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Colchicine and antineoplastic therapy for the prevention of restenosis after percutaneous coronary interventions.

The complexity of the events that culminate in intimal proliferation after arterial injury and similarities between this response and benign neoplasia suggest that conventional medical therapies will continue to be unsuccessful in preventing recurrent stenosis after percutaneous coronary revascularization. By preventing cell division after smooth muscle cell activation, antimitogenic therapy may inhibit the final common pathway in this complex chain of events and offset the apparent loss of local growth control. Colchicine, which causes metaphase arrest of cell division, has been shown in experimental studies to decrease the extent of atheromatous plaque formation and reduce the severity of arterial restenosis after balloon angioplasty. However, preliminary results from a randomized placebo-controlled clinical trial suggest that low dose colchicine (0.6 mg twice a day orally) does not prevent restenosis. The use of more potent antineoplastic agents is limited by the potential for life-threatening side effects. It is possible that these adverse effects can be averted by using novel drug delivery systems to administer antimitogenic therapy locally at the site of arterial injury or by using low dose synergistic combinations of antiproliferative agents. This review examines the potential role of antimitogenic therapy in the prevention of restenosis after coronary interventions and considers the possibility of an overlap of the therapeutic realms of interventional cardiology and medical oncology.

Angioplasty, Balloon, Coronary↗

Effect of colchicine and vinblastine on identified leech neurons.

An identified neuron of the leech central nervous system is affected by the application of colchicine or vinblastine to its axon. It develops characteristic changes of membrane electrical properties, which are similar to those observed after surgical axotomy. The ionic mechanisms associated with the impulses induced by axotomy and colchicine treatment are not equivalent.

Animals↗

Dentate gyrus-selective colchicine lesion and performance in temporal and spatial tasks.

The effects of multiple-site, intradentate, colchicine injections on the performance of a temporal, 'differential reinforcement of low rates of responding' (DRL-20s) task and a spatial, 'delayed non-matching-to-place' (DNMTP) task in a plus-maze were investigated in rats trained in both tasks prior to the lesion. Quantitative analysis revealed a greater than 86% reduction in the dentate gyrus (DG) of the colchicine-injected rats compared to the sham-operated controls. Dentate gyrus damage rendered rats less efficient than sham-operated controls in the performance of the DRL-20s task. The DRL inter-response time (IRT) distribution for the DG-lesioned rats and the sham-operated controls was similar; however, while the distribution peak for the control rats was 20s, it was 16s for the DG-lesioned rats, indicating that the latter rats underestimated time. Performance of the DG-lesioned rats was also disrupted in the DNMTP task. However, DG-lesioned rats recovered control levels of performance during repeated training with an intertrial interval equal to 3s. An increase in intertrial interval in lesioned and sham-operated controls disrupted performance in both groups; however, while DG-lesioned rats performed at chance levels when the intertrial interval was increased to 4min or longer, the sham-operated controls performed at chance levels only when the intertrial interval was increased to 16min. These results seem most parsimoniously interpreted following the cognitive map theory of hippocampal function.

Analysis of Variance↗

Antitumor agents. Part 236: Synthesis of water-soluble colchicine derivatives.

Water-soluble colchicine derivatives were synthesized from 2-demethylcolchicine and 2-demethylthiocolchicine and evaluated in vitro against human tumor cell replication and for inhibition of tubulin polymerization. The glycinate esters (4, 5) and their tartaric acid salts (4a, 5a) showed potent cytotoxic activity in three different tumor cell lines with IC(50) values ranging from 0.02 to 0.88 microg/mL. The thiocolchicine analogs (5, 5a) were more potent than the colchicine analogs (4, 4a) in the tubulin polymerization assay. In particular, the water-soluble salt 5a merits preclinical development as an antitumor agent.

Antineoplastic Agents↗

Fatal colchicine poisoning by accidental ingestion of meadow saffron-case report.

A 62-year-old male died of colchicine poisoning after accidental ingestion of Colchicum autumnale (meadow saffron). He ate a salad of plant with green leaves regarded as wild garlic (Allium ursinum). A few hours later he developed symptoms of gastroenteritis and was admitted to hospital. In spite of gastric lavage, activated charcoal and supportive measures, multi-organ system failure developed over the next two days. Laboratory analysis showed highly elevated blood concentrations of hepatic enzymes, creatine kinase, lactate dehydrogenase and blood urea nitrogen, as well as leukocytopenia and thrombocytopenia. Mechanical ventilation, dopamine, noradrenaline, crystalloid solutions and fresh frozen plasma were applied but despite treatment the patient died five days after the ingestion. Post-mortem examination revealed hepatic centrilobular necrosis, nephrotoxic acute tubular necrosis, petechial bleeding in fatty tissue, blunt and shortened intestinal villi and cerebral toxic edema. Botanical identification of incriminated plant gave Colchicum autumnale which confirmed colchicine poisoning. Although the accidental ingestion of Colchicum autumnale is rare and to our knowledge only five such cases have been described in detail, this is the second fatal case in Croatia described in the last 3 years.

