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PubMed2005

[Lectin and mitotic activities in root meristems of winter wheat under oryzalin effect].

The effect of oryzalin, a microtubule polymerization inhibitor (10 MM), on lectin and mitotic activities (mitotic index and duration of mitotic phases) was studied in unhardened (23 degrees C) and hardened (7 days, 2-3 degrees C) winter wheat seedlings. Three wheat cultivars differing in their frost tolerance were compared. Oryzalin treatment (3 h) decreased activity of soluble lectins, increased activity of cell wall lectin mitotic index. Under these conditions, prolongation of anaphases and disappearance of telophases were detected. Plant hardening reduced the sensitivity of cell wall lectins and mitotic activity to the cytoskeleton inhibitor due, presumably, to the appearance of cold-stable microtubules. Plant growing and hardening with oryzalin stopped mitoses and caused the appearance of polyploid cells and cells with micronuclei. These abnormalities were preserved after hardening. The results obtained demonstrate an important role of microtubules in adaptation of plants to low temperature.

Adaptation, Physiological↗
PubMed2006

Current development status of small-molecule vascular disrupting agents.

There is increasing interest in small-molecule drugs that can selectively disrupt the abnormal vasculature associated with disease processes such as cancer and macular degeneration. These agents are distinct from anti-angiogenic strategies, which do not target existing vessels but prevent additional vessel growth, althouglh they may potentially be complimentary with these antiangiogenic strategies. Several vascular disrupting agents (VDAs) are now undergoing clinical evaluation. The main focus of research has been on two drug classes: the first is comprised of agents that bind reversibly with tubulin and prevent microtubule assembly; the second are the flavanoids, which can induce intratumor cytokine release. Data from phase I studies have established that these agents can selectively reduce tumor blood flow at well-tolerated doses. Preclinical data indicate that VDAs can improve the tumor response to cytotoxic chemotherapy, radiation and antiangiogenic treatments. This activity has been attributed to the ability of these agents to selectively destroy the central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. The VDA compounds combretastatin A4 phosphate (CA4P) and 5,6-dimethylxantlenone-4-acetic acid (DMXAA) are being evaluated in phase II clinical trials in combination with conventional cytotoxic therapies for the potential treatment of cancer. This review discusses the small-molecule VDAs in clinical development. In addition, the potential for combination therapy with VDAs and traditional anticancer therapies, such as radiation, chemotherapy and anti-angiogenics is described.

Angiogenesis Inhibitors↗
PubMed2006

Current chemotherapeutic approaches for androgen-independent prostate cancer.

This review describes the current state of chemotherapy for androgen-independent prostate cancer. Landmark clinical trials, including TAX 327, a randomized trial comparing docetaxel and prednisone with mitoxantrone and prednisone, and SWOG 9916, a randomized clinical trial comparing docetaxel and estramustine with mitoxantrone and prednisone, are reviewed. Novel combination therapies, involving taxane administered with compounds such as calcitrol and thalidomide, newer cytotoxic agents, vaccine therapies, and targeted modalities are also detailed. This review mainly focuses on agents with activity in phase II/III clinical trials.

Antibodies, Monoclonal↗
PubMed2006

Drug evaluation: STA-4783--enhancing taxane efficacy by induction of Hsp70.

The apoptosis stimulator STA-4783 acts by inducing expression of heat shock protein (Hsp)70 on tumor cell surfaces and disrupting the cytoskeletal network. Currently in development by Synta Pharmaceuticals for the potential treatment of solid tumors, phase II clinical trials in non-small-cell lung cancer, melanoma and sarcoma have been initiated.

Animals↗
PubMedDate not supplied

Dermatological toxicity of ixabepilone.

Ixabepilone is a new class of non-taxane microtubule-stabilizing agents. These agents bind tubulin, stabilize microtubules and, thus, block mitosis and result in cell death (1-8). In phase I studies, neutropenia was the only grade 4 toxicity while fatigue, anorexia and mucositis occurred as grade 3 toxicities. Neuropathy, myalgia, arthralgia, alopecia and gastro-intestginal toxicities also occurred at grades 1 and 2. No dermatological effects have been documented to date. Here, a case is reported of a 62-year-old woman with stage 4 breast cancer being treated with Ixabepilone (40 mg/m2) who developed a dermatological reaction not previously described as a toxicity from Ixabepilone therapy.

Breast Neoplasms↗
PubMed2006

Clinical evidence on polymer-based sirolimus and paclitaxel eluting stents.

