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At least 19 recordsLinked to original sources
PubMed1977

Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on axonal fibrillar organelles in vitro.

Axonal ultrastructural changes induced by three Vinca alkaloids, vincristine, vinblastine, and desacetyl vinblastine amide, were studied in vitro at concentrations of 0.01, 0.05, and 0.1 mM in the cat vagus nerve. Disruption of microtubules, appearance of paracrystalline structures, and increase in neurofilaments were induced by all three agents at 0.1 mM. A new type of paracrystal with an electron-dense central core in each subunit was also observed with each drug. Whereas all three compounds affected unmyelinated fibers (vinblastine more so than the other two), only vinblastine significantly damaged the myelinated fibers. The greater effectiveness of vinblastine in causing these in vitro ultrastructural changes contrasts strikingly with the clinical in vivo situation in which vincristine is the most neurotoxic. This suggests that clinical neurotoxicity is associated with additional factors aside from the direct interaction of the Vinca alkaloids with microtubules or tubulin.

Animals↗
PubMed1978

Variables for predicting serious toxicity (vinblastine dose, performance status, and prior therapeutic experience): chemotherapy for metastatic testicular cancer with cis-dichlorodiammineplatinum(II), vinblastine, and bleomycin.

Combination chemotherapy utilizing high-dose vinblastine, bleomycin, and cisdichlorodiammineplatinum(II) (CDDP) is effective treatment for metastatic testicular cancer. Unfortunately, it is frequently associated with serious toxicity. In a series of 14 patients receiving 65 treatment cycles, several variables were examined as putative risk factors for prediction of serious toxicity. These included drug dose normalized to body weight or surface area, interval since previous cycle, prior therapeutic experience with either radiation therapy or other cytotoxic chemotherapy, and Karnofsky performance status. The strongest determinant of serious toxicity was the vinblastine dose calculated according to body weight. The next most influential prognostic variables were the performance status and a history of previous treatment with either radiation therapy or chemotherapy. Serious toxicity may be anticipated at a frequency of 40% when vinblastine is administered at a total dose of 0.36 mg/kg with bleomycin and CDDP. In our group of patients, the nephrotoxicity of CDDP appeared to be cumulative despite intensive diuresis at the time of administration. Pulmonary toxicity was not observed. Modest reductions in vinblastine dose, especially in patients with poor performance status or a history of previous radiation or other chemotherapy, will substantially lower the frequency of serious toxicity.

Adolescent↗
PubMed1976

Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro.

The Vinca alkaloids differ in their chemotherapeutic effectiveness and their toxicities. To determine whether differences are due to a differential effect on the assembly of tubulin into microtubules, we examined the effects of vincristine, vinblastine, and a newer alkaloid, desacetyl vinblastine amide, on the assembly of bovine brain tubulin in vitro. The three compounds block bovine tubulin polymerization in vitro and almost equally effectively at a 1 muM concentration (tubulin, 6.5 muM). At 10 muM, the three alkaloids also interact with preformed microtubules in vitro, causing spiral-like distortions of the microtubules. No effect of the alkaloids on polymerization of another fibrous protein, actin, was observed. Thus the differential actions of vinblastine, vincristine, and desacetyl vinblastine amide in vivo seems to be based on some biological process other than the reaction with tubulin or the microtubules per se.

Animals↗
PubMed1977

Cyclophosphamide, vinblastine, procarbazine and prednisone with CCNU and vinblastine maintenance for advanced Hodgkin's disease.

