Immunopharmacology. 1978 Dec;1(1):71-82.
Enhancement of macrophage adenylate cyclase by microtubule disrupting drugs.

Grunspan-Swirsky A, Pick E.

Department of Human Microbiology, Tel-Aviv University, Sackler School of Medicine, Israel.

The accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in guinea-pig macrophages exposed to the adenylate cyclase (AC) stimulators prostaglandin E1 (PGE1) and isoproterenol (IP), was markedly enhanced by pretreatment of the cells with colchicine, vinblastine, and podophyllotoxin--agents which prevent microtubule assembly. The same agents did not augment basal cAMP levels. The facilitating effect of the drugs on the response to PGE1 and IP developed both in the absence and presence of a phosphodiesterase (PDE) inhibitor. The same drugs also enhanced the accumulation of cAMP induced by cholera toxin (CT) but the presence of a PDE inhibitor was required for such enhancement to become evident. Pretreatment of macrophages with cytochalasin B, an agent interfering with microfilament function, had no effect on the responsiveness of the cells to AC stimulators. The microtubule stabilizer, deuterium oxide (D2O) partially reversed the colchicine effect. Microtubule disrupting drugs did not block the release of cAMP from the cells into the surrounding medium. Macrophages incubated as monolayers or in suspension showed the same degree of increased responsiveness to stimulators after preexposure to colchicine. Preincubation with the ionophore A23187, which elevates the intracellular concentration of Ca2+, also enhanced the stimulation of AC by PGE1 and IP. Microtubule disrupting agents did not potentiate AC activity in broken cell preparations, whether added to the intact cells before disruption or directly to the enzyme assay mixture, nor did they affect PDE activity of macrophage sonicates. Moderate enhancement of PGE1-induced cAMP formation was also seen in colchicine- and vinblastine-treated lymphocytes. It was concluded that microtubules control the activity of AC by restricting the mobility of membrane receptors. Disruption of microtubules by drugs results in the removal of such restraints and an augmented chance of productive interactions between receptors and catalytic units of AC.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=45791&dopt=Abstract colchicine



Ann N Y Acad Sci. 1975 Jun 30;253:670-84.
Action of colchicine on axonal flow and pituicytes in the hypothalamopituitary system of the rat.

Dustin P, Hubert JP, Flament-Durand J.

Changes in the hypothalamo-pituitary tract and the pituicytes of the rat were studied after intrathecal and intraperitoneal injections of colchicine. Radioautography with 35S-cysteine demonstrates that intrathecal colchicine prevents the migration of neurosecretory granules from the supraoptic and paraventricular nuclei to the posterior lobe of the pituitary. This results in accumulations of neurosecretory granules and in the formation in the axons of elongated structures resembling neurosecretory products, although they sometimes have a fibrillary content. Neurotubules appear to remain intact in these conditions. The stimulation of the posterior pituitary by dehydration, in particular after injection of the diuretic furosemide, leads to an increased activity of pituicytes. When colchicine is injected at the same time as furosemide, a considerable new formation of centrioles is observed in the pituicytes. These become associated with ciliary vesicles, and form numerous cilia of the 9 + 0 type. An increased number of centrioles is also seen in the endothelial cells of the posterior lobe of the pituitary. These apparently paradoxical results were briefly discussed in relation to the action of colchicine on neurotubules and axonal flow and to the limited data from the literature indicating a stimulation of cilia formation under the action of colchicine and other drugs.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=50037&dopt=Abstract colchicine



J Cell Biol. 1975 Nov;67(2PT.1):461-7.
Microtubules and axoplasmic transport. Inhibition of transport by podophyllotoxin: an interaction with microtubule protein.

Paulson JC, McClure WO.

Pharmacological evidence is presented for the involvement of microtubules in the process of fast axoplasmic transport. A quantitative measure of the inhibition of axoplasmic transport in an in vitro preparation of rat sciatic nerve is described. The alkaloids colchicine, podophyllotoxin, and vinblastine, which are known both to disrupt microtubules and to bind to the protein subunit of microtubules, are inhibitors of axoplasmic transport. Lumicolchine and picropodophyllin, unlike their respective isomers colchicine and podophyllotoxin, are poor inhibitors of axoplasmic transport. The dissociation constants for the binding of colchicine, lumicolchicine, podophyllotoxin, and picropodophyllin to purified microtubule protein from rat brain have been measured. Inhibition of axoplasmic transport by these drugs correlates favorably with their affinities of microtubule protein.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=53233&dopt=Abstract colchicine



J Physiol. 1975 Oct;252(1):283-94.
A correlation between the effects of anti-mitotic drugs on microtubule assembly in vitro and the inhibition of axonal transport in noradrenergic neurones.

Banks P, Till R.

1. Podophyllotoxin, colchicine and griseofulvin inhibit the intra-axonal movement of noradrenaline storage vesicles in cat hypogastric nerve/inferior mesenteric ganglion preparations maintained in vitro, cause the disappearance of axonal microtubules and inhibit the assembly of microtubules from tubulin in vitro. The order of potency of the three effects is podophyllotoxin greater than colchicine greater than griseofulvin. 2. Lumicolchicine is without effect on the three parameters and does not interfere with the binding of tritiated colchicine to tubulin. 3. Podophyllotoxin causes a more rapid loss of microtubules from axons than the same concentration of colchicine. 4. The experiments provide strong evidence that microtubules are components of the system responsible for the intra-axonal migration of noradrenaline storage vesicles.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=53281&dopt=Abstract colchicine