Assembly-inhibiting drugs, microtubules

The answer is d. (Hardman, p 1258. Katzung, pp 935-9.36.) Vinblastine binds to tubulin and blocks the protein from polymerizing to microtubules. The drug-tubulin complex binds to the developing microtubule, resulting in inhibition of microtubule assembly and subsequent depolymerization. 

As noted earlier, microtubule elongation has been characterized largely with respect to the involvement of guanine nucleotides and the modes of drug inhibition of microtubule formation. There have also been a number of important studies on the influence of microtubule-associated proteins and solution variables on the kinetics and thermodynamics of microtubule self-assembly. Of these, the characterization of the so-called mitotic spindle poisons has been particularly complex because of the variety of agents and the diversity of systems studied. For this reason, we shall concentrate on the other factors affecting the elongation process. 

Podophyllotoxin is an aryltetralin lignan which has been isoiated from severai plants of the Podophyllum species, it is a potent cytotoxic agent against various cancer celi iines, stopping the cell cycle in metaphase through the inhibition of microtubules assembly by binding the colchicine site of the tubulin [112]. Because of numerous side effects, podophyllotoxin cannot be used as a drug. 

This drug is an inhibitor of microtubule assembly. It therefore inhibits cell division (spindle formation), cellular movement, and transport of substances within a cell (gel-sol transformations, through microtubule dissolution and reformation). The therapeutic action of the drug lies in the inhibition of microtubule assembly in neutrophils—neutrophil migration into affected areas is inhibited, as is the secretion of inflammatory substances (due to inhibition of gel-sol transformations). Thus, inflammation is reduced. 

Due to its effect on microtubule assembly, this drug has the ability to arrest mitotic cells in metaphase. Particularly affected are rapidly dividing cells, such as those in skin, hair and bone marrow. In addition, the activity of secretory cells is diminished, as movement of secretory substances out of a secretory cell is inhibited. This could potentially affect all systems in the body (e.g., endocrine systems and systems heavily regulated by the autonomic nervous system). In short, this drug is extremely toxic if administered improperly, and could result in fatality. 

Mechanisms The mechanism of action of albendazole is unclear. The drug blocks glucose uptake in both larval and adult parasites, which leads to decreased formation of ATP and subsequent parasite immobilization. The actions of albendazole may also include inhibition of microtubule assembly, as has been described for mebendazole and thiabendazole. 

Diazonamide A causes cells to arrest in mitosis, and after exposure to the drug, treated cells lose both interphase and spindler microtubules. It has equivalent activity to dolastatin 10 and is far more potent than dolastatin 15. This inhibition of microtubule assembly is accompanied by potent inhibition of tubulin-dependent... 

Estramustine, an oral drug, also inhibits microtubule assembly and has weak estrogenic activity at the estradiol hormone receptors of the cell. Approximately 75% of a dose of estramustine is absorbed.15 The terminal half-life ranges between 20 to 24 hours, with nonrenal excretion as the major route of elimination. This drug is used primarily for the treatment of prostate cancer, but its use is limited by the side effects, which include nausea and vomiting, diarrhea, thromboembolic events, and gynecomastia. 

The role of microtubules in secretion is more clearly defined. Colchicine and vinblastine inhibit secretion, even in cytochalasin-B-treated cells, and D2O (which promotes tubulin assembly) enhances secretion in cytochalasin-treated cells. Microtubules may also be necessary for the translocation of phagocytic vesicles from the neutrophil periphery into the central region of the cytoplasm. Drugs affecting microtubule assembly may inhibit particle-induced oxidase activation or else increase oxidase activation in response to soluble agents such as fMet-Leu-Phe. 

Vinflumine (Javlor ) is a second-generation Vinca alkaloid. It is more active than the nonfluorinated parent compound (vinorelbine) in several cancers (Figure 8.7). Vinflumine is currently in Phase III clinical trials as a chemotherapeutic agent against a variety of cancers (metastasic breast cancer, small cell lung cancer, and bladder cancer). This drug inhibits mitotic assembly, via inhibition of tubulin polymerization in microtubules, a major element of the cytoskeleton. Effects of fluorine substimtion on tubulin affinity or on metabolism are not responsible for the increased efficiency and decreased toxicity. The synthesis of vinflumine is reported in Chapter 4. ... 

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... 

Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division. 

Colchicine Inhibits microtubule assembly and cell division Rabbit femoral artery Local infusion of drug-containing biodegradable microparticles Did not reduce restenosis Induced toxicity to adjacent musculature (102)... 

Thiabendazole inhibits the helminlh-speciflc enzyme fu-maralc reductase. It is not known whether metal ions are involved or if the inhibition of the enzyme is related to thiabendazole s anthclmintie effeel. Benzimidazole anthelmin-tie drugs such as thiabendazole and mebendazole also aire.st nematode cell division in metaphase by interfering with microtubule assembly."- They exhibit a high affinity for tubulin, (he precursor protein for tnicrotiibulc synthesis. 

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