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At least 19 recordsLinked to original sources
PubMed1992

Preclinical and clinical pharmacology of vinca alkaloids.

Vinca alkaloids, including vinblastine, vincristine, vindesine and vinorelbine, are widely used antineoplastic drugs, either as single agents or in combination with other drugs. The mechanism of action of these cell cycle-dependent agents is the inhibition of tubulin polymerisation into microtubules. Numerous studies have been conducted in animals and humans, using various in vivo and in vitro models, to investigate the pharmacological behaviour of this class of antitumour drug. Studies in cellular pharmacology demonstrate that vinca alkaloids are transported by multiple mechanisms, including passive diffusion and energy- and temperature-dependent active transport systems. Moreover, active efflux of drug is involved in the P-glycoprotein-mediated multidrug resistance to vinca alkaloids. This phenomenon may be modulated, in vivo and in vitro, by calcium antagonists and calmodulin inhibitors. The clinical pharmacokinetics of vinca alkaloids after intravenous bolus injection, continuous infusion and oral administration are characterised by a large apparent total volume of distribution, high total plasma clearance and long terminal elimination half-life. Biliary excretion is the main elimination pathway, with low urinary excretion. Pharmacokinetic parameters of vinca alkaloids are time- and dose-dependent, and large inter- and intra-individual variabilities have been observed. Human hepatic P-450IIIA cytochromes are involved in the metabolism of vindesine, vinblastine and probably other vinca alkaloids. Therefore, the possibility of drug-drug interactions must be considered when coadministering drugs in combination cancer chemotherapy. Development of newer semisynthetic analogues of vinca alkaloids and conjugation of vinca alkaloids with monoclonal antibodies may result in derivatives with increased antitumour activity and less clinical toxicity.

Animals↗
PubMed1988

Axotomy-induced ornithine decarboxylase activity in the mouse dorsal root ganglion is inhibited by the vinca alkaloids.

Vinca alkaloids were used to study the role of retrograde axon transport (RT) in activating neuron perikaryal repair response to nerve transection. Mouse lumbar dorsal root ganglia (DRG) (L4-L6) were excised 48 hours after unilateral transection of the sciatic nerve and ornithine decarboxylase (ODC) activity determined. ODC activity in DRG ipsilateral to nerve transection was increased 10-20 fold over contralateral values. Typical ODC activities in ipsilateral and contralateral DRG samples were 6.18 +/- 1.4 and 0.31 +/- 0.09 pmol 14CO2 released/h/3DRG, respectively. Systemic administration of single doses of either vincristine (1 mg/kg) or vinblastine (5 mg/kg) immediately prior to axotomy attenuated ODC induction in ipsilateral DRG by 39% and 47%, respectively. A direct inhibition of ODC activity in the DRG appears unlikely since only high concentrations of vinblastine (0.5-1.0 mM) were able to inhibit ODC activity in vitro. We suggest vinca alkaloids inhibit ODC induction as a consequence of disrupting retrograde axonal transport. Interruption of this intracellular communication mechanism may be etiologically linked to the the distal axon degeneration which follows repetitive exposure to vinca alkaloids and other agents that induce toxic axonal neuropathy.

Animals↗
PubMed1988

[Clinical pharmacokinetics of vinca alkaloids].

Vinca alkaloids (VA) represent a family of closely related molecules, which includes vincristine (VCR), vinblastine (VLB), vindesine (VDS) and navelbine (NVB), a new synthetic VA presently in phase II clinical trial. Development of sensitive and specific analytical tools (polyclonal and monoclonal antibodies) enabled us to investigate the kinetic behavior of VDS and NVB after IV bolus or long term administration. Following IV bolus injection, the mean pharmacokinetic parameters are: total plasma clearance: 0.53 l/h-1kg-1, 0.72 l/h-1kg-1 and apparent elimination half-life: 23.2 h, 39.5 h for VDS and NVB, respectively. Chronic treatment reveals time- and dose-dependence relationships and detailed observations of individual kinetics demonstrate an important interindividual variability for both drugs. Renal excretion of VDS and NVB is low (from 5 to 12% of the total dose), suggesting the important role of the liver in their rapid elimination.

Antineoplastic Agents↗
PubMedDate not supplied

Positive interaction of bisbenzylisoquinoline alkaloid, cepharanthin, with vinca alkaloid agents against human tumors.