Accidents↗

Spectroscopic studies of charge transfer complexes between colchicine and some pi acceptors.

Charge transfer complexes between colchicine as donor and pi acceptors such as tetracyanoethylene (TCNE), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), p-chloranil (p-CHL) have been studied spectrophotometrically in dichloromethane at 21 degrees C. The stoichiometry of the complexes was found to be 1:1 ratio by the Job method between donor and acceptors with the maximum absorption band at a wavelength of 535, 585 and 515 nm. The equilibrium constant and thermodynamic parameters of the complexes were determined by Benesi-Hildebrand and van't Hoff equations. Colchicine in pure form and in dosage form was applied in this study. The formation constants for the complexes were shown to be dependent on the structure of the electron acceptors used.

Benzoquinones↗

Inhibition of tubulin polymerization by vitilevuamide, a bicyclic marine peptide, at a site distinct from colchicine, the vinca alkaloids, and dolastatin 10.

Vitilevuamide, a bicyclic 13 amino acid peptide, was isolated from two marine ascidians, Didemnum cuculiferum and Polysyncranton lithostrotum. Vitilevuamide was cytotoxic in several human tumor cell lines, with LC(50) values ranging from 6 to 311nM, and analysis in a 25-cell line panel revealed a weak correlation with several taxol analogs. Vitilevuamide was strongly positive in a cell-based screen for inhibitors of tubulin polymerization. Vitilevuamide at 9 microg/mL (5.6 microM) had an effect equivalent to the maximal effect of colchicine at 25 microg/mL (62.5 microM). Vitilevuamide was active in vivo against P388 lymphocytic leukemia, increasing the lifespan of leukemic mice 70% at 30 microg/kg. We hypothesized that at least part of the cytotoxic mechanism of vitilevuamide was due to its inhibition of tubulin polymerization. Vitilevuamide was found to inhibit polymerization of purified tubulin in vitro, with an IC(50) value of approximately 2 microM. Cell cycle analysis showed that vitilevuamide arrested cells in the G(2)/M phase with 78% of treated cells tetraploid after 16hr. Therefore, vitilevuamide was tested for its ability to inhibit binding of known tubulin ligands. Vitilevuamide exhibited non-competitive inhibition of vinblastine binding to tubulin. Colchicine binding to tubulin was stabilized in the presence of vitilevuamide in a fashion similar to vinblastine. Dolastatin 10 binding was unaffected by vitilevuamide at low concentrations, but inhibited at higher ones. GTP binding was also found to be weakly affected by the presence of vitilevuamide. These results suggest the possibility that vitilevuamide inhibits tubulin polymerization via an interaction at a unique site.

Animals↗

Effect of colchicine on viscoelastic properties of neutrophils.

The effect of colchicine (15-60 micrograms/ml) on the viscoelastic properties of human neutrophils was studied by the micropipette technique. The small deformation of the neutrophil in response to a step aspiration pressure was analyzed by using a three-element model in which an elastic element, K1, is in parallel with a Maxwell element composed of another elastic element, K2, in series with a viscous element, mu. Colchicine treatment of neutrophils caused decreases in K2 and mu without affecting K1. The results indicate that the integrity of the microtubules plays a significant role in providing the viscoelastic resistance (as represented by the Maxwell element in the model) of neutrophils to deforming stress.

Calcium↗

PTH-related peptide-like immunoreactivity in the median emminence, paraventricular and supraoptic nuclei in colchicine-treated rats.

The existence of PTH-related peptide (PTHrP) in the hypothalamus was examined by immunohistochemistry in colchicine-treated rats. Two days after intracerebroventricular administration of colchicine dense PTHrP-like immunoreactivity (LI) was observed in the external zone of the median emminence (ME). PTHrP-LI cells were found in the paraventricular nucleus, the supraoptic nucleus and the periventricular region of the third ventricule. The effects of PTHrP on intracellular Ca2+ concentrations ([Ca2+]i) were examined by a Ca2+ imaging method using fura-2 in perifused preparations of isolated rat anterior pituitary cells. The rise in [Ca2+]i induced by PTHrP was found in approximately 17% of the cells examined. These results suggest that PTHrP-LI cells in the hypothalamus may project to the ME and contribute to the anterior pituitary function.

