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PubMed1990

Reversal of advanced colchicine toxicity in mice with goat colchicine-specific antibodies.

Colchicine-specific antibody (IgG(C] was tested in mice for reversal of colchicine toxicity. The mouse model was chosen because it reflects human pathophysiology in colchicine poisoning. IgG(C) was administered when at least 85% of colchicine was distributed in tissues. It resulted in a dramatic decrease in lethality from 85% (control group) to 10% (treated group). The decrease in toxic effects was confirmed by evaluating physiological parameters. The recovery of thermoregulation was very rapid in mice treated with IgG(C), while recovery in body weight was less marked. IgG(C) administration, therefore, decreases the intensity but may extend the duration of colchicine toxicity (reversible binding). The total neutralizing binding capacity of IgG(C) used was such that administered IgG(C) neutralizing binding sites were either 7 or 15% of the injected colchicine dose. In spite of this low neutralizing capacity the treatment was successful because of the ability of IgG(C) to buffer the amount of colchicine molecules on the critical slope of the dose-lethality curve.

Animals↗

PubMed1987

The role of the B-ring of colchicine in the stability of the colchicine-tubulin complex.

The binding of colchicine to tubulin is a slow, temperature-dependent and a poorly reversible process. Colchicine analogues modified in the B-ring of colchicine have been reported to bind to tubulin fairly rapidly (Ray, K., Bhattacharyya, B. and Biswas, B.B. (1981) J. Biol. Chem. 256, 6241-6244). In an effort to test the role of the B-ring in the reversibility of the colchicine-tubulin binding reaction, we have studied the kinetics of dissociation of the drug-tubulin complex for two B-ring-modified colchicine analogues under conditions in which the association reaction was blocked with a 40-fold excess of podophyllotoxin. In both cases, the dissociation was biphasic. The off-rate constants were determined and the results strongly suggest that the B-ring part of colchicine is responsible for the stability of the drug-tubulin complex. The dissociation data have been explained in terms of a binding model in which the binding of colchicine to tubulin involves a three-subdomain interaction rather than the previously suggested two-subdomain model (Andreu, J.M. and Timasheff, S.N. (1982) Biochemistry 21, 534-543).

Colchicine↗

PubMed1997

Response of microtubules to the addition of colchicine and tubulin-colchicine: evaluation of models for the interaction of drugs with microtubules.

The effects of free drug and tubulin-drug complexes on steady-state GTP/GDP-associated microtubules and on equilibrium guanosine 5'[beta,gamma-imido]triphosphate-associated microtubules are compared. The addition of colchicine or the tubulin-colchicine complex (TuCol) to steady-state microtubules induces microtubule disassembly. Only limited disassembly of equilibrium microtubules is observed under similar conditions. Addition of colchicine or the bifunctional colchicine analogue 2-methoxy-5-(2'3',4'-trimethoxyphenyl)tropone to preassembled steady-state or equilibrium microtubules does induce disassembly, but establishment of the new steady state or equilibrium is very slow. These observations are related to the fact that TuCol readily adds to the microtubule end, but is only incorporated into the lattice with difficulty. As a result, microtubule growth is effectively inhibited and the critical concentration is significantly increased. Nevertheless, drug-induced disassembly can be extremely slow, because the frequency of addition reactions increases as the concentration of soluble dimers increases. The efficiency of incorporation of TuCol decreases as it concentration increases. The work further confirms the existence of colchicine-binding sites with low affinity (association constant KMT approximately 3 x 10(2) M-1) along the microtubule lattice. This value suggests that part of the colchicine-binding site on tubulin remains available in the polymer. The interaction of colchicine with these sites has no appreciable effect on microtubule dynamics. These observations are reproduced and rationalized by the model described elsewhere [Vandecandelaere, Martin, Bayley and Schilstra (1994) Biochemistry 33, 2792-2801], and the possibility that there are co-operative effects in the inhibition is considered.

Animals↗

PubMed1987

Comparison of the effects of colchicine and beta-lumicolchicine on cultured adrenal chromaffin cells: lack of evidence for an action of colchicine on receptor-associated microtubules.

