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PubMed1994

Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.

OBJECTIVE: To elucidate factors possibly influencing the outcome of colchicine therapy in patients with amyloidosis of familial Mediterranean fever (FMF). METHODS: Retrospective analysis of data abstracted from the charts of all 68 FMF patients with amyloidosis who presented during the study period (1974-1992) with proteinuria (> or = 0.5 gm/24 hours) and creatinine values < or = 2.5 mg/dl, received colchicine, and were followed up for > or = 5 years. RESULTS: At the end of the study period, kidney disease had worsened in 31 patients and remained stable in 22. Proteinuria had regressed in 15 patients. Deterioration was related to initial serum creatinine values > or = 1.5 mg/dl (P < 0.01) and to mean colchicine dosage < or = 1.5 mg/day (P < 0.001). The 3 groups were comparable in terms of initial urinary protein levels, duration of proteinuria, presence of hypertension, occurrence of febrile attacks, sex distribution, and proportion of non-compliant patients. CONCLUSION: The therapeutic dosage of colchicine for amyloidosis of FMF is > 1.5 mg/day. This dosage is effective only in patients with initial serum creatinine levels < 1.5 mg/dl.

Adult↗
PubMed2005

Inhibition of mitosis by glycopeptide dendrimer conjugates of colchicine.

Glycopeptide dendrimers have been prepared bearing four or eight identical glycoside moieties at their surface (beta-glucose, alpha-galactose, alpha-N-acetyl-galactose, or lactose), natural amino acids within the branches (Ser, Thr, His, Asp, Glu, Leu, Val, Phe), 2,3-diaminopropionic acid as the branching unit, and a cysteine residue at the core. These dendrimers have been used as drug-delivery devices for colchicine. Colchicine was attached to the dendrimers at the cysteine thiol group through a disulfide or thioether linkage. The biological activities of the glycopeptide dendrimer conjugates were evaluated in HeLa tumor cells and non-transformed mouse embryonic fibroblasts (MEFs). The concentrations of glycopeptide dendrimer drug conjugates required to achieve inhibition of cell proliferation by interference with the tubulin system were found to be higher (IC50 > 1 microM) compared to the required colchicine concentration. On the other hand, the glycopeptide dendrimer conjugates inhibited the proliferation of HeLa cells 20-100 times more effectively than the proliferation of MEFs. In comparison, non-glycosylated dendrimers and colchicine itself showed a selectivity of 10-fold or less for HeLa cells.

Animals↗
PubMed1989

Selective destruction of mossy fibers and granule cells with preservation of the GABAergic network in the inferior region of the rat hippocampus after colchicine treatment.

Lesions induced by colchicine injection into the rat hippocampus were investigated by means of electron microscopy and GABA immunocytochemistry. Granule cells were nearly completely destroyed 3 days after colchicine injection; since the necrosis of their axonal endings was delayed, an anterograde degeneration of the mossy fibers had probably taken place. The selectivity of the lesions was not limited to granule cells, for some pyramidal neurons in CA1 pyramidal layer were damaged. It was, however, striking to observe that throughout the hippocampal structure GABAergic neurons were spared from the effects of colchicine. For instance, GABAergic neurons were found in the vicinity of the completely destroyed granule cell layer. GABAergic neurons and terminals were also present in the CA3 region where the GABA-containing terminals formed a dense network of synapses with somata and dendrites of pyramidal cells. It was interesting to note that, consistent with previous studies, the GABAergic neurons in CA3 are innervated by mossy fibers. We conclude that after colchicine treatment the destruction of the granule cells was not associated with a lesion of the GABAergic network. This selective lesion provides a useful model with which to study the properties of CA3 neurons deprived of their major excitatory input but with an intact inhibitory network.

Animals↗
PubMed1992

Distribution of nerve growth factor-like immunoreactive neurons in the adult rat brain following colchicine treatment.