Percutaneous coronary interventions with the use of stents have become the mainstay treatment of patients with various clinical manifestations of coronary artery disease. Despite their remarkable success, restenosis has remained the major drawback and its prevention has absorbed intensive experimental and clinical research work. After the failure of multiple efforts with systemic use of various drugs, local application of antiproliferative and anti-inflammatory agents released by specially designed coated stents led to considerable suppression of neointima and opened new prospects in the prevention of restenosis. An increasing body of evidence is showing the advantages provided by drug-eluting stents (DES) in almost all subsets of patients with coronary artery disease with a drastic decrease in the need for reintervention. To date, the most commonly used and the only US Food and Drug Administration (FDA) approved DES are a sirolimus-eluting stent (Cypher) and a paclitaxel-eluting stent (Taxus), both of which are polymer-based DES and will constitute the focus of this review. Recent data demonstrate that DES are not equal in their safety and efficacy. A less optimistic aspect of DES technology are the reiterated concerns about a more prolonged risk of stent thrombosis. Although all agree on the need of a longer duration of dual antiplatelet therapy in patients treated with DES, its optimal length is still to be defined. Because polymers used for stent coating are often seen at the origin of the compromised long-term safety of DES, new technologies able to avoid permanent polymers may offer a valuable alternative.

Combined Modality Therapy↗
PubMed2006

How to treat diabetic patients with multivesseal disease in the DES era.

Patients with type 2 diabetes mellitus represent the 25% of those requiring myocardial revascularization. Choice of treatment in diabetic patients is much more controversial than in non-diabetics: this because coronary artery disease is more often complex and diffuse, left ventricular function is depressed, and concomitant multiple risk factors are present. These subset of patients experience worse outcomes than non diabetic patients undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary interventions (PCI). Large randomized trials performed both in the early era of PCI and in the stent era suggest that CABG is superior to bare metal stent implantation in the treatment of diabetic patients with multivessel coronary artery disease. These findings are reflected in current guidelines, which favor CABG over PCI in most diabetics who require revascularization. However, substantial variability exists in practice patterns among individual hospital, suggesting a lack of clinical consensus. The major advantage of CABG over bare metal stent implantation in diabetic patients is the lower risk of repeat revascularization procedures through the follow-up. Better angiographic results have been demonstrated in the new era of drug-eluting stents (DES). Data from both the sirolimus and paclitaxel-eluting stents trials support the potential advantage of DES implantation both in diabetic and non-diabetic patients. Preliminary data from studies comparing DES versus CABG in diabetic patients with multivessel coronary artery disease suggests that 1) no significant difference exists in the 12-month rate of death, myocardial infarction and cerebrovascular events in patients treated with DES as compared to off-pump bypass surgery, 2) a difference of 7.1% in the rate of repeat revascularization at 12-month exists in favor of bypass surgery and 3) diabetic retinopathy identifies a subgroup with poor outcome after both percutaneous and surgical myocardial revascularization.

Combined Modality Therapy↗
PubMedDate not supplied

Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents.

OBJECTIVE: Regular colchicine treatment cannot control the typical febrile attacks of FMF in about 5-10% of the compliant patients. Here we report the effect of thalidomide and etanercept in 5 colchicine-resistant cases. METHODS: Five (4M/ 1F) FMF patients between April 2005 and March 2006, who were experiencing at least 2 attacks per month, despite regular colchicine were included to the study. Four male patients were given thalidomide 100 mg/d initially. Two of these patients unresponsive to thalidomide were prescribed subcutaneous injections of etanercept 25 mg, twice a week. The female patient received etanercept as the first choice due to potential side effects. She then had to be converted to thalidomide due to a severe injection site reaction. RESULTS: The median follow up period with thalidomide and etanercept was 8 months. Both thalidomide and etanercept lowered the number of the abdominal attacks. CONCLUSION: Thalidomide and etanercept might be effective as additional treatment in colchicine-resistant cases of FMF.

Adult↗
PubMedDate not supplied

[Antimicrotubule agents can activate different apoptotic pathways].

The effect of agents (taxol, vincristine, and nocodazole) disturbing the microtubule network in MCF-7 human breast carcinoma cells has been examined. The aim of the study was to determine the subtypes of mitotic catastrophe and the dependence of cell death on the status of protein p53. Antimicrotubule agents can not only induce mitotic catastrophe, that is, cell death during mitosis and the death of micronucleated cells, but also activate apoptosis in interphase cells. We assume that the G1 checkpoint activation in this case occurs as a result of microtubule disruption. Apoptosis can be activated in a p53-independent manner in K-mitotic cells and after the complete disruption of the microtubule network.

