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PubMed1996

Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only.

PURPOSE: A clinical trial designed to test whether treatment with melphalan, prednisone, and colchicine (MPC) is superior to colchicine (C) alone was performed in patients with primary amyloidosis (AL), a nonmalignant plasma cell dyscrasia. PATIENTS AND METHODS: Patients were randomized to MPC or C with stratification according to sex, time from diagnosis to study entry (ie, less than 3 months or 3 to 12 months), and dominant organ system involvement (ie, cardiac, renal, neurologic, or others). Data were gathered monthly from patients, quarterly from physicians, and annually in the Clinical Research Center. One hundred consecutive patients with AL amyloidosis admitted between 1987 and 1992 who met eligibility requirements were treated and followed for a minimum of 18 months. Fifty patients (group A) received daily oral colchicine and 50 patients (group B) received cycles of oral melphalan and prednisone every 6 weeks for 1 year as well as colchicine. RESULTS: The principal outcome measure was median survival, which was compared in the two treatment groups and in the subgroups. The overall survival of all patients from study entry was 8.4 months. Comparing group A (C) to group B (MPC), the survival was 6.7 months versus 12.2 months (P = 0.087). Both treatment groups had poor survival for patients in the cardiac subgroup, longest survival in the renal group, and significant differences favoring MPC treatment only in patients whose major system manifestations were neurologic (P = 0.037) or other (P = 0.007). Multivariate analysis showed a strongly significant treatment effect (P = 0.003) and improved survival associated with not having cardiac or gastrointestinal involvement. CONCLUSIONS: MPC was advantageous for patients whose major manifestations of amyloid disease were other than cardiac or renal. Better survival regardless of treatment was noted in patients for whom a satisfactory supportive treatment such as transplant or dialysis exists for their organ failure.

Amyloidosis↗
PubMed1975

Mechanism of action of colchicine. I. Effect of colchicine and its analogs on the reversed passive Arthus reaction and the carrageenan-induced hindpaw edema in the rat.

Colchicine and N-desacetyl-N-methylcolchicine suppressed both the reversed passive Arthus reaction and the carrageenan-induced edema in the rat. Colchicine, 2-desmethyl-colchicine glucoside and trimethylcolchicine acid had no effect on either model of inflammation. The ability or inability of these compounds to suppress the development of experimental inflammation correlated with their antimitotic activities. The findings lend support to the hypothesis that the anti-inflammatory and the antimitotic effects of colchicine may depend on the same basic, biophysical mechanism of action, i.e., the disruption of the microtubules.

Administration, Oral↗
PubMedDate not supplied

Mechanism of action of colchicine. VI: Effect of colchicine on generation of leukotriene B4 by human polymorphonuclear leukocytes.

Three microtubule-disruptive agents (colchicine, oncodazole, and vinblastine) are shown to suppress ionophore A23187-induced generation of LTB4 in a dose-related manner. The slopes of the dose-response regression lines were similar for the three drugs. Trimethyl-colchicinic acid has no effect on LTB4 generation. The suppressive effect of colchicine (1 x 10(-6) M) can be blocked completely by taxol (1 x 10(-6) M) which promotes and stabilizes microtubule assembly. The data suggest that colchicine suppresses the generation of LTB4 via its effect on microtubules.

Alkaloids↗
PubMed1985

Effect of colchicine on atherosclerosis. II. Biochemical studies on skin biopsies from patients treated perorally with colchicine.