Fifty patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in a 21-day cyclic regimen. Thirty-one patients (62%) achieved a pathologically documented complete remission (CR). Of the 23 previously untreated patients, 13 obtained CR. Twenty-seven patients had been previously treated and 15/19 (79%) of those with prior major radiation therapy and 3/8 (37.5%) of those who had received both irradiation and chemotherapy achieved CR. Sixteen of the patients who attained CR received maintenance therapy with monthly alternating CCNU and vinblastine but as of this report, neither remission duration nor survival is significantly prolonged when compared to the 14 patients followed in remission on no therapy. Patients who received more than six courses of induction therapy (median 9.5, range 8-12) have had significantly fewer relapses and longer remissions than have those patients who received only six courses of therapy. It is concluded that: 1) CVPP is an effective regimen at inducing CR in patients with advanced Hodgkin's disease and has less gastrointestinal and neurologic toxicity than MOPP; 2) maintenance therapy with CCNU and vinblastine to date has not been beneficial; and 3) greater than six courses of induction chemotherapy prolongs remission duration and is associated with fewer disease relapses.

Adult↗
PubMed1979

Adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) therapy for advanced Hodgkin's disease resistant to mustine, vinblastine, procarbazine and prednisolone (MVPP).

Forty-one previously treated patients with advanced Hodgkin's disease were treated with a combination chemotherapy regimen -- ABVD (adriamycin, bleomycin, velbe/vincristine, imidazole carboxamide). Complete remission was achieved in three patients (7%), partial remission in 23 (56%), and no response in 15 patients (37%). The median survival of the group was 12 months from the start of therapy. Survival correlated with response to treatment. No apparent benefit resulted from giving more than six courses of therapy (3 months' treatment time). There was no serious haematological toxicity in patients without bone marrow disease, and bleomycin and adriamycin toxicity was not apparent clinically or at autopsy in the dosages employed in the regime. Alopoecia was very frequent. The role for ABVD, other than as a primary induction regimen, appears to be in conjunction with other regimens in the induction of patients with adverse features at presentation or during induction; or in the salvage and palliation of patients who demonstrate a response but fail to achieve remission, either initially or at relapse, with MOPP (mustine, vincristine rpocarbazine, and prednisolone) or MVPP (mustine, vinblastine, procarbazine and prednisolone.

Adolescent↗
PubMed1976

In vitro studies on the nature of vinblastine inhibition of thyroid secretion.

The effects of vinblastine on thyroid secretion have been studied in mouse thyroid glands in vitro. Inhibition of the secretory response to TSH was observed within the first 30 min of exposure to vinblastine and was largely complete after 1 h. Inhibition of colloid droplet formation and hormonal radioiodine release was comparable for both TSH and cyclic AMP stimulation. No reversal of inhibition was seen when thyroids exposed to vinblastine were subsequently washed 2 or 4 h in vinblastine free mediu, nor could previous vinblastine inhibition be overcome by high levels of TSH or dibutyryl cyclic AMP. Ultrastructural effects of vinblastine (1 X 10(-5)M) were studied under conditions similar to those used to demonstrate inhibition of secretion. Microtubules present in thyroids incubated in control medium were reduced after 30 min and almost completely abolished after 1 or 2 h exposure to vinblastine. No other reproducible structural changes were seen. A higher concentration of vinblastine (5 X 10(-5)M), however, produced lysosomal clumping and the formation of numerous vinblastine crystalloids. Uptake and washout of [3H]-vinblastine were studied with both phases showing fast and slow components. The initial uptake phase (T1/2 approximately 12 min) correlates well with the disappearance of microtubules and the inhibition of thyroid secretion. A prolonged washout component (T1/2 = 10-18 h) may account for the irreversibility of vinblastine inhibition of in vitro thyroid secretion. It is concluded that inhibition of thyroid secretion produced by vinblastine is consistent with its actions on thyroidal microtubules.

Animals↗
PubMed1978

The effects of vinblastine on acinar cells of the exorbital lacrimal gland of the rat.

