PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “MITOTIC POISONS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed1982

Podophyllotoxin poisoning of microtubules at steady-state: effect of substoichiometric and superstoichiometric concentrations of drug.

Depolymerization kinetics of microtubules assembled to steady-state by podophyllotoxin treatment show a dose-dependent effect of this mitotic poison on the net rate of microtubule disassembly. Pulse-chase experiments with microtubules at steady-state indicate that the depolymerization effect induced by superstoichiometric concentrations of podophyllotoxin relative to tubulin is polar and time-dependent, i.e. the rate of tubulin loss decreases along with the time of treatment in the presence of the drug. Under these conditions the rate of microtubule disassembly is much faster than one could expect from a unique effect of drug-tubulin complex on the microtubule assembly end. Podophyllotoxin-tubulin complex is not able to induce active depolymerization of microtubules, while free podophyllotoxin is. These results are consistent with the hypothesis that this drug acts on the microtubule assembly-disassembly process by two different mechanisms: 1) as a free drug, it actively promotes polar depolymerization of microtubules, and 2) as a drug-tubulin complex, it retards the addition of subunits into the microtubule ends.

Animals↗
PubMed2001

In vitro polyploidy induction in Rhododendron simsii-hybrids.

Three in vitro protocols for the induction of tetraploid Rhododendron simsii hybrids were evaluated. The most successful technique was a daily application of mitotic poison on the apical meristem of seedlings. However, this technique was rather labour intensive. Direct sowing on media enriched with these compounds required less work but was less efficient. Mitotic inhibitors, when added to multiplication media, induced ploidy chimeras of existing genotypes.

Chimera↗
PubMed2003

Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells.

Loss of p53 sensitizes to antimicrotubule agents in human tumor cells, but little is known about its role during mitosis. We have identified the Polo-like kinase family member serum inducible kinase (Snk/Plk2) as a novel p53 target gene. Snk/Plk2 mutagenesis demonstrated that its kinase activity is negatively regulated by its C terminus. Small interfering RNA (siRNA)-mediated Snk/Plk2 silencing in the presence of the mitotic poisons paclitaxel (Taxol) or nocodazole significantly increased apoptosis, similar to p53 mutations, which confer paclitaxel sensitivity. Furthermore, we have demonstrated that the apoptosis due to silencing of Snk/Plk2 in the face of spindle damage occurs in mitotic cells and not in cells that have progressed to a G(1)-like state without dividing. Since siRNA directed against Snk/Plk2 promoted death of paclitaxel-treated cells in mitosis, we envision a mitotic checkpoint wherein p53-dependent activation of Snk/Plk2 prevents mitotic catastrophe following spindle damage. Finally, these studies suggest that disruption of Snk/Plk2 may be of therapeutic value in sensitizing paclitaxel-resistant tumors.

Animals↗
PubMed1986

Comparison of cellular effects of phomopsin and colcemid in Chinese hamster cells in vitro.

The effects of the fungal toxin phomopsin A, which produces the disease lupinosis in farm animals fed on lupins infected with Phomopsis leptostromiformis, were studied in cultures of Chinese hamster cells. The results show that phomopsin A inhibits proliferation by blocking cells in metaphase, but that higher concentrations are needed than for colcemid, another mitotic poison. As with colcemid, there is an increase in both micronuclei formation and DNA synthesis. Unlike colcemid, phomopsin is also clastogenic.

Animals↗
PubMed1995

Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours.

1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs. 2. This applies particularly to two general classes of anti-cancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue. 3. The specific questions posed here is whether anti-cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue). Two possible principles may be involved, the first based on cytokinetic considerations and then second on self-inhibition of drug cytotoxicity. 4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S-phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure to correspondingly lower drug concentrations for a longer time (with the same concentration x time of exposure). We also show that the drug DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self-inhibition of cytotoxicity. 5. Matching of the cytokinetic or self-inhibitory profile of a drugs' action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti-tumour effects.

Acridines↗
PubMed1980

In vitro induction of segregational errors of chromosomes by natural cannabinoids in normal human lymphocytes.