Cepharanthin (CE), a bisbenzylisoquinoline alkaloid drug, was tested in vitro and in vivo with chemotherapeutic agents, vincristine (VCR), vinblastine (VLB), and vindesine (VDS). The activity of these agents alone or in combination was tested against a human colon cancer cell line (RPMI 4788) or a human uterine cervical cancer cell line (HeLa), using a modified microcytotoxicity-viable cell staining assay. In the in vitro study, the antiproliferative activities of each vinca alkaloid were enhanced additively or synergistically by combination with CE in RPMI 4788 cells as well as HeLa cells. The sequential exposure of the RPMI 4788 cells or HeLa cells to both CE and each vinca alkaloid agent showed evidence of a more significant potentiation. The antiproliferative activity of the combination of each vinca alkaloid agent(VCR, VLB, or VDS) with CE was almost equivalent to the effect of each vinca alkaloid agent alone which was potentiated by CE tenfold through several hundredfold. In an experimental model of tumor growth and survival, in which RPMI 4788 cells were transplanted subcutaneously or intraperitoneally into BALB/c nu/nu mice respectively, CE (1 mg/kg) alone exerted not significant inhibitory activity against tumor growth or survival, and VCR (0.25 mg/kg) alone partially inhibited these antitumor activities. Furthermore, the antitumor effects of VCR were elevated synergistically by the simultaneous administration of CE. These studies indicate that due to their therapeutic potential, combinations of vinca alkaloid agent with CE might be a promising therapy for some human cancers.

Alkaloids↗
PubMed1995

Reduction of toxicity of a vinca alkaloid by an anti-vinca alkaloid antibody.

Inadvertent oncolytic overdoses occur rarely, but can have serious consequences. We have investigated the possibility of using an antibody, 27.8.1A, reactive with vinca alkaloids, as a means of reducing the toxicity associated with overdose situations. In vitro cytotoxicity of a vinca derivative, 4-desacetyl- vinblastine-3-carbox-hydrazide (DAVLBHYD), with and without the addition of 27.8.1A, was determined. Using CCRF-CEM, a human acute lymphoblastic leukemia cell line, as a target in this assay, we observed a greater than 90% increase in cell viability using 100 micrograms/ml 27.8.1A with a 0.1 microgram/ml concentration of DAVLBHYD. 27.8.1A had no effect on cell viability when doxorubicin was used as a control drug in this assay. Similarly, the addition of an irrelevant antibody. EGFrL11, had no effect on the toxicity of DAVLBHYD. In an in vivo survival experiment, nude mice were injected with a toxic dose of DAVLBHYD and subsequently given four doses of 27.8.1A. All anti vinca antibody-treated mice survived, in contrast to the untreated group or irrelevant antibody-treated group in which only 25% and 10% of the mice survived, respectively.

Animals↗
PubMed1988

Tumour therapy with Vinca alkaloids targeted by a hybrid-hybrid monoclonal antibody recognising both CEA and Vinca alkaloids.

The functional properties of a hybrid-hybrid monoclonal antibody (MAb) recognising both CEA and Vinca alkaloids have been explored in vivo in nude mice xenografted with MAWI, a human colorectal tumour. The hybrid-hybrid MAb localises specifically onto CEA-expressing tumour tissue and, furthermore, is able to target Vinca alkaloids to tumour. Under the influence of the hybrid-hybrid MAb a profound change in the bio-distribution patterns of the Vinca alkaloids is observed. Therapeutic data produced in this in vivo model indicates that treatment with Vinca alkaloids in conjunction with hybrid-hybrid MAb is significantly more effective in suppressing tumour growth of established tumour xenografts than the Vincas when given as free drug.

Animals↗
PubMed1997

Vinorelbine (Navelbine): a third-generation vinca alkaloid.

The vinca alkaloids represent one of the oldest classes of antineoplastic agents used in humans with a wide spectrum of activity against both animal and human tumors. These agents are known to inhibit microtubule polymerization. Vinorelbine is a semisynthetic analog that reached clinical trial on the basis of less preclinical evidence of toxicity to neuronal tissue and greater cytotoxic activity in preclinical models than the older compounds of this class. In humans, the clearance of this agent shows a wide variation among subjects with the predominant toxicity being hematological. Significant antitumor activity has been observed in diseases that previously have been shown to respond to vinca alkaloids.

Animals↗
PubMed1997

Synthesis of vinca alkaloids and related compounds. Part 84. Sulfonamide derivatives of some vinca alkaloids with cardiovascular activity.

(+)-Vincamine (1) and (+)-vinpocetine (2) were chlorosulfonylated and the resulting sulfonyl chloride isomers (3-6) were transformed into sulfonamides (7-10). The ester group of sulfonamides was modified by selective hydrolysis and transesterification. Apovincaminol derivatives (14-16) were also prepared by reduction. In addition to the known cerebrovascular effects of the unsubstituted compounds (1,2) sulfonamides also show a significant peripheral vasodilator effect.