The involvement of microtubules in adrenomedullary secretion is presently unclear. Evidence exists for a possible role of microtubules in cholinergic nicotinic receptor-related events. We now describe the actions of the microtubule disrupter, colchicine, on primary cultures of bovine adrenal chromaffin cells and compare these with corresponding actions of beta-lumicolchicine. beta-Lumicolchicine is a structural isomer of colchicine which neither binds microtubular protein (tubulin) nor interferes with microtubule assembly. Both colchicine and beta-lumicolchicine were found to inhibit acetylcholine-induced secretion with similar potencies (half maximal inhibitory concentration 0.2-0.5 mM). The inhibitory actions of both drugs are time-dependent and reversible. However, unlike colchicine which has no inhibitory effects on secretion evoked by depolarization with excess K+, beta-lumicolchicine also inhibits K+-induced secretion. Because colchicine and beta-lumicolchicine have similar effects, the selective inhibitory actions of colchicine on nicotinic receptor-mediated secretion cannot in itself be used as evidence in support of a role of microtubules in receptor-mediated events. However, our data do not preclude such a role. Differences in the effect of colchicine and beta-lumicolchicine on K+-evoked secretion suggests different modes of action of these structural isomers on chromaffin cell function.

Acetylcholine↗

PubMed1979

[Effect of some drugs on colchicine uptake by colchicine-sensitive and resistant cells].

The effect of several agents on 3H-colchicine, uptake by L cells and resistant to colcemide and colchicine L-53 cells was studied. Vinblastin to which L-53 cells are cross-resistant increases labeled colchicine uptake by L and L-53 cells 3- and 8-fold, respectively. The substances which decrease ATP level in the cells (olygomycin, etc.) enhance colchicine uptake by L and L-53 cells 2--4-fold. In the presence of these substances colchicine uptake by resistant cells is more intensive than by sensitive L cells. The structural analogue of colchicine, lumicolchicine, inactive in binding the microtubular protein tubulin enhances colchicine uptake by L and L-53 cells to about equal degree.

Adenosine Triphosphate↗

PubMed1983

[Amplification of portions of the genome in the somatic cells of mammals resistant to colchicine. IV. Genetic transformation using amplified genes from Djungarian hamster cells highly resistant to colchicine].

DNA-mediated transfer of colchicine-resistance from Djungarian hamster DM5/7 cell line, 750-fold resistant to the drug, was studied. The resistance to colchicine of DM5/7 cells is due to amplification of the genes, possibly coding for the polypeptide p22. Both high-molecular weight DNA (presumably, chromosomal DNA) and low-molecular weight DNA (presumably, extrachromosomal DNA) effectively transferred the colchicine-resistance to Djungarian hamster and mouse cells. DNA of sensitive to colchicine but resistant to ouabain mouse cells CAK-143OuaR was not capable to transfer colchicine-resistance, but effectively transferred ouabain-resistance connected with a mutation in Na+/K+-dependent ATP-ase locus. The differences in genetic transformation with amplified p22 genes and mutant Na+/K+-dependent ATP-ase genes were revealed. All cells of 3 colchicine-resistant transformants of DM-15 cells and all 10 spontaneously derived resistant clones contain the additional chromosome 4. The role of trisomy 4 in the development of colchicine-resistance in DM-15 cells is discussed.

Animals↗

PubMed1978

In vitro effect of colchicine on neutrophil granulocyte locomotion. Assessment of the effect of colchicine on chemotaxis, chemokinesis and spontaneous motility, using a modified reversible Boyden chamber.

The effect of colchicine on human neutrophil granulocyte chemotaxis, chemokinesis and spontaneous motility was examined, using a modified reversible Boyden chamber. Colchicine was shown to inhibit the attraction of neutrophils to casein and to a bacterial chemotactic factor at concentrations as low as 10(-7) M. Experiments in which the absolute concentrations and the concentration gradients of the chemotactic agent were varied, revealed that colchicine inhibited chemokinesis rather than chemotaxis. The spontaneous motility measured in the absence of chemotactic agents was not inhibited by colchicine. Pre-incubation of the cells with a bacterial chematactic factor did not change the sensitivity of the cells to colchicine. It is concluded that the integrity of microtubule function is not necessary for the ability of the cells to discern a concentration gradient or to react to this with directional locomotion. Thus the inhibitory effect of colchicine on neutrophil granulocyte chemokinesis may not depend on its inhibition of microtubule function. It is suggested that colchicine may block the still unidentified membrane mechanism involved in the translation of the recognition signal into an appropriate locomotory cell response.