Using immunohistochemical techniques, we have previously localized nerve growth factor (NGF)-like immunoreactivity in the normal adult rat central nervous system (CNS) exclusively in the hippocampal mossy fiber region and within basal forebrain cholinergic neurons--a cell population believed to be primary NGF consumers within the CNS. In the present investigation, we have attempted to identify potential producers of NGF by pretreating animals with colchicine. Such a treatment would be expected to block microtubule-assisted neuritic transport mechanisms, thus preventing the accumulation of antigens normally obtained by retrograde transport and forcing the accumulation of cell products normally exported anterogradely. Forty-eight hours after colchicine administration within their innervation territories, basal forebrain cholinergic neurons showed a marked loss of NGF-like immunoreactivity. Conversely, following colchicine treatment, many new populations of NGF-like immunoreactive cells were detected, several of which have been previously observed with in situ hybridization techniques for NGF mRNA. Many NGF-like immunoreactive populations, however, were not previously recognized by in situ hybridization methods, including cells of the striatum, reticular thalamic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, lateral and medial septum, substantia innominata, and nucleus basalis. Furthermore, evidence is provided that colchicine-blocked, NGF-like immunoreactive neurons within the basal forebrain are not cholinergic, thus reinforcing the hypothesis that trophic support for these NGF-dependent neurons may be derived from distant and local sources. The distinctive distribution of NGF-like immunoreactive cells observed in this study strongly correlates with the reported distribution of NGF mRNA in CNS neurons, thus suggesting that our antibodies are uniquely recognizing NGF and not other related neurotrophins.

Animals↗
PubMedDate not supplied

The effects of colchicine and vinblastine on the biliary excretion of carcinoembryonic antigen.

The biliary output of carcinoembryonic antigen (CEA) in bile fistula rats following treatment with the microtubule poisons vinblastine and colchicine increased 3-fold over a 4-hr period. Cytochalasin B and the inactive colchicine derivative lumicolchicine had no effect. These treatments did not effect the rate of CEA clearance from the circulation. Biliary output of low molecular weight fragments from CEA degradation was decreased in the presence of colchicine and vinblastine. Mechanical obstruction of the bile duct for 3 days followed by relief of obstruction resulted in a 3-fold increased output of CEA into the bile. These results are consistent with a paracellular mechanism for CEA transport from blood to bile. Biliary duct obstruction and vinblastine and colchicine probably affect the permeability of junctional complexes between hepatocytes allowing CEA to penetrate more easily.

Animals↗
PubMed1990

Effect of colchicine on lymphocyte and monocyte function and its relation to fibroblast proliferation in primary biliary cirrhosis.

Lymphocyte and monocyte function was investigated in eight patients with primary biliary cirrhosis and in age-matched and sex-matched controls. In three of the eight cirrhotic patients, two were in the late stage of the disease (stage III) and concanavalin A-induced suppressor cell function was markedly decreased; it returned to normal levels after 1 mo of treatment consisting of 5 mg per week of orally administered colchicine. The relative percentage of T cell subsets (CD3, CD4 and CD8) and the mean percentage of the helper and the suppressor phenotype were similar in cirrhotic patients and in controls. Basal production of interleukin-1 activity by a monocyte-enriched fraction of peripheral blood mononuclear cells of cirrhotic patients was three-fold above control values: after stimulation with endotoxin, interleukin-1 values increased tenfold above basal levels in monocyte-enriched fraction of peripheral blood mononuclear cells of both normal and cirrhotic patients. Colchicine normalized the basal production of interleukin-1 and inhibited its stimulation by endotoxin by 50%. Culture supernatants of endotoxin-stimulated monocyte-enriched fraction of peripheral blood mononuclear cells increased the proliferation of cultured human skin fibroblasts by 50%. In contrast, supernatants from stimulated monocyte-enriched fraction of peripheral blood mononuclear cells obtained from colchicine-treated patients significantly inhibited fibroblast proliferation. These findings suggest that stimulated chronic inflammatory cells may play an important role in liver fibrosis. Some of the actions of colchicine could be related to its effects on lymphocyte and monocyte function.

Adult↗
PubMed1991

Transcellular transport of organic anions in the isolated perfused rat liver: the differential effects of monensin and colchicine.

Nonbile salt cholephiles and bile salts are two classes of organic anions that are efficiently taken up and excreted by the liver. Recent evidence suggests that a microtubular system-dependent, colchicine-sensitive transcellular pathway may transport both classes of these ligands. The relationship of this pathway to flux rates, however, remains unclear. Some structural evidence suggests an important role for a Golgi-associated vesicular system. Monensin, like colchicine, is a perturbing agent that is believed to target primarily Golgi and related organelles. The effects of a minimal effective dose of both colchicine (0.06 mg to 0.12 mg/100 gm body wt) and monensin (0.6 mg/100 gm body wt) were examined in the isolated perfused rat liver in a single-pass mode. The nonbile salt cholephile, phenol red, was studied at two doses: 1 nmol and 5 mumol. Sodium taurocholate was studied at three doses: 2 nmol, 1 mumol and 5 mumol. Colchicine affected the transcellular transport for both classes of organic anions equally. Partially inhibitory effects on both anions occurred only at high ligand flux rates. In contrast, monensin greatly impaired the transport of nonbile salt cholephiles but had no influence on transcellular bile salt flux. We conclude that the monensin effect appears to define a distinct transcellular transport pathway for each of the two classes of organic anions.