It has been shown that segregational errors (SE) of chromosomes can be induced by olivetol and several halogenated inhalation anesthetics. The purpose of this study was to examine the effects of natural cannabinoids - including delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) - on chromosome segregation. Lymphocytes obtained from healthy adult males were incubated with various concentrations of natural cannabinoids for 72 hours. Anaphase preparations were made from these cultures. A statistically significant increase in the incidence of SE of chromosomes was observed in the lymphocytes exposed to THC at a concentration of 3.2 x 10(-6) M, but not to CBN or CBD. A greater incidence of bridge formations, anaphase lags, micronuclei, and unequal segregations in bipolar divisions and multipolar divisions were observed in THC-treated lymphocytes, compared with the controls. However, only anaphase lags and unequal segregations in bipolar divisions reached statistically significant levels. It appears that THC affects the formation of microtubules and spindles and may be considered as a mitotic poison. The value of examining SE as a part of cytogenetic studies on chemical mutagens is emphasized. A description of a classification system of SE developed in our laboratory is also presented. This system can be applied to studies using both normal human lymphocyte cultures and lymphoid cell lines.

Adult↗
PubMed1980

Nitrous oxide availability.

Nitrous oxide (N2O) is marketed as an inhalation anesthetic and as a food ingredient (e.g., whipping cream propellant). In the human, inhalation has been associated with "highs," peripheral nerve damage, mitotic poisoning of bone marrow, psychosis, and mental impairment. Exposure to hypoxemic mixtures has resulted in death. The commercial N2O sources specifically studied were aerosol whipping cream containers (three brands) and 6.5-cm cylinders, or chargers (two brands). The gas content and N2O concentrations of these devices were measured. The aerosol cans, when not shaken, will dispense at least 3 liters of 87 to 90% N2O. Charger misuse may occur when they are substituted for identically designed carbon dioxide (CO2) chargers of a seltzer bottle; 4.3 to 5.0 liters of 93 to 98% N2O is expelled at a controllable rate. The toxicity of these inexpensive N2O products, their high potential for misuse, and the absence of labeling (chargers) argue that their distribution be discontinued.

Aerosols↗
PubMed1985

Potentiation of antitumor agents by calcium channel blockers with special reference to cross-resistance patterns.

The calcium channel blockers verapamil, diltiazem, nicardipine, and niludipine potentiated the antitumor activities of mitotic poison antitumor agents, such as vincristine, vinblastine, vindesine, VP16-213, and taxol in P388 leukemia cells resistant to vincristine. The potentiating effect was generally dependent on the extent of cross-resistance seen in the cell line for these drugs. Calcium channel blockers also potentiate the antitumor activities of several DNA-interacting drugs, such as adriamycin, THP-adriamycin, daunomycin, aclacinomycin A, mitomycin C, actinomycin D, mitoxantrone, and nogalamycin derivatives in P388 leukemia resistant to adriamycin. Greater potentiation was observed for those antitumor agents to which the ADM-resistant cell line had become markedly cross-resistant, with the exception of the nogalamycin derivatives. Only a two-fold enhancement was observed for mitomycin C and aclacinomycin, as the cell line was only weakly cross-resistant to these agents. These results suggest the potential for therapeutic gain through the use of calcium channel blockers in combination with classic chemotherapeutic agents.

Animals↗
PubMed1984

Antitubulin immunofluorescence studies of spermatogenesis in the mouse.

Immunofluorescence staining techniques, using antibodies against tubulin molecules, have been successfully used with somatic tissue culture cells. Their application to gametogenesis, however, has been more difficult, largely due to the presence of many different cell types in such a preparation. We have circumvented this problem by counterstaining with dilute hematoxylin, a biological stain that shows excellent cellular morphology without affecting the fluorescence of the antibody. We can then photograph the same field, using either ultraviolet light or conventional bright-field microscopy. Using this approach, we have examined the entire progression of murine spermatogenesis, from spermatogonial cells through mature spermatozoa. This technique has been especially valuable in the visualization of the manchette, and has allowed a reassessment of the staging of spermatid development. In the future, the antibody/hematoxylin double-staining approach will allow a more informative examination of the effects of tubulin-active mitotic poisons on mammalian germline cells.

Animals↗
PubMed1995

Induction of apoptosis in cultured retinoblastoma cells by the protein phosphatase inhibitor, okadaic acid.