Caseins↗

PubMed2005

Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial.

BACKGROUND: Colchicine seems to be a good drug for treating recurrences of pericarditis after conventional treatment failure, but no clinical trial has tested the effects of colchicine as first-line drug for the treatment of the first recurrence of pericarditis. METHODS: A prospective, randomized, open-label design was used to investigate the safety and efficacy of colchicine therapy as adjunct to conventional therapy for the first episode of recurrent pericarditis. Eighty-four consecutive patients with a first episode of recurrent pericarditis were randomly assigned to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months). When aspirin was contraindicated, prednisone (1.0-1.5 mg/kg daily) was given for 1 month and then was gradually tapered. The primary end point was the recurrence rate. Intention-to-treat analyses were performed by treatment group. RESULTS: During 1682 patient-months (mean follow-up, 20 months), treatment with colchicine significantly decreased the recurrence rate (actuarial rates at 18 months were 24.0% vs 50.6%; P = .02; number needed to treat = 4.0; 95% confidence interval 2.5-7.1) and symptom persistence at 72 hours (10% vs 31%; P = .03). In multivariate analysis, previous corticosteroid use was an independent risk factor for further recurrences (odds ratio, 2.89; 95% confidence interval, 1.10-8.26; P = .04). No serious adverse effects were observed. CONCLUSION: Colchicine therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of recurrent pericarditis.

Adult↗

PubMed2000

Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on beta-tubulin.

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophilicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2 = 0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2 = 0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n = 6) and those of [3H]colchicine displacement with an R2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.

Bibenzyls↗

PubMed2005

Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial.

BACKGROUND: Colchicine is effective and safe for the treatment and prevention of recurrent pericarditis and might ultimately serve as the initial mode of treatment, especially in idiopathic cases. The aim of this work was to verify the safety and efficacy of colchicine as an adjunct to conventional therapy for the treatment of the first episode of acute pericarditis. METHODS AND RESULTS: A prospective, randomized, open-label design was used. A total of 120 patients (mean age 56.9+/-18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes, and connective tissue diseases) were randomly assigned to conventional treatment with aspirin (group I) or conventional treatment plus colchicine 1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/d for 3 months (group II). Corticosteroid therapy was restricted to patients with aspirin contraindications or intolerance. The primary end point was recurrence rate. During the 2873 patient-month follow-up, colchicine significantly reduced the recurrence rate (recurrence rates at 18 months were, respectively, 10.7% versus 32.3%; P=0.004; number needed to treat=5) and symptom persistence at 72 hours (respectively, 11.7% versus 36.7%; P=0.003). After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences. Colchicine was discontinued in 5 cases (8.3%) because of diarrhea. No serious adverse effects were observed. CONCLUSIONS: Colchicine plus conventional therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of acute pericarditis. Corticosteroid therapy given in the index attack can favor the occurrence of recurrences.

Acute Disease↗

PubMed1999

Supercritical fluid CO2 extraction of colchicine from colchicine Autumnele liliaceae.

Colchicine was successfully extracted from the corms of colchicine autumnele Liliaceae using supercritical fluid (SF) CO2. The pressure range used in the experiments was 20-40 MPa and the temperature was 40 degrees C. Being its high molecular polar, colchicine or other alkaloids are not easy to be extracted by SF CO2. In order to increase the mass transfer from the sample matrix to SF, different presoakers (such as methanol, ethanol, acetone etc.) were employed. Among the selected pre-soakers, best results were obtained with ethanol both in the aspects of yield and selectivity. At 35 MPa, 40 degrees C and with ethanol as pre-soaker, the yield was 1.8 mg/g, and the colchicine could be almost completely extracted from the sample matrix. The average concentration increased from 0.18% in natural sample to 6.92% in extract with SFE processing only once under the given conditions. The comparison of liquid ethanol extraction (LEE) and SFE showed that SFE is greatly superior to LEE in colchicine separation with SFE not only higher yield and selectivity but also a quick, safe and non-toxic method were obtained in colchicine extraction.

