Mitotic

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

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. 

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). 

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). 

Assay for mitotic recombination in yeast and Drosophila Assay for unscheduled DNA synthesis in cultured hepatocytes and rodents... 

Certain proteins endow cells with unique capabilities for movement. Cell division, muscle contraction, and cell motility represent some of the ways in which cells execute motion. The contractile and motile proteins underlying these motions share a common property they are filamentous or polymerize to form filaments. Examples include actin and myosin, the filamentous proteins forming the contractile systems of cells, and tubulin, the major component of microtubules (the filaments involved in the mitotic spindle of cell division as well as in flagella and cilia). Another class of proteins involved in movement includes dynein and kinesin, so-called motor proteins that drive the movement of vesicles, granules, and organelles along microtubules serving as established cytoskeletal tracks. ... 

In recent years there has been some interest in monastrol (62), a potentially important chemotherapeutic for cancer which acts as an inhibitor of mitotic kinesin Kappe and coworkers successfully synthesized racemic monastrol (62) using microwave-mediation in 60% yield from ethyl acetoacetate (6), 3-hydroxybenzaldehyde (63), and thiourea (3b) in the presence of PPE." ... 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

Griseofulvin is the first antimycotic drug detected that is only active against dermatophytes. Its activity manifests as nuclear and mitotic abnormalities followed by distortions in the hyphal motphology. 

Some are mitosis inhibitors which affect microtubule function and hence the formation of the mitotic spindle, others are topoisomerase I and II inhibitors. 

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. 

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

In contrast to the DNA damage checkpoint, the mitotic spindle checkpoint is essential for cell viability. Dierefore, targeting kinases of the spindle checkpoint including Bubl, BubRl, and Mpsl might be a valid strategy for anticancer treatment. 

Centrosomes, also called the microtubule organizing centre, are protein complexes that contain two cen-trioles (ringlike structures) and y- tubulin. They serve as nucleation points for microtubular polymerization and constrain the lattice structure of a microtubule to 13 protofilaments. They are responsible for organizing the mitotic spindle during mitosis. 

Karsenti E, Vernos I (2001) The mitotic spindle a self-made machine. Science 294 543-547... 

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... 

Mayer TU, Kapoor TM, Haggarty SJ et al (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286 971... 

The phase of the cell cycle where the sister chromatids are separated and distributed onto two daughter nuclei. First, upon entry into mitosis the chromosomes are condensed followed by the breakdown of the nuclear-envelope (prophase). The two centrosomes are separated and induce the formation of the mitotic spindle. Then, the chromosomes are captures by the spindle and aligned on the metaphase plate (metaphase). The sister-chromatids are separated and pulled to the poles of the spindle (anaphase). In telophase, two new nuclei are formed around the separated chromatids. 

Tubulin is a major component of the cellular cytoskele-ton. Tubulin polymers (microtubules) are important for cell division (mitotic spindle) and the chemotaxis and phagocytosis of neutrophils. Prevention of tubulin polymerisation by colchicine accounts for the therapeutic effects of this drug in acute gouty arthritis and its anti-mitotic effects. 

APC is active from mid-M phase (anaphase) to the end of G1 phase and required for disconnecting sister chromatids and exit from M-Phase to Gl. The complex mediates the ubiquitination of Securin and Cyclin B. Degradation of these proteins, which block mitotic progression, promotes anaphase onset and exit from mitosis. 

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