Apoptosis↗
PubMed1991

Temperature dependence of prolactin endocytosis and casein exocytosis in epithelial mammary cells.

As previously reported in epithelial mammary cells of lactating rabbit, prolactin exerts a stimulatory effect on casein secretion. After binding to a membrane receptor, the complex hormone-receptor is internalized in mammary cells. Peptide hormone action involves the generation of second messengers. These second messengers can be emitted as soon as hormone is linked to the membrane receptor. However, it is not excluded that endocytosis and transfer of prolactin inside the cell take part in the emission of second messenger and related secretory response. In order to precise intracellular transport pathways in the lactating mammary cell, we have examined the effects of reduced temperature on the one hand on prolactin endocytosis, on the other hand on casein secretion and on the stimulating effect of prolactin on casein secretion. Endocytosed prolactin was cytochemically localized mainly on the plasma membrane at 4 degrees C. At 25 degrees C, the hormone accumulated, during 60 min, in endosomes and multivesicular bodies. At 37 degrees C, prolactin was detectable after 15 and 30 min inside the cells and disappeared after 60 min. Transport and exocytosis of secretory proteins were only partly inhibited at 25 degrees C as attested by autoradiography localization and biochemical assays of newly synthesized caseins. However, at 25 degrees C, prolactin was no more able to stimulate casein exocytosis. These results show that intracellular transport of prolactin and secretagogue effect of the hormone does not proceed at 25 degrees C. However, secretory mechanisms of the cell are always able to be stimulated by exogenous arachidonic acid at this temperature. Low temperature appears as a good means to study intracellular transport in the mammary cell.

Animals↗
PubMed1990

Effect of anticalmodulin and antitubulin on LDL-receptor synthesis in aortic smooth muscle cells cultured in vitro.

Effect of trifluoperazine and colchicine on LDL-receptor synthesis in smooth muscle cells exposed to hypercholesterolemic medium in vitro have been studied. While trifluoperazine at 25 microM concentration caused stimulation of LDL-receptor synthesis, colchicine acted as a dose-dependent inhibitor of LDL-receptor synthesis. Thus calmodulin down regulates LDL-receptor synthesis independent of microtubular involvement.

Animals↗
PubMed1989

Tubulin-dependent hydrolysis of guanosine triphosphate as a screening test to identify new antitubulin compounds with potential as antimitotic agents: application to carbamates of aromatic amines.

Tubulin-dependent GTP hydrolysis was evaluated for its potential as a relatively simple screening assay for new antimitotic drugs. Carbamates of aromatic amines were chosen as the test system because of the relatively diverse structures of compounds in this class already known to have antimitotic properties and because of the large number of such compounds in the NSC collection of the National Cancer Institute. Of 162 compounds evaluated, significant alterations in the GTPase reaction were observed with 26 agents. Sixteen of these had substantial inhibitory effects on tubulin polymerization (true positives), while ten did not (false positives). There were no false negatives (i.e., no agent inactive in the GTPase assay inhibited tubulin polymerization). The true positives were examined for effects on cell growth and mitosis, and four compounds had 50% inhibitory concentration values of 2 microM or less with L1210 murine leukemia cells. All four caused the accumulation of cells in metaphase arrest. We conclude that tubulin-dependent GTP hydrolysis can be used effectively to select new antitubulin compounds with potential as antimitotic agents from a large group of compounds of unknown activity.

Antineoplastic Agents↗
PubMed1988

Induction of multiple germ tubes in Neurospora crassa by antitubulin agents.