The biosynthesis of proteins and glycosaminoglycans (GAGs) was determined in skin biopsies from atherosclerotic patients treated perorally for 3 months with 1 mg/day colchicine. The biopsies were incubated with 3H-glucosamine and 14C-proline for 5 h and subsequently digested with pronase. In an aliquot of the pronase digest, the specific radioactivity of 14C-proline and 14C-hydroxyproline were determined. The 3H-glucosamine-labeled GAGs were identified by specific enzymic assay and quantified after electrophoretic separation. 3 months treatment with colchicine did not modify the total amounts of proline and hydroxyproline in skin proteins, but diminished the amount of the GAGs as expressed by uronic acid content. Colchicine treatment decreased also the specific radioactivity of proline and hydroxyproline, which reflects a decrease of total protein and collagen synthesis. The incorporation of 3H-glucosamine in the 3H-GAGs was also decreased, mainly in hyaluronic acid. These results suggest that peroral administration of colchicine modifies the synthesis of extracellular matrix proteins and polysaccharides by skin fibroblasts.

Adult↗
PubMed1985

A photoaffinity derivative of colchicine: 6'-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine. Photolabeling and location of the colchicine-binding site on the alpha-subunit of tubulin.

A photoaffinity analog of colchicine, 6-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine, was synthesized by reacting deacetylcolchicine or [3H]deacetylcochicine with N-succinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate. Homogeneity of the photoaffinity analog was established by thin-layer chromatography and high-pressure liquid chromatography. The structure of the photoaffinity analog was determined by 1H and 13C NMR, infrared and ultraviolet-visible spectroscopies, and elemental analysis. Binding of 6-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine to bovine renal tubulin was measured by competition with [3H]colchicine. The value of the apparent Ki for the photoaffinity analog was 0.28 microM in the concentration range of 0.8-1.2 microM of the analog. A value of 0.50 microM for the apparent Kd was measured by the direct binding of the tritiated photoaffinity analog to tubulin. The analog is slightly more potent an inhibitor of microtubule formation than colchicine. The photoaffinity analog reacted with renal tubulin upon irradiation with a mercury lamp equipped with a 420-nm cutoff filter. Spectral and radiochemical analyses of the tubulin after photolysis and dialysis have demonstrated a stoichiometric incorporation of the photoaffinity analog in the alpha-subunit of the tubulin. Covalent labeling of tubulin with the photoaffinity analog decreases the extent of [3H]colchicine binding by more than 90%.

Affinity Labels↗
PubMed1993

Determination of colchicine in biological fluids by reverse-phase HPLC. Variation of colchicine levels in rats.

A reverse-phase HPLC method for the determination of colchicine in biological fluids is proposed. Blood, liver and kidney colchicine concentrations were determined in rats at different times following intraperitoneal (i.p.) injection of 10 mg/kg of the drug. Colchicine was extracted from the samples studied using dichloromethane at pH 8. The dry extract was redissolved in the mobile phase and analyzed with simultaneous detection at 254 and 350 nm.

Animals↗
PubMed2000

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial.

BACKGROUND: Sight-threatening eye involvement is a serious complication of Behçet's disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. METHODS: Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. FINDINGS: Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. INTERPRETATION: Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçet's disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

Adult↗
PubMed1994

Effect of colchicine analogues on the dissociation of alpha beta tubulin into subunits: the locus of colchicine binding.

A combination of ligand binding and sedimentation equilibrium studies was used to characterize the thermodynamic linkages between alpha beta tubulin association, nucleotide binding, and the interaction of colchicine analogues with dimeric and dissociated tubulins. The strength of binding of allocolchicine to the tubulin dimer was identical (8 x 10(5) M-1) whether the exchangeable nucleotide site (E site) was occupied by GTP or GDP. This drug bound to dimeric (alpha beta) tubulin and to one of the monomeric subunits, and the binding affinity for the dissociated state was linked to occupancy of the exchangeable nucleotide site. When the exchangeable site was occupied by GTP, the drug bound with very similar affinities to the dimeric and dissociated states of the protein. For tubulin-GDP, the binding of the drug to the dissociated state was significantly weaker (6.3 x 10(4) M-1) than to the dimeric state, suggesting the existence of an E-site-related conformational change in the dissociated state. Podophyllotoxin, which contains the A-ring portion of colchicine, bound with equal affinity to the dimeric and dissociated forms of both tubulin-GTP and tubulin-GDP, indicating that it is the C-ring portion of colchicine that is linked to the E-site-related conformational change.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Biological effects of modified colchicines. Improved preparation of 2-demethylcolchicine, 3-demethylcolchicine, and (+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines.