The effects of vinblastine treatment on acinar cells of the rat exorbital lacrimal gland were studied by electron microscopy. Experimental animals of both sexes were given single intraperitoneal injections of (1) vinblastine (4 mg/kg body weight) at 1 to 24 h before sacrifice; (2) pilocarpine (20 mg/kg b.w.) for 1 h; or (3) vinblastine for 1 h followed by pilocarpine for 1 h. Vinblastine treatment caused a number of changes including autophagocytosis, formation of intracisternal granules, and alteration of secretory granules. These changes varied in extent and onset between male and female rats. In addition, the Golgi apparatus was reduced in size and dispersed throughout the cytoplasm. Mitotic figures were commonly observed. Moreover, vinblastine inhibited the pilocarpine-stimulated degranulation of the acinar cells. In view of the known anti-microtubular action of vinblastine, these results suggest that microtubules are involved in various aspects of the transport, packaging, and secretion of exportable proteins in the lacrimal gland. Additionally, autophagocytosis and alteration of secretory granules may partially result from the interaction of vinblastine with membranes.

Animals↗
PubMed1975

Effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell following sulphonylurea and isopropyl-noradrenaline.

The effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell was studied in mice. Treatment with vinblastine (1.1 mumole/mouse) resulted in a 75% decrease of the amount of normal microtubules and the appearance of characteristic paracrystals. Basal plasma immunoreactive insulin levels were depressed to about 60% of the control level. The dose-response pattern for insulin release (first phase) following two chemically unrelated insulin secretagogues, the potent sulphonyl-urea derivative, glibenclamide, and the beta-adrenegic agonist L-isopropylnoradrenaline, (L-IPNA), was tested with and without vinblastine pretreatment. The dose-response curves for L-IPNA-induced insulin release in vinblastine-treated and control animals did not deviate significantly from each other, whereas insulin release following glibenclamide was almost totally suppressed by vinblastine except at the lowest dose level. Injection of maximal doses of glibenclamide or L-IPNA did not alter the ultrastructural changes induced by vinblastine in the B-cells. It is suggested that the microtubular system of the B-cell might play a minor role for certain insulin-releasing processes and/or that vinblastine might have other important effects on the insulin secretory machinery.

Animals↗
PubMed1978

Effect of colchicine and vinblastine on rat intestinal water transport and Na-K-ATPase activity.

The hypothesis that colchicine and vinblastine, which are commonly used for therapeutic purposes and known to cause diarrhoea, decrease intestinal water transport by inhibition of Na-K-ATPase activity was tested in rats. Net fluid transport by jejunal segments was measured four hours after intraperitoneal injection of either 0.15 M NaCl (0.5 ml/100 g), colchicine (0.5 mg/100 g b.w.), or vinblastine (1.0 mg/100 g b.w.). Colchicine and vinblastine decreased net fluid transport: 3.0 +/- 0.9 (SE) and 4.6 +/- 0.4 (SE) respectively, as compared to that transported by segments from rats injected with 0.15 M NaCl, 8.6 +/- 0.7 (SE) g fluid/hour/g. Methylprednisolone (3.0 mg/100 g b.w.) abolished the inhibitory effect of cholchicine and vinblastine on fluid transport. Colchicine and vinblastine were found to decrease significantly mucosal Na-K-ATPase activity, 18.2 +/- 4.9 (SE); 25.2 +/- 2.4 (SE) respectively, as compared to that measured in rats injected with saline 40.6 +/- 3.4 (SE) mumol/mg protein/hour. Pretreatment with methylprednisolone prevented the decrease in enzyme activity observed in rats injected with colchicine and vinblastine. The degree of inhibition in intestinal Na-K-ATPase activity was similar to that observed in fluid transport following colchicine and vinblastine. It is thus suggested that colchicine-induced inhibition of water transport is caused by inhibition of Na-K-ATPase activity, an effect which can be prevented by pretreatment with methyl-prednisolone.

Adenosine Triphosphatases↗
PubMed1978

The effects of lumicolchicine, colchicine and vinblastine on pigment migration in fish chromatophores.

