Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tubulin Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 145 records · Page 8Linked to original sources
PubMed1995

Azatoxin derivatives with potent and selective action on topoisomerase II.

Azatoxin was rationally designed as a DNA topoisomerase II (top2) inhibitor [Leteurtre et al., Cancer Res 52: 4478-4483, 1992] and was also found to inhibit tubulin polymerization. Its cytotoxicity is due to action on tubulin at lower concentrations and on top2 at higher concentrations. At intermediate concentrations, the combination of the two mechanisms appears antagonistic [Solary et al., Biochem Pharmacol 45: 2449-2456, 1993]. The aim of this study was to design azatoxin derivatives that would act only on tubulin or on top2. Selective targeting of top2 or tubulin was tested using top2-mediated DNA cleavage assays, and tubulin polymerization and tubulin proteolysis assays, as well as COMPARE analyses of cytotoxicity assays in the National Cancer Institute in vitro Drug Screening Program. Selective inhibitors of top2 and tubulin polymerization have been obtained. Top2 inhibition, abolished by methylation at position 4', was enhanced by the addition of a bulky group at position 11. Bulky substitution at position 11 determined different patterns of top2 cleavage sites and suppressed the action on tubulin. Selective inhibition of tubulin was obtained with 4'-methylazatoxin that was found to bind to the colchicine site. These results are consistent with those obtained in the podophyllotoxin family to which azatoxin is structurally related. Some azatoxin derivatives are under consideration for further preclinical development.

Antineoplastic Agents↗
PubMed1985

Effect of the antitubulin drug nocodazole on meiosis and postmeiotic development in Tetrahymena thermophila. Induction of achiasmatic meiosis.

Nocodazole (ND), a potent antitubulin drug, can be used to dissect the steps of meiosis in Tetrahymena, presumably by interfering with the assembly of microtubules. Its effects depend upon the time during conjugation at which the drug is applied. When applied prior to the elongation of the micronucleus into the characteristic 'crescent' configuration, no crescent is formed and the chromosomes of prepachytene and pachytene condense into spherical nuclei. If ND is applied after micronuclear elongation has begun, but before it is fully elongated, the chromosomes fail to synapse and appear in metaphase I as unpaired monovalents. In contrast, the metaphase I chromosomes appear as bivalents when ND is applied later, during or after the crescent has reached its maximum elongation. Still later, application of ND inhibits chromosome movements during anaphase and telophase of either meiotic division, but does not prevent separation of kinetochores. In some of the blocked restitutive nuclei an additional round of chromosome replication occurs, corresponding to the third pregamic division in normal conjugation. The hyperploid micronuclei produced by such treatment may be useful in certain genetic manipulations and in studying the regulation of nuclear DNA content.

Animals↗
PubMed1986

Effects of colchicine on cardiac cell function indicate possible role for membrane surface tubulin.

The effects of the tubulin-binding drug colchicine on cultured neonate cardiac cell function were investigated. Application of low doses of colchicine (but not lumicolchicine) caused an early reversible increase in beating rate with a concomitant decrease in amplitude. Treatment of the cells with trypsin at a dose that removes surface tubulin but does not inhibit spontaneous beating, diminished the colchicine effect. Surface radio-iodination of the live cultures followed by two-dimensional gel electrophoresis and radioautography revealed that two spots were heavily labeled. These spots co-migrated with purified brain tubulin. Fibroblasts derived from the cardiac cultures did not label over the tubulin spots. Trypsin treatment removed the presumptive tubulin from the radioautographs but only removed the most basic portion of the alpha-tubulin spot from the stained gel. These results are consistent with a surface membrane role for an iso-form of tubulin in neonate cardiac cells.

Animals↗
PubMed1995

Interaction of cryptophycin 1 with tubulin and microtubules.

