Mitotic arrest

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). 

Nasmyth I was interested by the long mitotic arrest you showed. Perhaps you should get together with Peter Sorger, who has knocked out Mad2 in mouse (Dobles et al 2000). One of the early phenotypes he saw was a failure to arrest when nocadazole was added. 

In a recent study, LNCaP and PC3 prostate cancer cells treated with lycopene-based agents have been reported to undergo mitotic arrest. Lycopene s antiproliferative effects were likely achieved through a block in Gl/S transition mediated by decreased levels of cyclins D1 and E and cyclin-dependent kinase4 and suppressed retinoblastoma phosphorylation (Ivanov et al., 2007). 

Swanton, C., Marani, M., Pardo, O. et al. 2007. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell, 11 (6) 498—512. 

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. 

One of the major difficulties in the synthesis of these binary indole-indoline alkaloids is the necessity of generating the natural PARF (priority antireflective) (12) relative stereochemistry between C-14 and C-16, as well as the requirement for controlling the absolute stereochemistry at C-16, which must be (5). Other epimers at these positions lack the high cytotoxicity, with mitotic arrest at metaphase, that is the basis of the anticancer activity of these compounds (13,14). 

The activities of the various C-20 alkyl congeners of VBL in cellular assays of growth inhibition and mitotic arrest are presented in Table I. Only one type of substitution, the 20 -methyl derivatives (3 and 4) of... 

Vincristine and vinblastine are generally considered to act specifically on the metaphase portion of the mitotic (M) stage of the cell cycle as a consequence of perturbations of the structure and function of tubulin. A characteristic action of the drugs is production of mitotic arrest in which the tJercentage of cells in mitosis in a given population of cells will rise from a few percent to 50% and more after treatment with a drug such as vinblastine. There are reports, however, that these drugs can interfere with other phases of the cell cycle in ways not clearly related to interference with tubulin function (5). 

The mechanism of action of Catharanthus alkaloids involves entry into the cell, binding to tubulin, and interference with cellular metabolic functions. The predominant observed effect is often mitotic arrest, but other effects on cellular organization and movement can also be demonstrated. It is not unequivocally clear that the mitotic effect is, in vivo, of greater importance than other tubulin-mediated effects (33). 

Podophyllotoxin (38) Podophyllum peltatum L.), colchicine (9) Colchicum autumnale L.), vinblastine (4), and vincristine (5) Catharan-thus roseus (L.) G. Don] are standard microtubule-destabilizing agents used in cancer research. Paclitaxel (21), from Taxus brevifolia Nutt., acts as a promoter of stabilization of microtubules and causes mitotic arrest in an unusual fashion. ... 

The loss of p5J-dependcnt G, arrest promotes the progression of cells to G2/M phase where they are the target of mitotic arrest. 

With loss of p53 function, p2lWAF1/CIP1 is no longer upregulated and is unable to help cells escape from their state of mitotic arrest. 

Milas L, Hunter NR, Kurdoglu B, et al. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol 1995 35 297-303. 

Symmans W, Volm M, Shapiro R, et al. Paclitaxel-induced apoptosis and mitotic arrest assessed by serial needle aspiration implications for early prediction of breast cancer response to neoadjuvant treatment. Clin Cancer Res 2000 6 4610-4617. 

Destruction of cohesin allows the spindle microtubules to pull the separated chromatids to opposite poles of the cell. Failure of spindle attachment to a single kinetochore activates the SAC (spindle assembly checkpoint), which arrests cells at metaphase until corrections are effected and equal distribution of chromosomes has been ensured. A sensory mechanism initiates the wait anaphase signal from an imattached kinetochore and triggers the accu mulation of the checkpoint components that comprise the Bub (budding uninhibited by benomyl)-Mad (mitotic arrest deficient) families of proteins. 

Cheung HW, Jin DY, Ling MT et al. Mitotic arrest deficient 2 expression induces chemosensitiza-tion to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res 2005 65 1450-1458. 

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... 

Toluene did not induce sex-linked recessive lethal mutations or translocations, but did induce sex-chromosome loss and nondisjunction in male Drosophila melanogaster and induced mitotic arrest (C-mitosis) in embryos of the grasshopper, Melanoplus sanguinipes. 

Additionally, a number of marine toxins with medical and toxicological importance have been isolated from marine flora and fauna. Okadaic acid, Fig. (62) is the main toxin produced by dinoflagellates, which can accumulate in the hepatopancreas of mussels and caused diarrhetic shellfish poisoning in consumers [505,506], However, this toxin is also a tumor promoter and a specific potent inhibitor of protein phosphatases which may provokes mitotic arrest and apoptosis of leukemia cells [507-509], These types of compounds have been reported in shellfish and phytoplankton, and more recently, in Spanish mussels [510], Portuguese bivalves [511], and the diatom Thalassiosira weissflogii [512],... 

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. 

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