A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding. The most potent compounds were N-acylated analogues of colchicine and demecolcine. Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine. Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85% phosphoric acid and concentrated sulfuric acid, respectively. Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.

Animals↗
PubMed1983

Biological effects of modified colchicines. 2. Evaluation of catecholic colchicines, colchifolines, colchicide, and novel N-acyl- and N-aroyldeacetylcolchicines.

A series of natural and synthetic colchicine derivatives was examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. The natural alkaloids cornigerine and colchifoline and several N,O-substituted analogues of colchifoline were found to be as potent and as toxic as colchicine in the P388 screen with good affinity for tubulin. The 1,2-(methylenedioxy)-substituted isomer of cornigerine was considerably less potent in vivo than could have been anticipated from the in vitro tubulin binding data. Several N-acyl and N-aroyl derivatives prepared from deacetylcolchicine showed high potency in the in vitro and in vivo screens. Colchicide was found to be highly potent in vivo, and N-carbethoxydeacetylcolchicine, a synthetic analogue of colchicine with a N-carbethoxy instead of an N-acetyl function, showed interesting biological properties.

Animals↗
PubMed1997

The mechanism of tubulin-colchicine recognition--a kinetic study of the binding of a bicyclic colchicine analogue with a minor modification of the A ring.

2-Methoxy-5-(2',3',4'-trimethoxy)-2,4,6-cycloheptatrien-1-one (MTC) is a colchicine analogue that lacks the B ring. 2-Methoxy-5-(2',4'-dimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MD) is an A-ring analogue of MTC, in which one methoxy group is replaced by a hydrogen atom. This paper describes the kinetic features of MDC binding to tubulin, and compares its behaviour with MTC to analyse the effect of the A-ring modification on the recognition process by tubulin. Binding is accompanied by a strong enhancement of MDC fluorescence and quenching of protein fluorescence. The kinetic and thermodynamic parameters were obtained from fluorescence stopped-flow measurements. The kinetics are described by a single exponential, indicating that this drug does not discriminate between the different tubulin isotypes. The observed pseudo-first-order rate constant of the fluorescence increase upon binding increases in a non-linear way, indicating that this ligand binds with a similar overall mechanism as colchicine and MTC, consisting of a fast initial binding of low affinity followed by a slower isomerisation step leading to full affinity. The K1 and k2 values for MDC at 25 degrees C were 540 +/- 65 M(-1) and 70 +/- 6 s(-1) respectively. From the temperature dependence, a reaction enthalpy change (deltaH(o)1) of the initial binding of 49 +/- 11 kJ/mol(-1) and an activation energy for the second step of 28 +/- 9 kJ/mol(-1) were calculated. Displacement experiments of bound MDC by MTC allowed the determination of a rate constant of reverse isomerisation of 0.60 +/- 0.07 s(-1) at 25 degrees C and the activation energy of 81 +/- 6 kJ/mol(-1). The overall binding constant was (6.3 +/- 0.2) x 10(4) M(-1) at 25 degrees C. Combination of these results with the kinetic parameters for association gives a full characterisation of the enthalpy pathway for the binding of MDC. The pathway of MDC is shown to differ considerably from that of MTC binding. Since its structural difference is located in ring A, this result indicates the use of ring A in the first step. The kinetics of the binding of MDC in the presence of some A-ring colchicine analogues (podophyllotoxin, 3',4',5'-trimethoxyacetophenone and N-acetylmescaline) and a C-ring analogue (tropolone methyl ether) suggest that the A and C rings are involved in the binding of MDC.

Animals↗
PubMed1975

Mechanism of action of colchicine. II. Effects of colchicine and its analogs on phagocytosis and chemotaxis in vitro.