The cryptophycins are newly discovered antimitotic agents isolated from the cyanobacterium Nostoc. Previous studies using cultured cells demonstrated that microtubules are the target of these compounds. We have studied the interaction of cryptophycin 1 with tubulin and microtubules in vitro. Cryptophycin 1 is an effective inhibitor of tubulin polymerization, causes tubulin to aggregate, and depolymerizes microtubules to linear polymers somewhat similar to the spiral-like structures produced by the Vinca alkaloids. Cryptophycin 1 also inhibits vinblastine binding to tubulin but not colchicine binding. Thus, it appears that the cryptophycins may bind to the Vinca site in tubulin or to a site that overlaps with the Vinca site.

Animals↗
PubMed1985

Aprotic polar solvents inducing chromosomal malsegregation in yeast interfere with the assembly of porcine brain tubulin in vitro.

A number of aprotic solvents which had previously been found to induce mitotic aneuploidy in yeast were tested for their effects on re-assembly of twice recycled tubulin from pig brain. Some of the solvents which were strong aneuploidy-inducing mutagens in yeast slowed down tubulin assembly in vitro at concentrations lower than those required for aneuploidy induction. Ethyl acetate, methyl acetate, diethyl ketone and acetonitrile fell into this category. Other strong aneuploidy-inducing agents like acetone and 2-methoxyethyl acetate accelerated tubulin assembly. Non-genetically active methyl isopropyl ketone and isopropyl acetate both accelerated assembly, whereas methyl n-propyl ketone and n-propyl acetate were weak inducers of aneuploidy and slowed down the rate and extent of assembly. Those chemicals which slowed down the assembly rate also reduced the extent of assembly. Most chemicals which accelerated assembly also led to an increased extent of assembly, with the exception of isopropyl acetate. At the higher concentrations, however, a maximum assembly rate was reached which was followed by a slow decline. Although a perfect correlation between effects on the induction of chromosomal malsegregation and the interference with tubulin assembly in vitro was not seen, the experiments with tubulin were carried out using this class of chemicals because some of them strongly induced mitotic aneuploidy under conditions which suggested tubulin to be the prime target. The lack of a perfect coincidence might be due to species differences between the porcine brain and the yeast spindle tubulin, or the test for aneuploidy induction may have been negative because the concentrations required for an effect on yeast tubulin may be greater than the general lethal toxicity limit. Bearing this reservation in mind, the results suggest that the yeast aneuploidy test has a considerable predictive value for mammalian mutagenicity.

Acetates↗
PubMed1984

Induction of aneuploidy by oncodazole (nocodazole), an anti-tubulin agent, and acetone.

Oncodazole (nocodazole) is a compound which interacts with yeast and bovine tubulin. We have shown that it induces aneuploidy in the yeast Saccharomyces cerevisiae at very low concentrations. In the course of a search for an appropriate solvent for oncodazole we observed that acetone also induces mitotic aneuploidy in yeast. This effect of acetone was greatly enhanced when the treatment of growing cells at 28 degrees C was interrupted by a period of holding at ice-bath temperature.

Acetone↗
PubMed1984

Inhibition of tubulin polymerization with ribose-modified analogs of GDP and GTP. Reduced inhibition with microtubule-associated proteins and magnesium.

Inhibitory effects of ribose-modified GDP and GTP analogs on tubulin polymerization were examined to explore nucleotide structural requirements at the exchangeable GTP binding site. With microtubule-associated proteins and Mg2+, GTP-supported polymerization was only modestly inhibited by GDP, and still weaker inhibitory activity was found with two analogs, dGDP and 9-beta-D-arabinofuranosylguanine-5'-diphosphate (araGDP). Omission of Mg2+ significantly enhanced the inhibitory effects of GDP, dGDP and araGDP and resulted in weak inhibition of the reaction by several other GDP analogs. The relative inhibitory activity of the GDP analogs had no discernible relationship to the relative activity of cognate GTP analogs in supporting microtubule-associated protein-dependent polymerization. One GTP analog, 2',3'-dideoxyguanosine 5'-triphosphate (ddGTP), supports polymerization both with and without microtubule-associated proteins. The inhibitory activity of GDP and GDP analogs in ddGTP-supported polymerization was much greater in the absence of microtubule-associated proteins than in their presence; and both reactions were more readily inhibited than was microtubule-associated protein-dependent, GTP-supported polymerization. Microtubule-associated protein-independent, ddGTP-supported polymerization was also potently inhibited by GTP and a number of GTP analogs. GTP was in fact twice as inhibitory as GDP. The relative inhibitory activity of the GTP analogs was comparable to the relative inhibitory activity of the cognate GDP analogs and very different from their relative activity in supporting polymerization.