Animals↗

Protective effect of a low dose of colchicine on the delayed cell death of hippocampal CA1 neurons following transient forebrain ischemia.

Transient forebrain ischemia in rats preferentially causes neuron death in the striatum and hippocampal CA1 area. Prior injection of a low dose (1 microl) of colchicine (1 microM) into the unilateral hippocampus prevented ischemic damage of CA1 neurons in both hippocampal hemispheres, whereas no protection against ischemic damage was seen in the striatum. These results suggest that disconnection of hippocampal neurons by blockade of axoplasmic transport with colchicine specifically protects ischemic damage of CA1 neurons.

Animals↗

Colchicine affects protein kinase C-induced modulation of synaptic transmission in cultured hippocampal pyramidal cells.

Spontaneous excitatory postsynaptic currents (sEPSC) through AMPA-type channels were recorded on cultured hippocampal pyramidal neurons by means of the whole-cell patch-clamp technique. The protein kinase C (PKC) agonist 4beta-phorbol 12-myristate 13-acetate (4beta-PMA) produced a long-lasting increase in sEPSC frequency not mimicked by the inactive analogue 4alpha-PM and blocked by the protein kinase inhibitor staurosporine. The 4beta-PMA-induced change in sEPSC frequency occurred without detectable change in [Ca2+]i. After treatment with the microtubule-disrupting agent colchicine, 4beta-PMA caused a small and transient increase in sEPSC frequency. It is concluded that colchicine affects the PKC-induced functional plasticity of nerve cells most likely by disturbing the axonal transport.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

High-performance liquid chromatographic application of the Hummel and Dreyer method for the determination of colchicine-tubulin binding parameters.

An application of the Hummel and Dreyer gel chromatography procedure modified for high-performance liquid chromatography has been used to determine the dissociation constant for the colchicine-tubulin interaction at 25 degrees C. The results obtained are compared with results of other equilibrium and non-equilibrium techniques and demonstrate that the initial interaction of colchicine with tubulin must be rapid and probably reversible. This rapid and sensitive technique, which does not require radioisotopes for measurement of the binding parameters, will be extremely useful for characterization of tubulin-ligand interactions.

Animals↗

Tamoxifen and colchicine-modulated vinblastine followed by 5-fluorouracil in advanced renal cell carcinoma: a phase II study.

OBJECTIVES: Chemotherapy resistance of renal cell carcinoma (RCC) has been attributed in large part to multidrug resistance (MDR). Reported MDR-modulated chemotherapy for RCC, however, has resulted in only marginal response benefits. In this study, the MDR-modulated effect of paired tamoxifen and colchicine on vinblastine and the possible additive effect of 5-fluorouracil (5-FU) were investigated in the treatment of advanced RCC. METHODS: Chemotherapy was administered every 4 weeks with biweekly vinblastine (4 mg/m(2)/day, intravenously on days 1 and 15) modulated by oral tamoxifen (100 mg/day) and colchicine (1 mg/day) from days -1 to 2 and from days 13 to 16. 5-FU (800 mg/m(2)/day from days 2 to 5) was administered after vinblastine administration as a continuous infusion. RESULTS: Of 17 eligible patients with advanced RCC available for evaluation, 1 achieved a complete response (CR) and 3 a partial response (PR), with an overall response (CR plus PR) rate of 23.5%. The median overall survival time of all patients was 10 months (95% confidence interval [CI] 3.5 to 16.5); that of our patients with poor, intermediate, and favorable risks as stratified by Motzer's model was 6 (95% CI 1.7 to 10.3), 10 (95% CI 7.9 to 12.2), and 26 (95% CI 24.4 to 27.6) months, respectively. These results are encouraging in view of the poor efficacy of chemotherapy in RCC observed previously. Additionally, the treatment toxicity was limited: toxicity of grade 3 or greater occurred in only 1 patient with leukopenia, and no treatment-related mortality was found. CONCLUSIONS: The encouraging response rates and overall survival with limited toxicity warrant further investigation of this combination therapy as an integrated part of immunochemotherapy for RCC.

Adult↗

Structure of Tetrahymena CCT theta gene and its expression under colchicine treatment.