Animals↗
PubMed1993

Pharmacokinetics and metabolism of vinca alkaloids.

The anti-mitotic vinca alkaloids, vinblastine, vincristine, vindesine and navelbine, are widely used both as single agents and in combination with other antitumour drugs in cancer chemotherapy. Data on clinical pharmacokinetics following intravenous bolus injection, continuous infusion and oral administration show that vinca alkaloids are characterized by a large apparent total distribution volume, rapid total plasma clearance and a long terminal half-life. Faecal excretion is the main elimination route of vinca alkaloids in humans. Urinary excretion of these agents is generally low. Moreover, vinca alkaloid pharmacokinetics are time- and dose-dependent and show large inter- and intraindividual variability. When studied in various in vitro hepatic models (freshly isolated human and animal hepatocytes in suspension and in primary culture, isolated liver perfusion and human hepatic microsomal fractions), the vinca alkaloids were extensively biotransformed into a number of metabolites which have not yet been identified structurally. Incubation of vindesine and vinblastine with a library of human liver microsomal fractions demonstrated the involvement of the human hepatic cytochromes P4503A in the biotransformation of these and probably other vinca alkaloids. This finding is of great importance with regard to possible drug interactions between vinca alkaloids and other drugs administered concurrently in combination cancer chemotherapy.

Biotransformation↗
PubMed2002

Novel aspects of natural and modified vinca alkaloids.

The clinical interest of Vinca alkaloids was clearly identified as early as 1965 and so this class of compounds has been used as anticancer agents for more than 30 years. Today, two natural compounds, vinblastine and vincristine and two semi-synthetic derivatives, vindesine and vinorelbine, have been registered and thus Vinca alkaloids can be considered to represent a chemical class of definite utility in cancer chemotherapy. Today, relatively few groups actively research in the chemistry of Vinca alkaloids. However, using superacidic chemistry, a new family of such compounds was synthesised and vinflunine, a difluorinated derivative, was selected for clinical testing. A consideration of the pharmacological data relating to these new derivatives appears to reveal a lack of any marked correlation between in vitro and in vivo results. Furthermore, structure/activity relationships have failed to assist the chemist in the rational design. Such rational design of new derivatives is limited by the fact that the Vinca binding site(s) on tubulin and the exact mechanism(s) of action of Vinca alkaloids remain unclear. Nevertheless, the preclinical evaluations of the new derivative vinflunine have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identified properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semi-synthetic Vinca alkaloids. Thus, Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy.

Antineoplastic Agents, Phytogenic↗
PubMed1988

New cytoskeletal proteins are induced in HeLa cells by Vinca alkaloids.

The effects of Vinca alkaloids, vinblastine, vincristine, and vindesine, on protein synthesis were determined using HeLa cells. Vinblastine at the concentration of 1 microgram/ml induced new proteins, isoelectric points 4.8 and 7.0-7.5 and molecular weights 48 and 92 kd, in the HeLa cells, identified using two-dimensional gel electrophoresis. The 48-kd and the clustered (4-components) 92-kd proteins were also noted in HeLa cells treated with vincristine or vindesine. As most of the 48- and 92-kd proteins were Triton insoluble, they can be considered components of the cytoskeletal structure. Syntheses of these proteins were blocked by actinomycin D, therefore, new messenger RNA synthesis is required for induction. These proteins were not induced by an alkylating agent, antitumor antibiotics, or an antimetabolite. Our findings show that the 48- and the clustered 92-kd proteins are Vinca alkaloid reactive components and can be considered candidates for the elucidation of the antineoplastic effect of Vinca alkaloids.

Carbazilquinone↗
PubMed1995

Cytotoxicity, cell cycle kinetics and morphonuclear-induced effects of Vinca alkaloid anticancer agents.

The effects of four Vinca alkaloids (vinblastine, vincristine, vindesine and vinorelbine) on three neoplastic cell lines (the MXT mouse mammary cell line and the T24 and J82 bladder cell lines) were studied at three biological levels, i.e. cell proliferation, cell cycle kinetics and morphonuclear characteristics. These effects were studied by means of digital cell image analysis on Feulgen-stained nuclei. The aim of the present work was to characterize the effects specifically induced by Vinca alkaloids as compared with those obtained previously with other pharmacological classes of anticancer drugs. The results show that Vinca alkaloids inhibit the cell proliferation of neoplastic cell lines at a concentration of 10(-8) M except in the case of the J82 cell line, for which only a slowing down of cell proliferation was observed. Concerning the cell cycle kinetics, the results show that the Vinca alkaloids induce an accumulation of cells in the mitosis phase. This accumulation of mitotic cells was maximal after 15 h incubation in the presence of the drugs. A study of the morphonuclear-induced effects of Vinca alkaloids showed that the variance of the optical density (VOD) is strongly influenced by these Vinca alkaloids. The development of the VOD was parallel with the development of the percentage of mitosis; thus, the VOD enabled the Vinca alkaloid-induced effects to be specifically characterized from a morphonuclear point of view. On the other hand, the results show that the mean value of the variance of the optical density was very highly correlated (P < 0.001) with the efficiency of the Vinca alkaloids in terms of cytotoxicity. In clinical studies, the analysis of the development of this parameter would make it possible to assess the response to chemotherapy in the case of patients treated with Vinca alkaloids.