Colchicine, desacetylmethylcolchicine and colchiceine suppress the phagocytosis of starch granules by rabbit peritoneal polymorphonuclear leukocytes in vitro. Trimethylcolchicinic acid and 2-desmethylcolchicine glucoside have no effect on phagocytosis. Colchicine, at concentrations as high as 1 X 10(-4) M, has no effect on chemotaxis of polymorphonuclear leukocytes in response to immune complex-activated chemotactic factors or on the motility of these cells. These results do not support the contention that the suppression of phagocytosis or chemotaxis plays a significant role in the anti-inflammatory activity of colchicine.

Animals↗
PubMed1989

Inhibition of delayed hypersensitivity reactions by colchicine. II. Colchicine inhibits interferon-gamma induced expression of HLA-DR on gut epithelial cell line.

The effects of colchicine and vinblastine on interferon-gamma (IFN-gamma) induced expression of HLA-DR antigens on the HT-29 colonic carcinoma cell line was investigated in vitro. Both drugs prevented the expression of HLA-DR only if applied before or together with IFN-gamma. Methotrexate, an antimitotic drug, failed to inhibit DR expression by these cells. Colchicine and vinblastine, but not methotrexate, act on the cellular microtubules, interfering with the transport of proteins from the protoplasm to the cell surface and thus preventing the appearance of HLA-DR antigens. The reported findings may explain the role of colchicine in preventing delayed hypersensitivity reactions.

Cell Line↗
PubMed1991

Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout.

In order to establish the degree of renal malfunction necessary for colchicine toxicity in patients receiving it daily for the prevention of recurrent acute gout, we obtained serum creatinine levels and measured or estimated creatinine clearances in a consecutive series of 17 patients with demonstrated colchicine myotoxicity. An estimate of creatinine clearance, based on ideal body weight and age, was nearly always 50 ml/min or less, and was the most practical predictor of the risk of toxicity. By comparison, patients with gout from the same clinical data base, but without myotoxicity, had normal renal function. The data yield clear guidelines for safe use of colchicine chronically.

Adult↗
PubMed1967

The mechanism of action of colchicine. Colchicine binding to sea urchin eggs and the mitotic apparatus.

Colchicine forms a complex in vivo with a protein present in fertilized or unfertilized sea urchin eggs; similar binding was obtained in vitro with the soluble fraction from egg homogenates. Kinetic parameters and binding equilibrium constant were essentially the same in vivo and in vitro. The binding site protein was shown to have a sedimentation constant of 6S by zone centrifugation. The protein was present in extracts of the isolated mitotic apparatus at a concentration which was several times higher than in whole-egg homogenates. It was extracted from the mitotic apparatus at low ionic strength under conditions which lead to the disappearance of microtubules. No binding could be detected to the 27S protein, previously described by Kane, which is a major protein component of the isolated mitotic apparatus. The properties of the colchicine-bindinG protein, (binding constant, sedimentation constant, Sephadex elution volume) are similar to those obtained with the protein from mammalian cells, sea-urchin sperm tails, and brain tissue, and thus support the conclusion that the protein is a subunit of microtubules.

Animals↗
PubMed1976

Metabolic transformation of colchicine, IV[1]. On the interaction of colchicine and colchiceine with sulfhydryl compounds.

The interaction of colchicine and one of its metabolites, O10-demethylcolchicine (colchiceine), with sulfhydryl compounds was studied in several experimental systems. Colchiceine protects reduced glutathione from oxidation by atmospheric oxygen. Inactivation of enzymes with catalytically essential sulfhydryl groups is prevented by colchiceine. In affinity chromatographic experiments, Agarose-bound colchiceine adsorbs sulfhydryl enzymes which may be eluted specifically by SH-compounds like mercaptoethanol. No such effects are shown by colchicine. The data demonstrate a novel type of biochemical reactivity in the metabolite colchiceine with potential biological relevance.

Adenosine Deaminase↗