Animals↗
PubMed2004

A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results.

Primary biliary cirrhosis frequently progresses despite treatment with ursodeoxycholic acid (UDCA), the only approved therapy. Previous studies suggested that colchicine and methotrexate may improve biochemical tests of liver function, symptoms, and liver histology. The aim of the present study was to determine if the addition of colchicine or methotrexate to UDCA would improve survival free of liver transplantation. Eighty-five patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase levels were at least twice the normal level and who were not yet candidates for liver transplantation were randomly assigned to receive colchicine or methotrexate in a double-blind study. UDCA was administered to all patients after 2 years. The primary end point was survival free of liver transplantation. Patients were followed up for a total of up to 10 years or until treatment failure. Data were analyzed on an intention-to-treat basis. Transplant-free survival was similar in both groups: 0.57 for colchicine plus UDCA and 0.44 for methotrexate plus UDCA, results that are similar to those predicted by the Mayo prognostic model. Significant improvement in liver biochemical tests and liver histology was observed in a subset of patients in both treatment groups who remained in the study for all 10 years. In conclusion, neither colchcine plus UDCA nor methotrexate plus UDCA improved survival beyond that predicted by the Mayo prognostic model. However, clinical, histologic, and biochemical improvement observed among those who remained in the study for 10 years suggests a possible benefit of these drugs in a subset of patients.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Protective effect of colchicine on acute liver damage induced by CCl4. Role of cytochrome P-450.

The aim of this work was to study if colchicine protects against. CCl4-induced changes in hepatic biochemical parameters by reducing cytochrome P-450, by comparing the effects of colchicine and SKF 525-A, a well-known inhibitor of cytochrome P-450. Our results show that both drugs reduced the cytochrome P-450 content and p-nitroanisole o-demethylase activity to the same extent. However, colchicine afforded a total protection from markers of liver injury, while SKF 525-A protected only partially. The difference in the hepatoprotective activity of both drugs indicates that the beneficial effect of colchicine cannot be attributed solely to the inhibition of the activation of CCl4. Other actions, perhaps at the level of the propagation of lipid peroxidation or a 'membrane-stabilizing' effect cannot be ruled out.

Alanine Transaminase↗
PubMed1986

Tubulin-colchicine complex (TC) inhibits microtubule depolymerization by a capping reaction exerted preferentially at the minus end.

The effects of colchicine and tubulin-colchicine complex (TC) on microtubule depolymerization were studied using the axoneme-subunit system described previously [Bergen LG, Borisy GG; J Cell Biol 84:141-150, 1980]. This system allows the independent analysis of the polymerization kinetics at both the plus and minus ends of a microtubule. Depolymerization was induced by isothermal dilution with 10 volumes of an experimental solution containing colchicine, TC, or buffer alone. Colchicine alone (5-100 microM) blocked depolymerization at the minus end, whereas depolymerization at the plus end occurred at almost control rates. A similar effect was produced by TC (0.4:1-1:1 molar ratio to free tubulin). High molar ratios of TC to tubulin (10:1) blocked depolymerization at both plus and minus ends, and intermediate molar ratios of TC:T allowed depolymerization of the plus ends but at attenuated rates. The blockage was not readily reversible; TC-affected ends neither shortened upon dilution nor grew longer upon incubation with additional tubulin. We conclude that TC at suprastoichiometric ratios to tubulin inhibits microtubule depolymerization by a capping reaction and that this effect is exerted preferentially at the minus end.

Animals↗
PubMed1976

Pleiotropic phenotype of colchicine-resistant CHO cells: cross-resistance and collateral sensitivity.

Colchicine resistant (CHR) mutants of CHO cells with reduced permeability to colchicine display extensive cross-resistance to a number of apparently unrelated compounds including puromycin, daunomycin, emetine, ethidium bromide and gramicidin D. A positive correlation was observed between the level of cross-resistance and the relative hydrophobicity of these compounds. The mutants also showed increased (collateral) sensitivity to local anaesthetics (procaine, tetracaine, xylocaine and propanolol), steroid hormones (1-dehydrotestosterone, corticosterone and 5beta-pregnan-3,20-dione) and some Triton X compounds. In general, the degree of the pleiotropic response (cross-resistance or collateral sensitivity) correlated with the degree of colchicine resistance in mutant lines. These results are consistent with the pleiotropic phenotype being the result of the same mutation(s) which confer colchicine resistance and support a model for resistance in which the reduced permeability is assumed to be the result of an alteration in the modulation of the fluidity of the surface membrane.

