Spindle apparatus

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 processes of meiosis and mitosis involve many motile events, from the separation of the daughter chromosomes to the final act of cell separation at cytokinesis (Wadsworth, 1993). DNA replication itself may be considered as a motile event, because the polymerase complex moves along the linear DNA. One of the most obvious motile events is the separation of the chromosomes along the mitotic spindle at anaphase. Details of the structure and polarity of microtubules in the spindle apparatus in meiosis and mitosis are known through electron and light microscopy, but it is not yet clear whether the chromosomes are pushed, pulled or... 

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... 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Alkaloids such as vinblastine and vincristine are known to bind to the microtubules of the spindle apparatus. They are active agents that influence DNA synthesis and amino acid metabolism. They are also known to reduce mitosis at metaphase. Vinblastine and vincristine also have some immunosuppressive activity. There are many applications of these alkaloids. They have been used in the treatment of Hodgkin s disease, cancers and blood disorders. Vincristine is a basis for the development of clinic agents used to treat cerebral and pulmonary disorders. Vinblastine and vincristine are well-known anficancer agents. 

Other important cell cycle transitions are entry into S phase and the G2/M transition. At the G2/M transition, it is registered whether S phase has been completely executed, and the integrity of the DNA is examined at a DNA damage checkpoint. There are other important cell cycle transitions in M phase between metaphase and anaphase. At this point, an important and irreversible decision is made for progress of mitosis if the spindle apparatus is correctly formed and the sister chromatids are correctly aligned, the cell cycle may proceed. 

In M phase, new phosphorylation of many proteins is observed that starts, in particular, from the CDC2-cyclin B complex. The phosphorylation mostly affects proteins involved in the reorganization of the cytoskeleton, the nuclear membrane and the formation of the spindle apparatus. As a consequence of phosphorylation events, inhibition of vesicular transport and general inhibition of transcription occur. 

The metaphase-anaphase checkpoint controls the formation of the spindle apparatus and the correct alignment of chromosomes, and may initiate metaphase arrest (see Chapter 13). On failure of the control system, the occmrence of abnormal chromosomes is favored. In various cancer cells, chromosomal instabUity is associated with loss of function of the BUBl gene, which is part of the metaphase-anaphase checkpoint (Cahill et al., 1998). 

Thus, they prevent an arrangement of the spindle apparatus. The tubuline-benzimidazole-interactions have been studied in detail (.6). It is known that carbendazim, for example, after entering the nucleus, specifically binds to the 3 -subunit of tubuline and by this inhibits the dimerization of the a and 3 -subunits to a functional tubuline unit. Resistant strains possess altered 0 -subunits with a decreased affinity for benzimidazoles (7). The modes of action of other inhibitors of mitosis, like dicarboximides, aromatic hydrocarbons, or dithiocarbamates, have not yet been precisely described on a molecular basis. 

Only ADP is phosphorylated to form ATP in glycolysis, oxidative phosphorylation, and photophosphorylation. ATP provides the energy, directly or indirectly, to drive most biosynthetic reactions. The functions of membranes such as active transport and osmotic relations, which regulate the volume of cells, are energy dependent. The structural organization, contraction, and orientation of chromosomes and microtubules of the spindle apparatus during mitosis depend on ATP energy. The intracellular concentrations and stoichiometric relations of ATP, ADP, and AMP also modulate cellular metabolism. 

Benzimidazoles primarily act on cell and nuclear division. Nuclear division is inhibited by the binding of the MBC to the microtubular proteins involved in the synthesis of the mitotic spindle apparatus. 

In telophase, nuclei for each daughter cell form at the two poles, and the mitotic spindle apparatus disappears. Furthermore, nuclear membranes, nuclear lamina, nuclear pores, and nucleoli are reformed. The cell is now ready for cytokinesis, which is physical division of the cytoplasm. The cytoplasm divides as actin/myosin filaments contract and pinch off the plasma membrane, which results in two daughter cells that enter into Go or Gi for another round of division. The main checkpoint that exists during M phase in mammalian cells is the spindle checkpoint it is in place to ensure proper microtubule assembly, proper cell division, and that each daughter cell receives one copy of DNA. 

During prophase, the cells cytoskeleton or structural framework made of the protein tubulin breaks down into subunits. Erom these subunits, a bridge of microtubules called the spindle apparatus forms between the two pairs of centrioles as they move apart. When the centrioles reach opposite ends of the cell, they extend microtubules in all directions. Like a boat moored to a dock with multiple lines, the centriole anchors itself to... 

During telophase, or the clean-up stage of mitosis, the spindle apparatus is broken down, and the tubulin subunits stand ready to form the cytoskeleton of a new cell. The chromosomes, now clustered in two groups around the poles, uncoil into tangled threads again, and a new nuclear envelope forms around them. At this point, each new nucleus contains one copy of each chromosome. Mitosis is complete. 

Spindle apparatus—An axis of microtubules formed between centrioles in animal cells that aids the equal distribution of chromosomes to new cells being formed. 

The patient s symptoms are most likely due to her vincristine therapy. Vinca alkaloids exert antineoplastic effects by binding to tubulin and thereby inhibiting assembly of microtubules. This results in the dissolution of the mitotic spindle apparatus, and cell arrest occurs in the mitosis (M) phase of the cell cycle. Vinca alkaloids are used for a variety of hematologic malignancies and solid tumors, such as lung, testicular, and breast cancers. The most common vinca alkaloids include vincristine, vinblastine, and vinorelbine. 

WlOA Inhibits mitosis by promoting and maintaining assembly of microtubules. Cell cycle specific (G2 and IVl phases). May also lead to chromosome breakage by distorting mitotic spindle apparatus. 

Griseofulvin is a mitotic spindle poison. In vitro, ii rapidly arrests cell divirsion in metaphase. It causes a rapid, reversible dissolution of the mitotic spindle apparatus, ably by binding with the tubulin dimer that is required for microtubule assembly. The selective toxicity to fungi o probably due to the propensity of the drug to concentrate in ti.ssues rich in keratin, where dermatophytes typically cstalv li.sh infections. 

Sallasidis K, Schmid E and Bauchinger M (1991). Mitotic spindle damage induced by 2-chlorobenzylidene malononitrile (CS) in V79 Chinese hamster cells examined by different staining of the spindle apparatus and chromosomes. MutatRes, 262, 263-266. 

This cultured rat kidney cell in metaphase shows condensed chromosomes (blue), microtubules of the spindle apparatus (red), and the inner nuclear envelope protein POM121 (green). The POM121 staining demonstrates that the inner nuclear envelope proteins retract into the ER during mitosis. 

---