Spindle formation

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). 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

The vast majority of in vivo tests show no geno-toxicity of mono- and dialkyltins. Results from in vitro tests are variable, with little indication of DNA reactivity. There are, however, indications of clastogenicity and effects on spindle formation in mitosis in vitro. 

Whether the DNA replication checkpoint directly affects the Plxl activation pathway for Cdc25C has not yet been established. It is possible that the replication checkpoint arrests the cell cycle prior to initiation of the Plxl kinase cascade. Further characterization of upstream components of the cascade should reveal whether it is directly regulated by replication checkpoint activation. Such a characterization will also have importance for other M phase events, inasmuch as Plxl also regulates bipolar spindle formation, APC activation and cytokinesis (Qian et al 1998, 1999). These multiple functions of Plxl are associated with changes in localization of Plxl, and are most likely mediated by protein—protein interaction with the polo box motif in the non-catalytic C-terminal half of Plxl. 

Brunet S, Polanski Z, Verlhac M-H, Kubiak JZ, Maro B 1998 Bipolar meiotic spindle formation... 

Kubiak In mouse, there is a weak checkpoint in meiosis for spindle formation. There are some responses where if the spindle is destroyed, the passage from metaphase I to metaphase II is blocked. There is other evidence that there is no checkpoint. I think there is a special checkpoint in meiosis. Starting from the first mitotic division there is no spindle checkpoint. 

Anderson HJ, Coleman JE, Andersen RJ, Roberge M. (1997) Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother Pharmacol 39 223-226. 

Spindle formation Chromosome condensation Disappearance of nuclear membrane Transcription stop Cyclin degradation... 

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

The normal cell cycle consists of a definable sequence of evenfs fhaf characferize fhe growfh and division of cells and can be observed by morphological and biochemical means. The cell cycle is depicfed in Fig. 55.1. Two of the four phases of the cell cycle can be studied directly the M-phase, or mitosis, is easily visible using light microscopy because of chromosomal condensation, spindle formation, and cell division. The S-phase is the period of DNA synthesis and is observed by measuring the incorporation of tritiated thymidine into cell nuclei. 

One of the major features in the sequence of cell division is the formation of the mitotic spindle and the subsequent separation of chromosomes into their respective daughter cells. An important element of the spindle is the highly conserved, helical molecule tubulin. In addition to spindle formation and the segregation of chromosomes in cell division, alternating helices of a- and -tubulin form the microtubules that form part of the cytoskeleton and have active roles in cell organelle organisation. 

Colchichine is a natural material produced by the autumn crocus and meadow saffron. Its mechanism of CH3 action, as far as it is known, is three-fold it interferes with microtubule-spindle formation in the proliferation of the cells responsible for inflammation it has an antihistaminic effect it prevents the release of an inflammatory glycoprotein... 

As embryogenesis involves extensive cellular proliferation, any interference with this process is potentially teratogenic. Interference with spindle formation, inhibition or arrest of DNA... 

Inhibition of spindle formation such as that caused by vincristine or colchicine stops separation of chromosomes at anaphase (see chap. 6). Proper separation of chromatids may not occur because of "stickiness 7 or bridging between the chromatids. Clearly, interference with mitosis, and hence cell proliferation, is an important cause of teratogenic effects. 

Clearly, this complex process must be controlled by the cell such that there are checkpoint controls, which make sure that there are two centrosomes and two half spindles, that the correct chromatids associate with the correct half-spindle and that separation does not occur until all of the chromatids are in the correct place. Failure of any part of this system could lead to the wrong number of chromosomes in one daughter cell. This uneven segregation is known as chromosomal nondisjunction. A number of chemicals, including some drugs, will interfere with this process. Thus, spindle formation can be disrupted, so the chromosomes may segregate in a random fashion. 

Rehberg, M., and Graf, R. (2002). Dictyostelium EB1 is a genuine centrosomal component required for proper spindle formation. Mol. Biol. Cell 13, 2301-2310. 

Colchicine can arrest plant and animal cell division in vitro and in vivo. Mitosis is arrested in metaphase because of failure of spindle formation. Cells with the highest rates of division are affected earliest. High concentrations may completely prevent cells from entering mitosis, and they often die. The action also is characteristic of the vinca alkaloids (vincristine and vinblastine), podophyllotoxin, and griseofulvin. 

Bergnes (3) prepared quinazolinone derivatives, (III), that were effective in the treatment of cellular proliferative diseases by causing mitotic arrest and monopolar spindle formation. 

Inhibition of cell division, lack of spindle formation, inhibition of protein synthesis, increased cell size, radial elongation of cells, polyploid nuclei chromosome contraction, cell wall thickening. 

Fig. 12.15 Apparently, the RarvGAP, RCCl, and Ran BPl must all cooperate in order to propagate spindle formation. RCCl converts RanGDP to RanGTP. A Ran-GAP, with the help of Ran BPl, reconverts RarvGTP to the GDP form. Ran BMP accumulates on the centrosomes. from which the mitotic spindle starts to grow. (Drawn using Information from ref. 30 with permission of Science.)...

Crespo, N.C., Ohkanda, J., Yen, T.J., Hamilton, A.D., and Sebti, S.M. (2001). The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 276 16161-16167. 

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