antineoplastic dru covered in diis chapter include the alkylating dru, antibiotics, antimetabolites, hormones, mitotic inhibitors, and selected miscellaneous dru. Many antineoplastic dni not specifically discussed in diis chapter are listed in the Summary Drug Table Antineoplastic Dru. ... 

Phosphorylation and inactivation of the mitotic inhibitor Weel by the niml/cdrl kinase. Nature 363 736-8. 

Types of Cell Division Effects. Classification of herbicidal effects on cell division is not uniform. This has lead to confusion about the action of herbicides on cell division. Terms such as "mitotic poisons", "meristem active", and "mitotic inhibitors" have been used to describe the same effect of a herbicide on cell division. A more useful classification of herbicidal effects would be to divide herbicides into 2 classes those inhibiting cell division and those disrupting cell division (Figure 1). Inhibition of cell division will result in treated meristems that only contain interphase cells. If cell division is disrupted, one or more mitotic stages normally present in the meristem tissue will not be found. These two effects on cell division result from different mechanisms. 

Some diamino-IPs are mitotic inhibitors with antitumour activity. Thus, substituted 5,7-diamino-IbP notably extends the lifetime of mice when used in treatment of L1210 leukemia. 4,6-Diamino-IcP and 5-amino-7-chloro-IbP are known to inhibit the proliferation of L1210 cells and exhibit antimitotic activity (87JMC1746, 78JMC112). 

E. Mitotic inhibitors. These agents act in various ways to inhibit orderly mitosis, thereby arresting cell division. 

Mitotic inhibitors Docetaxel An+, D+, M++, N+ Severe fluid retention in 6% of patients. 

DNA synthesis/mitotic inhibitors Irinotecan Irinotecan is a drug that has been studied more recently within the context of malignant CNS tumors, especially in concert with bevicizumab (discussed below). Irinotecan is a semisynthetic derivative of camptothecin, a topoisomerase I inhibitor. Irinotecan binds and stabilizes topoisomerase-DNA complexes, preventing the unwinding of DNA, thereby causing irreparable DNA double-strand breaks and eventually cell death. 

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