The induction of apoptosis in cultured retinoblastoma cells by diverse drugs was examined by analyzing DNA fragmentation, a hallmark of apoptosis. First, the ability of six retinoblastoma cell lines to undergo apoptosis was surveyed using etoposide (30 micrograms/ml, 20 h exposure). The NCC-RbC-60 cell line, established in this laboratory showed DNA fragmentation clearly, whereas the other cell lines tested, including the representative retinoblastoma cell line, Y-79, did not show distinct DNA fragmentation. Biochemical modulators, such as A23187, forskolin, retinoic acid, phorbol 12-myristate 13-acetate and okadaic acid, were examined to ascertain whether they could induce apoptosis in NCC-RbC-60 and Y-79 cells after exposure for 20 h. Only okadaic acid induced DNA fragmentation in all the retinoblastoma cell lines tested and it induced DNA fragmentation in Y-79 cells in a time- and concentration-dependent manner. Flow-cytometric analysis and microscopic examination revealed that Y-79 cells treated with okadaic acid for 24-48 h accumulated at the G2/M, especially M, phases, before undergoing DNA fragmentation. Other mitotic poisons, nocodazole, colcemid and taxol, also induced apoptosis in Y-79 cells. In the K1034 cell line, established from non-malignant retinal pigmented epithelium, okadaic acid failed to induce both G2/M arrest and DNA fragmentation. These findings suggest that okadaic-acid-induced apoptosis occurs as a result of metaphase arrest.

Apoptosis↗
PubMed1984

Regulation of enzymes responsible for neurotransmitter synthesis and degradation in cultured rat sympathetic neurons. II. Regulation of 16 S acetylcholinesterase by conditioned medium.

The molecular forms of acetylcholinesterase (AcChE) have been studied in primary cultures of newborn rat sympathetic neurons grown either in the absence (CM- cultures) or in the presence (CM+ cultures) of muscle conditioned medium. The cultures were treated with a mitotic poison to eliminate non-neuronal cells. CAT activity increased with time in culture 4- to 20-fold faster in CM+ than in CM- cultures. In agreement with previous experiments (J.P. Swerts, A. Le Van Thaï, A. Vigny, and M.J. Weber, 1983, Develop. Biol. 100, 1-11), AcChE activity developed at a 3-fold lower rate in CM+ than in CM- cultures. This deficit in AcChE activity in CM+ cultures resulted from a deficit in the number of enzyme molecules immunoprecipitable with an antiserum raised against rat brain AcChE. In both types of cultures, AcChE forms were separated by sucrose gradient sedimentation into three main peaks corresponding to the 16 S and 10 S forms and a mixture of the 6.5 and 4 S forms. In 3-day-old CM+ and CM- cultures, the 16 S form represented 2% of the total activity. After 12-26 days, the percentage of 16 S form raised to 15-30% in CM- cultures, but remained lower than 5% in CM+ cultures. This difference was also observed when AcChE molecular forms were analyzed in the presence of protease inhibitors. A similar result was obtained by comparing cultures grown with and without a macromolecular factor partially purified from conditioned medium. These results suggest that an inverse relationship exists between the presence of 16 S AcChE and the presence of cholinergic synapses in these cultures.

Acetylcholinesterase↗
PubMed1977

Cytogenetic assays of chemical clastogens using mammalian cells in culture.

A protocol is described for cytogenetic assays of chemical mutagens using mammalian cells in vitro. The system employs continuous drug treatment (3 concentrations) for up to 8 h and recovery-cell populations after pulse treatments with a high dose. Both direct fixation (for recording spindle anomalies in anaphase) and colcemid-hypotonic fixation (for reading metaphase chromosome aberrations) are used in order to estimate the effects of an agent as a mitotic poison and as a clastogen respectively. Some DNA intercalating dyes (acridine orange, quinacrine mustard, neutral red) were found to be highly clastogenic whereas others (quinacrine dihydrochloride, 33258 Hoechst) are not.

Cell Line↗
PubMed1978

Cytogenetic toxicity of gentian violet and crystal violet on mammalian cells in vitro.

The cytogenetic toxicity of gentian violet in Chinese hamster CHO cells in vitro has been studied by analyzing (1) squash preparations from direct fixation for recording mitotic anomalies and (2) air-dried preparations (with colcemid--hypotonic pretreatments) for recording metaphase chromosome aberrations. It was concluded that this compound is a mitotic poison as well as a clastogen in vitro. Its clastogenic property was confirmed in 5 other different mammalian cel types. 10 samples of different gentian violet and crystal violet were surveyed and all were shown to be clastogenic. Unless in vivo studies prove otherwise, gentian violet and crystal violet should be regarded as biohazardous substances.

