Mitotic disruption mechanism

Root tips squashes were also used to examine the cross-resistance of the R biotype to other mitotic disrupters. Mudge gi al- (3) had previously shown that field applications of all of the dinitroaniline herbicides were ineffective in controlling the R biotype, and this was confirmed using root tip squashes as well (20). The phosphoric amide herbicide amiprophosmethyl also inhibits polymerization of tubulin into microtubules (21) and causes the same kinds of mitotic disruption as the dinitroaniline herbicides. The R biotype is also cross-resistant to this herbicide (20). Because the structure of amiprophosmethyl and trifluralin are quite different, it is likely that mechanisms of resistance based upon translocation and/or metabolism of herbicides is unlikely (but see 16 for an exception). 

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... 

Mechanism of action Colchicine binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area. Furthermore, colchicine blocks cell division by binding to mitotic spindles. Colchicine also inhibits the synthesis and release of the leukotrienes (see Figure 39.14). 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

The mechanism of action of the vinca alkaloids is that of the inhibition of the polymerization of tubulin to microtubules. The cellular protein tubulin, which occurs in a- and /3-forms, is essential for proper cellular function. During mitosis tubulin polymerizes to form microtubules, which are long tube-shaped protein polymers. The equilibrium between unpolymerized a- and /3-tubulin and microtubules is an important one and any disruption of this equilibrium can send dividing cells into mitotic block and apoptosis. The vinca alkaloids bind to /3-tubulin at a different site from paclitaxel (Taxol) and act to prevent tubulin assembly. 

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. 

Miura K, Imura N (1989) Mechanism of cytotoxicity of methylmercury, with special reference to microtubule disruption. Biol Trace Elem Res 21 313-315 Miura K, Suzuki K, Imura N (1978) Effects of methylmercury on mitotic mouse glioma cells. Environ Res 17 453-471... 

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