Cell death mitotic

The nervous system is subject to a unique set of constraints during development. Many more neurons are generated during development than are required in the mature nervous system. Importantly, after their last mitotic division neurons are unable to re-enter the cell cycle and can no longer proliferate. As development proceeds there is a period during which as many as half of all neurons die, a process known as normal or programmed cell death that occurs by apoptosis of the cell (see Ch. 35). 

Although taxanes bind to p-tubulin promoting microtubule polymerization and stabilization of the spindle complex, they serve to cause a sustained mitotic block at the metaphase/anaphase boundary. This block will occur at a lower concentration than that which is required to increase the microtubule mass (10). However, it is not completely clear how this interaction with microtubules translates into cell death. Morphologic features and the characteristic DNA fragmentation patterns seen in the setting of apoptosis have been documented in tumor cells after therapy with taxanes (10). These observations are accompanied by the phosphorylation of Bcl-2, an anti-apoptotic protein, changing the cellular balance between Bax and Bcl-2 to a status that favors apoptosis (11). 

Jordan MA, Wendell K, GardinerS, Derry WB, CoppH, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 1996 56(4) 816-825. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

Benzimidazoles have a high affinity for tubulin proteins10 and disrupt mitosis at metaphase by attacking the mitotic spindle. The ensuing failure of sister nuclei to separate results in cell death. 

Post-mitotic cell death of newly-generated neuronal cells in the adult SVZ (Morshead and van der Kooy, 1992)... 

Aberrations in chromosomes or chromatids, which are sometimes microscopically visible, may arise during mitotic division when newly divided chromosomes fail to separate or do so incorrectly. The absence of a chromosome is usually lethal, and an excess is often poorly tolerated, giving rise to serious defects. Aberrations of the sex chromosomes are more readily tolerated, however. Chromosome aberrations may be caused by foreign compounds as indicated in the section on mutagenesis (see chap. 6). However, those cells with aberrations seem to be rapidly eliminated and so may contribute to cell death rather than a heritable mutation. 

It is widely assumed in the oncology therapeutic area that paclitaxel is cytotoxic to cancer cells and induces apoptosis, a rapid, programmed cell death associated with the activation of caspases (48) and mediated via the mitotic arrest of cells. 

Dissolution of mitotic spindle leads to cell death... 

Hendry, J.H. and West, C.M., 1997, Apoptosis and mitotic cell death their relative... 

Treatment of human cancer cells with low nM concentrations of Epo B leads to profound growth inhibition and cell death (Table 1-1). In line with the effects on tubulin polymerization in vitro, Epo B is a more potent antiproliferative agent than Epo A, which in turn is about equipotent with paclitaxel. As observed for paclitaxel, Epo B treatment produces aberrant mitotic spindles, results in cell cycle arrest in mitosis, and eventually leads to apoptotic cell death. It is often assumed that apoptosis is a direct consequence of G2/M arrest, which in turn would be a prerequisite for growth inhibition and cell death. However, as has been elegantly demonstrated by Chen et al. in a series of recent experiments, the situation is clearly more complex, such that low concentrations of Epo B (and paclitaxel... 

---