Anesthetics, Local↗
PubMed1982

Commitment and proliferation kinetics of human lymphocytes stimulated in vitro: effects of colchicine on mitogen response.

We have examined the effects of colchicine on concanavalin A (Con A)-and phytohemagglutinin (PHA)-stimulated human peripheral blood lymphocytes and from the time course of proliferation have extracted the relative size of the responding cell population, the rate of entry of this population into S-phase, and the length of the lag period. Additions of colchicine at any time did not appear to influence the size of the responding population nor did it greatly affect the duration of the lag period. Only the rate at which the cell population enters initial S-phase is a function of the time of previous exposure to colchicine. Colchicine does not appear to inhibit the commitment of stimulated lymphocytes to enter the cell cycle. Rather, it merely serves to decrease the biochemical processes responsible for fixing a maximal rate of entry into S-phase.

Cell Division↗
PubMed1988

Effects of colchicine- and cytochalasin B-treatment on the intracellular distribution of yolk droplets, lipid bodies, and Golgi apparatus of the chick neuroepithelial cells.

Treatment with colchicine (antimicrotubular agent) and cytochalasin B (antimicrofilamentous agent) has been used to investigate the possible role played by the cytoskeleton in the maintenance of intracellular distribution of yolk droplets, lipid bodies, and Golgi apparatus of the chick neuroepithelial cells. On the one hand, embryos treated with colchicine showed modifications in their distribution patterns of yolk droplets and lipid bodies, which suggests the involvement of the microtubular integrity of neuroepithelial cells in the maintenance of normal distribution patterns. On the other hand, the close relationships between vitelline and lipid inclusions and Golgi apparatus observed in untreated embryos seems to be kept in the embryos treated with colchicine and cytochalasin B. Moreover, from the effects of colchicine on Golgi apparatus position a possible functional role for the microtubular system in the maintenance of Golgi apparatus polarity in the chick neuroepithelial cells can be proposed. The results provided here constitute new information about the cellular mechanisms involved in chick neurulation.

Animals↗
PubMed1976

Effects of denervation and colchicine treatment on the chloride conductance of rat skeletal muscle fibers.

Membrane potentials, cable parameters, and component resting conductances were measured in extensor digitorum longus (EDL) muscle fibers from adult rats in vitro at 24 degrees C, after 15 to 18 days of denervation by nerve section, and at seven to ten days following epineural injection of 100 to 450 mug of colchicine in the peroneal nerve. The denervated muscles were paralyzed throughout the experimental period, whereas the colchicine-treated preparations showed no clinical paralysis except for the first day or two. The EDL from the untreated side served as a control. Both the denervated and colchicine-treated fibers were depolarized, showed signs of fibrillation, had tetrodotoxin-resistant potentials, and membrane resistance was increased two- to sevenfold. In the denervated fibers, mean chloride conductance GC1 dropped from a control value of 3196 to 596 mumhos/cm2 while mean potassium conductance GK showed a tendency to rise from 260 to 332 muhos/cm2. Colchicine-treated fibers while showing a similar fall in mean GC1 from 2993 to 1066 mumhos/cm2, also showed a significant fall in mean GK from 213 to 116 mumhos/cm2. It was concluded that factors transported by the microtubular system are important for the maintenance of the high resting GC1 of mammalian skeletal muscle fibers.

Action Potentials↗
PubMed1995

Inhibition of prostate cancer growth by estramustine and colchicine.

Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that inhibit microtubule function have been found to be cytotoxic to prostate cancer cells in preclinical and clinical settings. It was the aim of this study to assess the activity of estramustine and colchicine, two microtubule inhibitors, in hormone-refractory prostate cancer. In clinically achievable concentrations, the combination of estramustine and colchicine was cytotoxic to both the Dunning rat prostate adenocarcinoma cell line MAT-LyLu (MLL) and human prostate cancer cells (PC-3). Microtubule function was assessed in vitro to evaluate possible mechanisms of action. In motility and cell cycle analysis assays, estramustine and colchicine inhibited cellular motility but not cell cycle transit. In vivo, these two agents both inhibited the growth of implanted Dunning rat prostate adenocarcinoma MLL cells but did not appear to have additive effects. The use of oral colchicine in the treatment of hormone-refractory prostate cancer requires further investigation.