The effects of lumicolchicine, colchicine, vinblastine and cold temperature on the pigment migration in melanophores and xanthophores of Fundulus heteroclitus and Oryzias latipes were examined by light and electron microscopy. Xanthophores of both species which contain numerous microfilaments and a poorly developed microtubule system were extremely sensitive to the alkaloids. Lumicolchicine and colchicine induced irreversible dispersion while vinblastine caused permanent aggregation of the pigments. Treatment in lumicolchicine or colchicine at 5 mM for 60 minutes did not disrupt microtubules of melanophores to an appreciable degree, however, melanosome aggregation was partially inhibited by these drug in Oryzias. When melanophores were kept in the cold in the presence of colchicine at 1 mM, almost all microtubules were disrupted and their repolymerization at room temperature was nearly completely inhibited by colchicine. These melanophores lacking in microtubules responded to epinephrine with slow aggregation. Vinblastine at 0.1 mM induced partial aggregation of melanosomes and disruption of microtubules but most melanophores were still able to respond with pigment migration. Vinblastine at 1 mM made all melanophores punctate and immobile. Large vinblastine-induced crystals were frequently seen in the dendritic processes. The results of the present investigation suggest that cytoplasmic microtubules in fish melanophores facilitate melanosome migration only in directional orientation and appear not be responsible for the motive force.

Animals↗
PubMed1975

Reversible ultrastructural changes of arcuate neurons after vinblastine injection into the median eminence of the rat.

The ultrastructural effects of vinblastine on the arcuate neurons and median eminence were studied in the rat. The animals were stereotaxically injected with solutions of 1 mM and 5 mM vinblastine into the median eminence and killed 3, 8 and 21 days after injection. Eight days after injection of 1 mM vinblastine the neurons of the arcuate nucleus showed marked changes. The Golgi complex was more distinct and considerable increases in the populations of dense bodies, granulated vesicles and coated vesicles were observed. Changes in the axo-somatic synapses and degenerating fibers in the surrounding neuropil were also characteristic of the experimental animals. The outer zone of the median eminence showed numerous degenerated nerve fibers and fibers engulfed by glial cell processes. Eight days after injection of 5 mM vinblastine arcuate neurons and median eminence showed similar changes, but quantitative differences were noted. A striking ultrastructural recovery of the arcuate neurons and axons in the outer zone of the median eminence was observed 21 days after injection of either 1 mM or 5 mM vinblastine. The results are discussed in relation to axoplasmic transport and axonal degeneration.

Animals↗
PubMed1978

The influence of vinblastine and colchicine on renin secretion in vivo and in vitro.

The effect of the microtubule inhibitors colchicine and vinblastine on renin release in vivo and in vitro was studied. Injection of 0.5 mg/100 g i.v. of colchicine or vinblastine to furosemide treated rats on a low salt diet resulted in a decrease of plasma renin as well as plasma angiotensinogen concentration during a 5 h observation period. Renin release from rat kidney slices was diminished by vinblastine (5 x 10(-5) M), when basal or stimulated (by isobutylmethylxanthine and isoproterenol) renin release was measured. Colchicine at 5 x 10(-5) M had no effect under these conditions. Renin release from the isolated perfused rat kidney was increased 2--3 fold by vinblastine (10(-5) M) or colchicine (10(-4) M). The maximal response of renin release to isoproterenol (10(-7) M) was not changed when vinblastine (10(-5) M) or colchicine (10(-4) M) were present in the perfusion medium. The contrasting results cast considerable doubts on the suitability of microtubule inhibitors in studies on renin secretion.

Angiotensinogen↗
PubMed1977

Radioimmunoassay of vinblastine and vincristine.