Adenocarcinoma↗
PubMed2001

Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells.

Vinca alkaloids are used extensively in the treatment of childhood acute lymphoblastic leukemia (ALL) and despite their usefulness, drug resistance remains a serious clinical problem. Vinca alkaloids bind to the beta-tubulin subunit of the alpha/beta-tubulin heterodimer and inhibit polymerization of microtubules. Recent studies have implicated altered beta-tubulin isotype expression and mutations in resistance to microtubule-stabilizing agents. Microtubule-associated protein (MAP) MAP4 binds to and stabilizes microtubules, and increased expression is associated with decreased sensitivity to microtubule-depolymerizing agents. To address the significance of beta-tubulin and MAP4 alterations in childhood ALL, two CCRF-CEM-derived Vinca alkaloid resistant cell lines, VCR R (vincristine) and VLB100 (vinblastine), were examined. Decreased expression of class III beta-tubulin was detected in both VCR R and VLB100 cells. VCR R cells and to a lesser extent VLB100 cells expressed increased levels of MAP4 protein. Increased microtubule stability was observed in these VCR R cells as identified by the high levels of polymerized tubulin (45.6 +/- 2.6%; P < 0.005) compared with CEM and VLB100 cells (24.7 +/- 3.3% and 24.7 +/- 2.5%, respectively). Expression was associated with a single MAP4 isoform in the polymerized microtubule fraction in CEM and VCR cells. In contrast, VLB100 cells expressed a lower molecular weight isoform in the polymerized fraction. Two-dimensional-PAGE and immunoblotting revealed marked posttranslational changes in class I beta-tubulin in VCR R cells not evident in CEM cells. Sequencing of the beta-tubulin (HM40) gene identified a point mutation in VCR R cells in nucleotide 843 (CTC-->ATC; Leu(240)-->Ile) that was not present in CEM or VLB100 cells. This mutation resides in a region of beta-tubulin that lies in close proximity to the alpha/beta tubulin interface. Multiple alterations related to normal microtubule function were identified in ALL cells selected for resistance to Vinca alkaloids, and these alterations may provide important insight into mechanisms mediating resistance to Vinca alkaloids.

Antineoplastic Agents, Phytogenic↗
PubMed1992

Aging of tubulin at neutral pH: the destabilizing effect of vinca alkaloids.

The effect of the vinca alkaloid drugs, vincristine, vinblastine, catharanthine, and vindoline, on the aging process of tubulin has been examined. It was found that addition of vincristine or vinblastine accelerated by a factor of 3-3.5 the transformation of tubulin from the 5.8 S alpha-beta-tubulin dimer to paucidisperse polymers, with an average sedimentation coefficient of 9 S, previously observed in the absence of drugs (V. Prakash and S. N. Timasheff, 1982, J. Mol. Biol. 160, 499-515). This transformation of tubulin from 5.8 S to "9 S" followed pseudo-first-order kinetics whether the starting protein was predominantly dimeric (i.e., at low drug concentration) or self-associated into the reversible linear polymers induced by the vinca alkaloid drugs at high drug concentration (G. C. Na and S. N. Timasheff, 1980, Biochemistry 19, 1355-1365; V. Prakash and S. N. Timasheff, 1985, Biochemistry 24, 5004-5010). Identical kinetics were found in a fluorescence examination of the loss by tubulin of its ability to bind colchicine specifically, indicating that the rate determining step is a protein conformational change that induces a major change in the far uv circular dichroism spectrum of tubulin. The found lack of an effect of dithiothreitol on the aging and aggregation processes is consistent with the irreversible aggregation being due to the intermolecular coalescence of nonpolar patches on the protein. The observations that vincristine binds to aged tubulin and that the aging of tubulin is accompanied by quenching of the tryptophan fluorescence similar to that which occurs on the binding of the vinca drugs has led to the proposal that the vinca alkaloids stabilize the aged conformation of the protein by interacting with nonpolar regions that may be related to the aggregation sites.

Animals↗