Animals↗
PubMed1995

Infection of cultured rat enterocytes by Ileal symbiont intracellularis depends on host cell function and actin polymerisation.

The mechanisms of entry of Ileal symbiont intracellularis into IEC-18 rat enterocyte cells and subsequent bacterial proliferation were examined in centrifuge-assisted and static infections. Live, oxygen or neomycin damaged, and formalin killed bacteria, each rapidly entered viable cells. Live or damaged bacteria did not enter cells nor proliferate within cells after static infection of cells cooled to 5 degrees C. Infection of cells was greatly reduced at 20 degrees or 32 degrees compared to infection at 37 degrees C. Centrifuge-assisted infection was also reduced by chilling the cells. Cytochalasin D but not B inhibited the entry process indicating an actin-dependent infection, although other pathways may also be involved in centrifuge-assisted infections. Drugs capable of modifying cell membrane charge, heparin receptors or trypsin-labile proteins were all inactive in preventing or enhancing infection. We therefore conclude that infection of enterocytes by IS intracellularis is dependent on host cell activity and actin polymerization, but is independent of bacterial viability.

Actins↗
PubMed1996

Camptothecin and taxol: from discovery to clinic.

Camptothecin (CPT) and taxol are secondary metabolites found in the stembark of Camptotheca acuminata, a native of China, and Taxus brevifolia, found in the northwest Pacific coastal region of the USA, respectively. The compounds were isolated through bioassay-guided fractionation of various extracts and through chromatographic fractions. Their unique and hitherto unknown structures were elucidated by nuclear magnetic resonance, mass spectrometry and X-ray analysis. Both compounds have unique mechanisms of antitumor activity; CPT uniquely inhibits an enzyme, topoisomerase I, involved in DNA replication, while taxol binds to a protein, tubulin, thus inhibiting cell division. Taxol has been called the best new anticancer agent developed from natural products, showing particular efficacy against ovarian cancer. CPT and analogs singly or combined with cisplatinum show efficacy against solid tumors, breast, lung, and colorectal, which hitherto have been unaffected by most cancer chemotherapeutic agents.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Computational and molecular modeling evaluation of the structural basis for tubulin polymerization inhibition by colchicine site agents.

The computer-automated structure evaluation programs MultiCASE and CASE were used to perform a quantitative structure-activity relationship study on tubulin polymerization inhibitors. A learning set of 536 chemicals (202 active. 27 marginal, and 307 inactive), built using IC50 values for inhibition of tubulin polymerization or mitosis from this and previous studies, was used for artificial intelligence self-teaching. The algorithms successfully predicted the activity of agents in the learning set with > 90% accuracy. Seventeen MultiCASE and twelve CASE (mostly included in the MultiCASE set) biophores (substructures significantly correlated with activity) were identified with a probability > 0.95. Here we present the biophores of podophyllotoxins, colchicinoids, and certain combretastatins, each examined for structure-activity relationships. For the podophyllotoxins and colchicinoids in the learning set, the correlations between observed and predicted potencies were > 0.85. The algorithms recognized the importance of several known site, electronic, and steric effects in the two classes. A predictive QSAR (R2 = 0.98) was developed for combretastain A-2 and dihydrocombretastatin analogues. The MultiCASE/CASE analyzes were used in combination with molecular models to study relative orientations of colchicine, podophyllotoxin, combretastatin A-4, and steganacin at the colchicine site. This resulted in a new hypothesis, consistent with extensive published experimental data, in which the C-ring and part of the B-ring of colchicine overlap with the A- and B-rings of podophyllotoxin. Consequently, the trimethoxyphenyl rings of colchicine and podophyllotoxin occupied different regions of space, each pointing out from a hydrophobic 'core' occupied by the overlapping biophores. The molecular model of the highly potent combretastatin A-4 could fit into the model binding site in at least three different ways. The developed QSARs were used to identify the potent microtubule stabilizer discodermolide. Its identification, in concert with recently reported findings, suggest potential overlap in the colchicine and paclitaxel binding sites on tubulin.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Polymer-based paclitaxel-eluting stents are superior to nonpolymer-based paclitaxel-eluting stents in the treatment of de novo coronary lesions.