1 The cytotoxic agent, vinblastine, was conjugated to albumin, using the Mannich reaction. Rabbits immunized with two conjugates, containing differing amounts of hapten, produce antibodies which bound [3H]-vinblastine. 2 Antisera from one rabbit cross-reacted with both vinblastine and vincristine and were used to develop radioimmunoassays for measuring their concentration in plasma. 3 The antisera showed no cross-reactivity with other alkaloids or cytotoxic drugs and provided assays sensitive to a concentration of 2.1 ng vinblastine or 3.8 ng vincristine/ml of plasma added direct to the assay tubes. 4 This is sufficiently sensitive to permit the measurement of plasma vinblastine levels for up to 24 h after the intravenous administration of 15 mg of the drug.

Animals↗
PubMed1975

Vinblastine: influence on nerve conduction and synaptic transmission.

Vinblastine injected into the eyes of pigeons had a detrimental effect on the amplitude of the postsynaptic evoked potential in the optic tectum; impulse conduction of the optic nerve was not influenced. The depression of the postsynaptic evoked potential was dependent on the dosage. Only 20 and 100 mug vinblastine had an influence; no influence was observed with 10 mug vinblastine. The reversible depression was seen from the third day after injection to between the 21st and the 28th day after injection, and in that period it remained constant. The latency of the response was not influenced by vinblastine.

Animals↗
PubMed1979

Specific inhibition of a calcium dependent activation of brain cyclic AMP phosphodiesterase activity by vinblastine.

Vinblastine selectively inhibits the activation of brain cyclic AMP phosphodiesterase activity by Ca++-protein activator (50% inhibition by 2 x 10(-5) M). This inhibitory effect was reversed by excessive amounts of the activator, whereas large quantities of Ca++ caused only a slight suppression of the vinblastine effect. This result of vinblastine suggests a new site of its action and also suggests the possible role of protein activator, phosphodiesterase proteins or cyclic nucleotides in the previously known effects of vinblastine in vivo and in vitro.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Effect of vinblastine on the brush border of proximal tubule cells of rat kidney.

A vinblastine-induced lesion of the brush border of proximal tubule cells of rat kidney was studied by scanning and transmission electron microscopy. Adult rats were given two tail-vein injections of vinblastine sulfate and then sacrificed either three or sixteen hours after administration of the first injection. The proximal tubules of animals treated with the drug for three hours differed from those of saline-treated controls in possessing (1) well defined areas of apical cell surface devoid of microvilli and (2) fewer microcraters in the brush border. In tubules of animals treated with vinblastine for sixteen hours, the areas devoid of microvilli were much more extensive, and microcraters were less frequently seen. Cilia did not appear to be affected by exposure to the drug and were observed both in regions devoid of microvilli and in areas with a well developed brush border. The mechanism of action of vinblastine in eliciting focal loss of microvilli of proximal tubule cells is not known. Several hypotheses to account for this lesion of the brush border are discussed.

Animals↗
PubMed1977

Inhibition of the rapid movement of optically detectable axonal particles colchicine and vinblastine.

The rapid saltatory motion of intra-axonal particles detected by dark-field microscopy in myelinated axons isolated from sciatic nerves of adult Xenopus laevis was inhibited by colchicine or vinblastine at a concentration of larger than or equal to 0.1 mM. Both the predominant somatopetal transport and the somatofugal transport of these round particles were inhibited. The reduction in numbers of moving particles was apparent first in the juxtanodal portions of the isolated axons within about 1 h. No particles could be detected moving by 3-5 h after application of the colchicine or vinblastine. During the phase of partial inhibition, those particles that were still progressing along the axon did so at apparently normal velocities while they were in motion, but remained stationary increasingly frequently and for progressively longer periods. Colchicine or vinblastine at a concentration of less than or equal to 10 micronM caused no observable inhibition within 4 h of application. Colchicine at a concentration of larger than or equal to 10 mM caused local accumulation of round particles, and vinblastine at a concentration of larger than or equal to 2.5 mM caused fragmentation of rod-shaped organelles, believed to be mitochondria. Electron microscopy of nerve fibers treated with 5 mM colchicine showed a progressive loss of microtubules from the axoplasm, such that approximately 70% of the microtubules had disappeared after 4h.

Animals↗