Carbon Dioxide↗

PubMed1982

[Amplification of portions of the genome in mammalian somatic cells resistant to colchicine. I. Chromosome 4 trisomy in the development of gene amplification and colchicine resistance in Djungarian hamster cells].

10 independent clones of Djungarian hamster DM-15 and DMCAP cells 16-22-fold resistant to colchicine were obtained. The drug resistance was unstable. During cultivation in a colchicine free medium, 1-2% cells per population doubling lost resistance to selective dosage of the drug (0,1 microgram/ml). The loss of colchicine resistance was stepwise: the cells lost resistance to some concentrations of the drug but retained resistance to the lower colchicine dosages toxic for the wild-type cells. The analysis of chromosomes stained by the trypsin G-banding technique showed the specific karyotypic alteration in all the cells of 10 clones, i.e. complete or partial trisomy of chromosome 4. In addition, in some cells of 7 clones small chromatin bodies (SCB) and chromosomes bearing long homogeneously staining regions (HSRs) were found. The loss of colchicine resistance was accompanied by the disappearance of cells containing SCB and HSRs and the decrease in the number of cells with trisomy 4. However, the direct correlation between the loss of drug resistance and that of additional material of chromosome 4 was not observed. Probably, the resistance to colchicine is connected in these clones with gene amplification, and trisomy 4 is involved in the development of gene amplification.

Animals↗

PubMedDate not supplied

Mechanism of action of colchicine. III. Antiinflammatory effects of colchicine compared with phenylbutazone and indomethacin.

Colchicine suppresses the development of carrageenan-induced edema in the rat with a minimum effective oral dose of 6.0 mg/kg. The slope of the dose-response regression line for colchicine differs significantly from that of indomethacin and phenylbutazone. Based on the dosages required to achieve a 50% suppression of this inflammation, colchicine is 0.6 and 1.5 times as potent as indomethacin and phenylbutazone, respectively. In the reversed passive Arthus reaction in the rat, the suppressive activity of colchicine is at least 50 times that of indomethacin and 100 times that of phenylbutazone. The possible significance of these results with regard to the unique effectiveness of colchicine in the treatment of gout is discussed.

Animals↗

PubMed1992

Colchicine-sensitive and colchicine-insensitive intermediate filament systems distinguished by a new intermediate filament-associated protein, IFAP-70/280 kD.

A monoclonal antibody was produced, using as antigen a BHK-21 cytoskeletal preparation enriched in intermediate filaments (IF) and their associated proteins. This antibody reacted exclusively with a reproducible set of 70-280 kD polypeptides present in minor quantities in this preparation, as detected by immunoblot analysis. Based upon several criteria, this immunologically related group of polypeptides was designated as IFAP-70/280 kD (IF-Associated Protein): (1) it co-isolated with IF in vitro, (2) it co-localized (by both immunofluorescence and immunoelectron microscopy) with IF in situ in all stages of cell spreading, and (3) it segregated in vitro with the 54/55 kD (desmin/vimentin) structural IF subunit proteins of BHK cells through two cycles of in vitro disassembly/assembly. Immunogold labeling further localized IFAP-70/280 kD to regions of parallel or loosely bundled IF in situ, suggesting a role in regulating the supramolecular organization of IF. When this monoclonal antibody was used for double-label immunofluorescence observations of colchicine-treated BHK cells, it demonstrated the presence of colchicine-sensitive and colchicine-insensitive IF. Anti-IFAP-70/280 kD localized entirely to the drug-induced juxtanuclear IF cap, while a polyclonal antibody directed against the desmin/vimentin structural IF subunits and the previously characterized monoclonal anti-IFAP-300 kD [Yang et al., 1985; J. Cell Biol. 100:620] localized to both the juxtanuclear IF cap and a colchicine-insensitive IF network peripheral to the cap in the same cells. The colchicine-insensitive IF pattern often exhibited similarities to that observed for the actin-based stress fiber system, suggesting that stress fiber association may be an additional factor in IF organization.

Animals↗

PubMed1997

A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.