Animals↗
PubMed1982

Differential staining of chromosomes and spindle and its use as an assay for determining the effect of diethylstilboestrol on cultured mammalian cells.

A differential staining technique that allows for the simultaneous visualization of chromosome and spindle fibres has been used to investigate the action of diethylstilboestrol (DES) on cultured human fibroblasts. It was found that the mitotic index increased while spindle-fibre formation was inhibited with increasing DES concentration. Normal cellular division was severely affected by DES exposure in a dose-related manner. It has been demonstrated that this new staining technique may help to show up some mitotic poisons which are an important group currently missed by bacterial and clastogenic tests.

Cell Line↗
PubMed1998

Induction of apoptosis by gemcitabine in BG-1 human ovarian cancer cells compared with induction by staurosporine, paclitaxel and cisplatin.

A variety of chemotherapeutic agents induce cell death via apoptosis. We had shown previously that gemcitabine (2',2'-difluorodeoxycytidine) induced an atypical apoptosis in BG-1 human ovarian cancer cells; therefore, further studies were conducted to characterize more precisely gemcitabine-induced apoptosis in BG-1 cells compared to a general inducer of apoptosis, staurosporine. BG-1 cells exposed to 0.5, 1.0 and 10 microM gemcitabine for 8 h, or staurosporine (1.0 microM) for 6 h, exhibited high molecular weight DNA fragmentation (50 kbp); however, only staurosporine treatment produced internucleosomal DNA fragments (200 bp) in a laddered pattern on the agarose gel. Staurosporine (1.0 microM) rapidly induced phosphatidylserine plasma membrane translocation that increased linearly with time as measured by annexin V-FITC binding, and similar kinetics were observed for caspase activation by staurosporine in BG-1 cells. In contrast, 10 microM gemcitabine increased phosphatidylserine expression in a small fraction of cells (5-10%) vs. untreated controls over the course of 48 h and significant caspase activity was detected within 12 h of drug exposure. Time-lapse video microscopy of BG-1 cells exposed to 1.0 microM staurosporine or 10 microM gemcitabine for up to 72 h showed that the morphologic changes and kinetics of cell death induced by these agents differed significantly. We also evaluated the apoptosis induced by paclitaxel (a mitotic poison) and cisplatin (an agent not dependent on cell cycle functions) in BG-1 cells by these methods because these drugs are used clinically to treat ovarian cancer. Our findings demonstrate that the kinetics of apoptotic cell death induced by gemcitabine and other chemotherapeutic agents should be taken into account when designing treatment strategies for ovarian cancer.

Journal Article↗
PubMedDate not supplied

[Familial Mediterranean fever].

Familial Mediterranean Fever is a genetically determined disease occurring predominantly in Arabs, Armenians, Jews and very rarely in Turks. It is characterized by moderately elevated body temperature and by abdominal, pulmonary or arthritic complaints. These symptoms are recurrent appearing at short intervals and persisting for not more than two days. Renal amyloidosis may be a complication. Thus, treatment should be continued for life. The pathomechanism of the disease is not clear. Colchicine has been shown to give good symptomatic relief. Surprisingly, the prolonged use of this mitotic poison is virtually devoid of untoward side effects, even in pregnancy and childhood.

Adult↗
PubMed1996

A conditional lethal mutant in the fission yeast 26 S protease subunit mts3+ is defective in metaphase to anaphase transition.

We have isolated a conditional lethal mutant mts3 in the fission yeast Schizosaccharomyces pombe which at the permissive temperature is resistant to the mitotic poison MBC and at the restrictive temperature is defective in metaphase to anaphase transition. The predicted amino acid sequence of mts3+ is 36% identical with the budding yeast gene NIN1. NIN1 cloned into a fission yeast expression vector can rescue both mts3 temperature-sensitive and null alleles demonstrating that NIN1 is the budding yeast homologue of the fission yeast mts3+ gene. The phenotype of the mts3 null is identical with the mts3 ts mutant demonstrating that the phenotype of the mts3 ts mutant is due to loss of mts3+ function. The deduced amino acid sequences of both mts3+ and NIN1 show homology to peptide sequences obtained from subunit 14 of the 26 S protease purified from bovine or human cells.

Amino Acid Sequence↗