Adenocarcinoma↗
PubMed1978

Teratogenic and cytogenetic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice.

The teratogenic effects of three new plant-derived antitumor agents, maytansine, VP-16-213 and VM-26, were compared to the effects of vincristine and colchicine in pregnant Swiss albino mice that received a single ip injection of drug on day 6, 7 or 8 of gestation. Cytogenetic studies were also performed using maternal bone marrow and embryos obtained 48 hours after injection of maytansine, vincristine, VP-16-213, VM-26 and colchicine on day 6, 7 or 8 of gestation. A close correlation between teratogenic and cytogenetic effects was not noted among the compounds tested. Vincristine had greater embryotoxic and teratogenic activity than maytansine at equimolar doses (0.36 mu moles/kg), with the peak effects appearing after injection on day 7 of gestation. Colchicine, VP-16-213 and VM-26 were comparatively less potent than maytansine and vincristine, since doses of 2.5 mu moles/kg (colchicine and VP-16-213) and 1.5 mu moles/kg (VM-26) were required to elicit embryotoxic effects. At their teratogenic doses, all compounds induced various cranial abnormalities including exencephaly, hydrocephalus, anophthalmia and microtia, as well as major skeletal malformations. The teratogenic dose of vincristine is comparable to its effective antitumor dose in transplantable rodent tumor systems; in contrast, the teratogenic dose of maytansine in approximately 10-fold higher than its antitumor dose. Of the compounds studied, VP-16-213 and VM-26 exerted the most consistent cytogenetic effects in embryonic tissue. Alarge proportion of the structural chromosome aberrations induced in embryonic cells by VM-26 were stable and are most likely capable of surviving at least one cell division.

Abnormalities, Drug-Induced↗
PubMed1997

Differential effects of colchicine and its B-ring modified analog MTPT on the assembly-independent GTPase activity of purified beta-tubulin isoforms from bovine brain.

Tubulin occurs as several isoforms whose physiological significance is not clear. The binding of colchicine to tubulin inhibits its assembly and is associated with a stimulation of the intrinsic GTPase activity of tubulin. In an effort to study the conformational states of different beta-tubulin isoforms in the drug-bound form, the intrinsic GTPase activity was studied in the presence of colchicine and its B-ring-modified analog MTPT. The results show that the GTPase activities of alpha beta II, alpha beta III, and alpha beta IV are 3.1, 2.8, and 2.6 nmole/h/ml. In the presence of colchicine, the values were increased to 4.5, 9.6, and 3 nmole/h/ml for alpha beta II, alpha beta III, and alpha beta IV respectively. In the case of MTPT, which lacks the B-ring, the GTPase activities were 5.8, 11.5, and 7.3 nmole/h/ml, respectively, for alpha beta II, alpha beta III, and alpha beta IV. The results show that the B-ring of colchicine contributes differentially to the conformational changes in the beta-tubulin isoforms.

Animals↗
PubMed1998

Colchicine differentially induces the expressions of nitric oxide synthases in central and peripheral catecholaminergic neurons.

This study was aimed at elucidating differences in nerve injury induced expression of nitric oxide synthases (NOS) between the peripheral and central catecholaminergic neurons. Colchicine was used to disrupt chemically the neuronal cytoskeletal integrity. A marked increase in the expression of neuronal NOS-IR and NADPH-diaphorase activity, a marker of neuronal NOS (nNOS), was seen in distinct populations of post-ganglionic sympathetic neurons of the superior cervical ganglion after intraganglionic colchicine injection. Similarly, immunoreactivity for the inducible form of NOS (iNOS) was induced in some sympathetic neuron somata. However, this immunoreactivity did not coincide with nNOS-IR. In contrast to the sympathetic neurons, hypothalamic arcuate and periventricular dopaminergic neurons did not show NOS-IR or NADPH-DA either in intact animals or in animals treated with an intracerebroventricular injection of colchicine. Immunoreactivity for the inducible form of NOS revealed no neuronal staining in the hypothalamic neurons in either group, while a large number of glia-resembling cells around the third ventricle showed slight expression of iNOS-IR. The present results show that expression of both neuronal and inducible forms of NOS may be induced by colchicine in some catecholaminergic neurons. It is suggested that these inductions are specific to certain catecholaminergic neuronal systems, like the sympathetic neurons, rather than a general property of catecholaminergic neurons.

Animals↗