Although polymer coating of coronary stents enables sufficient loading and release of incorporated drugs, it has also been associated with potentially negative effects. This study compared the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with polymer- versus nonpolymer-based paclitaxel-eluting stents (PESs). Sixty-five consecutive patients (70 de novo lesions) treated with polymer-based PESs (TAXUS, 1 microg/mm2 of paclitaxel; Boston Scientific Corp.) and 65 consecutive patients (65 de novo lesions) treated with nonpolymer-based PESs (V-Flex Plus, 2.7 microg/mm2 of paclitaxel; Cook, Inc.) were enrolled in the study. Six-month angiographic follow-up was performed on 54 lesions of the polymer-based PES group and 51 lesions of the nonpolymer-based PES group. IVUS at angiographic follow-up was performed in 61 of the first 70 included lesions. At 6-month IVUS follow-up, mean intimal hyperplasia cross-sectional area was 2.36 +/- 1.60 mm2 in the nonpolymer-based PES group versus 0.62 +/- 0.41 mm2 in the polymer-based PES group (p = 0.003). Implantation of polymer-based PESs resulted in significantly lower in-stent late lumen loss (0.22 +/- 0.27 vs 0.74 +/- 0.61 mm, respectively, p <0.001). In-stent binary restenosis rate was 5% versus 20%, respectively (p <0.001). Target lesion revascularization rate was 9% after implantation of polymer-based PES versus 18% (p = 0.128) after implantation of nonpolymer-based PES, and the major adverse cardiac event rate was 9% versus 23%, respectively (p = 0.032). In conclusion, polymer-based PESs result in superior angiographic and IVUS follow-up findings compared with nonpolymer-based PESs.

Coronary Angiography↗
PubMed2006

Twelve-month outcomes with a paclitaxel-eluting stent transitioning from controlled trials to clinical practice (the WISDOM Registry).

The WISDOM Registry tracked clinical outcomes in patients receiving a slow-release, polymer-based, paclitaxel-eluting stent during the transition from randomized trials to commercial use in everyday interventional cardiology practice. Although randomized trials of drug-eluting stents have demonstrated the safety and effectiveness of these devices in less complicated, de novo lesions, observation of long-term clinical outcomes is required to monitor safety as use of this revolutionary technology expands to broader patient populations. In total, 778 patients were enrolled at 22 sites in 9 countries where the TAXUS paclitaxel-eluting stent first received market approval. Patients with de novo or restenotic coronary lesions eligible for stenting were enrolled. Clinical follow-up was conducted by telephone at 3, 6, 9, and 12 months after the procedure to capture reported stent thrombosis and major cardiac events (death, myocardial infarction, and reintervention on the target lesion). Clinical follow-up at 12 months was completed for 92% of patients. The 12-month rate of physician-reported major cardiac events was 5.2%, with a target lesion reintervention rate of 2.0%. The low overall stent thrombosis rate of 0.6% included no stent thromboses >30 days after the index procedure. Low target lesion reintervention rates were also observed in the high-risk subgroups: patients with diabetes (4.0%), vessels <2.5 mm (2.5%), lesions >20 mm (3.6%), and multiple stents in a lesion (1.4%). In conclusion, the paclitaxel-eluting TAXUS slow-release stent exhibits long-term safety and efficacy in uncomplicated and higher risk patients and lesions seen in everyday clinical practice.

Coronary Disease↗
PubMed2005

[Drug eluting stents in 2005: have the initial expectations been met?].

Drug eluting stent is a new technology aimed to prevent the development of neointimal hyperplasia and restenosis following percutaneous coronary intervention. This review describes the direction for their use at the present time and the future of their utilization with the summary of the principals clinicals trials.

Angioplasty, Balloon, Coronary↗