BACKGROUND: Primary systemic amyloidosis is an uncommon disease characterized by the accumulation in vital organs of a fibrillar protein consisting of monoclonal light chains. METHODS: We treated 220 patients with biopsy-proved amyloidosis. The patients were randomly assigned to receive colchicine (72 patients), melphalan and prednisone (77), or melphalan, prednisone, and colchicine (71). They were stratified according to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50). RESULTS: The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (P<0.001). Among patients who had a reduction in serum or urine monoclonal protein at 12 months, the overall length of survival was 50 months, whereas among those without a reduction at 12 months, the overall length of survival was 36 months (P=0.03). Thirty-four patients (15 percent) survived for five years or longer. CONCLUSIONS: Therapy with melphalan and prednisone results in objective responses and prolonged survival as compared with colchicine in patients with primary amyloidosis.

Aged↗

PubMed1982

[Amplification of portions of the genome in mammalian somatic cells resistant to colchicine. II. Marker chromosomes with long homogeneously staining regions in colchicine-resistant cells of the Djungarian hamster].

The series of sublines 170-750 times more resistant to colchicine were obtained from 10 independent clones of Djungarian hamster cells possessing 16-22-fold resistance to the drug. From each clone, several sublines with different levels of colchicine-resistance were developed. The drug resistance was unstable. 2,7-4,0% of cells per population doubling lost resistance to selective dosages of colchicine. The loss of resistance was stepwise. The chromosomes stained by trypsin G-banding technique were studied in 17 sublines. 15 sublines derived from 9 independent clones contained chromosomes with long homogeneously staining regions (HSRs). These were, as a rule, primarily localized in the long arm of chromosome 4. During cultivation, HSRs were transferred from chromosome 4 into other chromosomes. Evidently, transposition of HSRs was due to translocations of different chromosomes of HSRs in the chromosome 4 and to subsequent breakages of the resulting dicentrics within HSRs. A great number of different chromosomal rearrangements was also found in the cells containing HSRs. Possibly, formation of HSR leads to destabilization of the karyotype and to the variability of the genome. The length of HSRs varied in different cells of each subline. The levels of colchicine-resistance in different sublines did not correlate with the average length of HSRs in their cells. The lack of connection between the lengths of HSRs and the levels of drug resistance as well as the existence of highly resistant sublines with gene amplification, but without HSRs, suggest that amplified genes are localized in Djungarian hamster colchicine-resistant cells both in chromosomes and extrachromosomally.

Animals↗

PubMed1987

Experiential factors in the expression of hypermotility produced by intradentate colchicine: lack of effect of GM1 ganglioside on colchicine-induced loss of granule cells and mossy fibers.

Adult male Fischer-344 rats were given bilateral injections of 2.5 micrograms colchicine or artificial cerebrospinal fluid into caudal and rostral sites of the dentate gyrus of the hippocampus. One group of rats received 21 consecutive daily injections of 20 mg/kg GM1 gangliosides, i.p., beginning the day prior to surgery. Another group received saline. Colchicine-induced hypermotility was not seen in animals repeatedly handled 21 d after surgery, in spite of significant decreases in granule cell number and decreases in the volume of hippocampal mossy fibers. Pretreatment with GM1 had no effect on behavior and it did not protect against the hippocampal damage produced by colchicine. Rats given colchicine, but not handled for 21 d, showed significant hypermotility, which was associated with decreases in hippocampal granule cells. These data underscore the importance of handling in postlesion functional recovery.

Animals↗

PubMed1987

Kinetics of association and dissociation of colchicine-tubulin complex from brain and renal tubulin. Evidence for the existence of multiple isotypes of tubulin in brain with differential affinity to colchicine.

The kinetics of colchicine binding to bovine brain tubulin have been reported to be biphasic under pseudo first order conditions [(1978) Biochemistry 17, 4466-4472]. Unlike brain tubulin, the kinetics of colchicine binding to bovine renal tubulin are monophasic. The apparent on-rate constant for the binding of colchicine to renal tubulin is found to be very close to that of the faster binding component in brain tubulin. Similarly, the dissociation of colchicine-tubulin complex in the presence of iodide is biphasic for brain tubulin but monophasic for renal tubulin. Since brain and renal tubulin apparently differ in beta-tubulin, our results suggest that the biphasic nature of the kinetics for bovine brain tubulin could possibly originate from the existence of multiple isotypes of tubulin differing in drug binding affinity.

Animals↗