The antitubulin fungicide benomyl suppressed the linear growth of Neurospora crassa wild type strain St. Lawrence 74 at micromolar concentrations. The rate of germination of macroconidia was not affected. Macroconidia exposed to 1.7 microM benomyl for 5 h formed multiple germ tubes. When germlings incubated for 4 h were exposed to 1.7 microM benomyl for 3 h, their germ tube stopped growing, swelled and emitted several branches. Normal linear growth was restored after removal of the fungicide. Linear growth of N. crassa was resistant up to 16 microM nocodazole. This drug induced multipolar germination at 8 microM, and griseofulvin only at 140 microM. The microtubule (MT) cytoskeleton of N. crassa could be revealed by indirect immunofluorescence with the monoclonal antibody YOL 1/34 directed against yeast alpha-tubulin. We detected no striking effects of the benomyl treatments on MT organization. The MT-stabilizing agents deuterium oxide (D2O) and cAMP have no antagonistic effects on the benomyl-induced multipolar germination. The positioning of nuclei and mitochondria was determined from the DAPI and Rhodamine 123 fluorescence patterns, respectively. Benomyl inhibited nuclear migration into multiple germ tubes. Quantitative scanning cytophotometry revealed a peak in the intensity of the mitochondria-associated Rhodamine 123 fluorescence near the apex of untreated germlings. This peak disappeared in multiple germ tubes. Benomyl-resistant mutant bml 511 (r), mutated in its beta-tubulin gene, germinated normally in the presence of the fungicide. This strongly suggests that multiple germ tube formation was due to the effect of benomyl on beta-tubulin. Benomyl-resistant strain 74-3, constructed by reintroducing the cloned mutant N. crassa beta-tubulin gene into the cells by transformation, displayed a partial resistance to benomyl with respect to multipolar germination. Its rate of germination was slow (50% germination reached after 4 h at 37 degrees C as compared to 2.5 h for the wild type). In contrast to N. crassa, the other ascomycete Aspergillus nidulans is nocodazole-sensitive (linear growth suppressed at 1.6 microM). It did not respond to the MT inhibitors benomyl and nocodazole with respect to the pattern of germ tube emergence. Our results suggest that microtubule or membrane beta-tubulin is involved in the maintenance of developmental polarity during germ tube emergence and growth of N. crassa.

Benomyl↗
PubMed1986

Inhibition of microtubule formation by uremic toxins: action mechanism and hypothesis about the active component.

We show in vitro inhibitory effect of a mixture of uremic toxins on tubulin 6S polymerization. It proves the existence of a direct interaction protein-toxin where micro-tubule associated proteins are not involved. A similar phenomenom could occur in uremic neuropathy. The action mechanism of this interaction is quite different from that of classical tubulin inhibitors: Vinca alcaloïdes and colchicine. Finally we hypothesize about the active molecule.

Animals↗
PubMed1977

Antimitotic and antitubulin activity of the tumor inhibitor steganacin.

Steganacin, a newly isolated tumor inhibitor, completely inhibits cleavage in sea urchin eggs at 3 X 10(-7) M by preventing the formation of the mitotic apparatus. Steganacin inhibits the polymerization of tubulin in vitro and also causes a slow depolymerization of preformed microtubules. Optical ultracentrifuge studies of steganacin-treated tubulin show a small reduction in 20 S and 30 S peaks at 0 degree. In electron microscope studies the ring structure of tubulin is seen at 0 degree but disappears if the temperature of tubulin incubated with steganacin is raised to 37 degrees. Steganacin inhibits the binding of colchicine to tubulin and thus resembles podophyllotoxin, which also competitively inhibits colchicine binding. Steganacin had a trimethoxybenzene ring and probably interacts with that portion of the colchicine-binding site that recognizes the trimethoxybenzene ring of colchicine.

4-Butyrolactone↗
PubMed1981

Inhibition of tubulinyl-tyrosine carboxypeptidase by brain soluble RNA and proteoglycan.

Rat brain extracts contain two heat-stable, nondialyzable inhibitors of tubulinyl-tyrosine carboxypeptidase. One of the inhibitors was sensitive to ribonuclease and insensitive to trypsin and pronase, indicating that the inhibitor is RNA. This is supported by the observation that purified RNA from rat brain inhibited the enzyme activity to the same extent as similar amounts of the endogenous RNA. Similar results were obtained with calf liver RNA. The other inhibitor was purified by chromatography on a DEAE-Sephadex and identified as proteoglycan. The elimination of the protein moiety of the proteoglycan resulted in a small increase of its inhibitory activity. Glycosaminoglycan was released from the proteoglycan by beta elimination, indicating that the linkage between glycosaminoglycan and the protein moiety is through an O-glycosidic bond. The glycosaminoglycan contains uronic acid, hexosamine and sulfate in a molar ratio of 1:1.01:0.99, respectively. Treatment of the glycosaminoglycan with chondroitinase ABC completely abolished its inhibitory activity. Chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, and the brain glycosaminoglycan inhibited tubulinyl-tyrosine carboxypeptidase to the same extent when used in comparable amounts.

Animals↗