We report here the cloning and the characterization of the Tetrahymena pyriformis chaperonin-containing-TCP1 theta gene (TpCCT theta), an orthologue of the mouse chaperonin gene CCT theta. TpCCT theta gene is interrupted by eight introns, ranging in size between 91 and 419 nucleotides, and encodes a protein consisting of 540 amino acid residues (59.1 kDa), with a putative pI of 5.73. The amino acid sequence of TpCCT theta reveals 39.4-46.0% identity with the sequences of Candida albicans and mouse CCT theta subunits and 28.0-32.6% identity with the other TpCCT subunits known so far. We have studied the expression of this gene in exponentially growing Tetrahymena cells and in cells treated with colchicine for different times. The steady-state levels of CCT theta mRNA rapidly decrease in the first 30 min of colchicine treatment. Interestingly, treatment for subsequent 60 min gives expression levels higher than those found in exponentially growing cells.

Amino Acid Sequence↗

Effect of colchicine and heat shock on multidrug resistance gene and P-glycoprotein expression in rat liver.

The multidrug resistance genes encode plasma membrane glycoproteins named P-glycoproteins, that act as an ATP-dependent drug efflux pump and decrease the cytosolic concentration of chemotherapeutic agents. It has been hypothesized that in rat liver, this protein may have a physiological role as a biliary transporter of xenobiotics and endobiotics. Some human tumor cell lines turn on the human multidrug resistance gene in response to high temperature and after exposure to toxic chemicals. Accordingly, it has been proposed that the human multidrug resistance gene is a heat shock gene. We have assessed whether two environmental stresses, heat shock or acute exposure to cytotoxic drugs (colchicine, vincristine, vinblastine and daunomycin), induce changes in the expression of multidrug resistance genes in the rat. Total cellular RNA extracted from rat liver was hybridized to a labeled human multidrug resistance gene cDNA probe. Temperature upshift did not increase the steady-state of mdr mRNA levels in the tissues studied, suggesting that the mdr genes are not activated as part of a heat shock response. The mdr mRNA levels increased in rat liver as early as 3 h after a single injection of colchicine, reached a peak (500%; p < 0.05) after around 24 h and returned to constitutive levels after 48 h. Changes in the relative content of mdr mRNA were not detected in kidney, adrenal gland and small bowel, suggesting that the in vivo induction of the mdr gene in the liver is a tissue-specific response. The other cytotoxic drugs that were tested did not increase the steady-state of mdr mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Behçet's syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy.

Immune regulatory dysfunction, circulating immune complexes (CIC), and polymorphonuclear (PMN) cell migration were investigated in patients with Behçet's syndrome. Six patients meeting rigorous clinical criteria were evaluated. Only one patient showed evidence of immune regulatory dysfunction (increased T4/T8 ratio). Although C1q binding and Raji cell assays for CIC yielded positive results in only one of five patients, all five patients had in vivo "histamine trap test" evidence of CIC (all controls had normal results). Sera from all Behçet's syndrome patients increased migration of neutrophils to zymosan-activated serum. Colchicine therapy abolished the enhancing effect of the patient's sera on movement of PMN cells from patients and controls. An immune complex-mediated injury that is followed by an excessive accumulation of PMN cells may lead to the cutaneous lesions and other lesions in Behçet's syndrome. Further evaluation of colchicine therapy is warranted on the basis of these studies.

Adult↗

[Good response to colchicine in amyloidosis secondary to inflammatory bowel disease].

Acquired systemic amyloidosis may develop during the course of a number of chronic inflammatory diseases, including inflammatory bowel disease. Amyloidosis, although rare, is life-threatening, especially when it involves the kidneys. It is important to recognize this complication, especially since colchicine has been proposed as a possible treatment.We present a 25-year-old female diagnosed at the age of 13 years with Crohn's disease with involvement of the terminal ileum and right colon. Surgery was performed because of inflammatory activity unresponsive to corticosteroid and immunosuppressive drugs. She subsequently presented nephrotic syndrome due to secondary amyloidosis, which responded well to colchicine treatment.

Adult↗

[Pseudotumorous presentation of neuro-Behçet: role of the withdrawal of colchicine?].

BACKGROUND: Neurological involvement occurs in 10 to 28% of patients with Behçet's disease. CASE REPORT: We report a case of neurological pseudotumoral presentation of Behçet's in a patient with a long standing disease treated with low dose of prednisone and colchicine (1 mg/day), 2 months after withdrawal of colchicine. CONCLUSION: Neurological manifestations during Behçet disease can be secondary to direct central nervous system involvement (encephalitis, encephalomyelitis) or vascular angitis (essentially cerebral venous thrombosis and, rarely, intracranial aneurysms). Neurological pseudotumoral presentation is rarely reported.

Anti-Inflammatory Agents↗