Vinflunine

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Anna Kruczynski - One of the best experts on this subject based on the ideXlab platform.

  • Anti-Migratory Effect of Vinflunine in Endothelial and Glioblastoma Cells Is Associated with Changes in EB1 C- Terminal Detyrosinated/Tyrosinated Status
    2016
    Co-Authors: Ine Rovini, Anna Kruczynski, Diane Braguer
    Abstract:

    We previously showed that Vinflunine, a microtubule-targeting drug of the Vinca-alkaloid family exerted its anti-angiogenic/ anti-migratory activities through an increase in microtubule dynamics and an inhibition of microtubule targeting to adhesion sites. Such effect was associated with a reduction of EB1 comet length at microtubule (+) ends. In this work we first showed that the pro-angiogenic vascular endothelial growth factor VEGF suppressed microtubule dynamics in living Human Umbilical Vein Endothelial Cells (HUVECs), increased EB1 comet length by 40%, and induced EB1 to bind all along the microtubules, without modifying its expression level. Such microtubule (+) end stabilization occurred close to the plasma membrane in the vicinity of focal adhesion as shown by TIRF microscopy experiments. Vinflunine completely abolished the effect of VEGF on EB1 comets. Interestingly, we found a correlation between the reduction of EB1 comet length by Vinflunine and the inhibition of cell migration. By using 2D gel electrophoresis we demonstrated for the first time that EB1 underwent several post-translational modifications in endothelial and tumor cells. Particularly, the C-terminal EEY sequence was poorly detectable in control and VEGF-treated HUVECs suggesting the existence of a non-tyrosinated form of EB1. By using specific antibodies that specifically recognized and discriminated the native tyrosinated form of EB1 and a putative C-terminal detyrosinated form, we showed that a detyrosinated form of EB1 exists in HUVECs and tumor cells. Interestingly, Vinflunine decreased the level of the detyrosinated form and increased the native tyrosinated form of EB1

  • stathmin potentiates Vinflunine and inhibits paclitaxel activity
    PLOS ONE, 2015
    Co-Authors: Soazig Malesinski, Philipp O Tsvetkov, Vincent Peyrot, Anna Kruczynski, Francois Devred
    Abstract:

    Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, Vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of Vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency.

  • Thermodynamic analysis of stathmin-tubulin interaction.
    2015
    Co-Authors: Soazig Malesinski, Philipp O Tsvetkov, Vincent Peyrot, Anna Kruczynski, Francois Devred
    Abstract:

    Vinflunine increases stathmin binding to tubulin whereas paclitaxel does not. Typical curves of: A: raw data obtained for 25–30 injections, each of 10 μL of stathmin (80 μM) into the sample cell containing tubulin (10 μM) in the presence or the absence of MTAs. The three titration curves (which were translated upward for clarity purposes) were obtained during one set of experiments; curve A corresponds to stathmin binding to tubulin in the absence of MTA, curve B corresponds to stathmin binding to tubulin in the presence of Vinflunine (10μM), whereas curve C corresponds to stathmin binding to tubulin in the presence of paclitaxel (10μM). B: integrated heats of reaction (symbols) in the absence of MTAs (squares), in the presence of Vinflunine (circles) and in the presence of paclitaxel (triangles) with the best fit to the data (lines). The measurements were carried out at 37°C in PM buffer (20 mM NaPi, GTP 0.1 mM MgCl2 4mM pH 6.5).

  • Anti-Migratory Effect of Vinflunine in Endothelial and Glioblastoma Cells Is Associated with Changes in EB1 C-Terminal Detyrosinated/Tyrosinated Status
    PLoS ONE, 2013
    Co-Authors: Amandine Rovini, Anna Kruczynski, Géraldine Gauthier, Raphael Berges, Diane Braguer, Stéphane Honoré
    Abstract:

    We previously showed that Vinflunine, a microtubule-targeting drug of the Vinca-alkaloid family exerted its anti-angiogenic/ anti-migratory activities through an increase in microtubule dynamics and an inhibition of microtubule targeting to adhesion sites. Such effect was associated with a reduction of EB1 comet length at microtubule (+) ends. In this work we first showed that the pro-angiogenic vascular endothelial growth factor VEGF suppressed microtubule dynamics in living Human Umbilical Vein Endothelial Cells (HUVECs), increased EB1 comet length by 40%, and induced EB1 to bind all along the microtubules, without modifying its expression level. Such microtubule (+) end stabilization occurred close to the plasma membrane in the vicinity of focal adhesion as shown by TIRF microscopy experiments. Vinflunine completely abolished the effect of VEGF on EB1 comets. Interestingly, we found a correlation between the reduction of EB1 comet length by Vinflunine and the inhibition of cell migration. By using 2D gel electrophoresis we demonstrated for the first time that EB1 underwent several post-translational modifications in endothelial and tumor cells. Particularly, the C-terminal EEY sequence was poorly detectable in control and VEGF-treated HUVECs suggesting the existence of a non-tyrosinated form of EB1. By using specific antibodies that specifically recognized and discriminated the native tyrosinated form of EB1 and a putative C-terminal detyrosinated form, we showed that a detyrosinated form of EB1 exists in HUVECs and tumor cells. Interestingly, Vinflunine decreased the level of the detyrosinated form and increased the native tyrosinated form of EB1. Using 3-L-Nitrotyrosine incorporation experiments, we concluded that the EB1 C-terminal modifications result from a detyrosination/retyrosination cycle as described for tubulin. Altogether, our results show that Vinflunine inhibits endothelial cell migration through an alteration of EB1 comet length and EB1 detyrosination/retyrosination cycle.

  • anti angiogenic vascular disrupting and anti metastatic activities of Vinflunine the latest vinca alkaloid in clinical development
    European Journal of Cancer, 2006
    Co-Authors: Anna Kruczynski, Bridget T Hill, Maura Poli, Romina Dossi, Eric Chazottes, Geraldine Berrichon, Christel Ricome, Raffaella Giavazzi, Giulia Taraboletti
    Abstract:

    Abstract The aim of this study was to investigate the anti-angiogenic, vascular-disrupting and anti-metastatic properties of Vinflunine, the latest vinca alkaloid in phase III clinical development. The effects of Vinflunine on in vitro endothelial cell functions relevant to the performance of an already formed vasculature and to the angiogenic process were evaluated. The in vivo anti-angiogenic properties of Vinflunine were also investigated, as were its activity against a model of experimental metastasis. In vitro Vinflunine induced a rapid change in the morphology of endothelial cells and disrupted the network of capillary-like structures, indicating potential vascular-disrupting activity. Furthermore, Vinflunine showed anti-angiogenic properties, since it inhibited endothelial cell migration and the capacity of these cells to organise into a network of capillary-like structures. All these effects were observed under conditions that only marginally affect endothelial cell proliferation. In vivo , Vinflunine inhibited bFGF-induced angiogenesis in Matrigel implants at doses 40–20-fold lower than its maximal therapeutic dose (MTD). Treatment of mice with Vinflunine reduced the number of liver metastases induced by intrasplenic injection of LS174T cells, with significant effects also observed at low doses; i.e. 16-fold lower than the MTD. This study demonstrates that Vinflunine expresses both vascular-disrupting and anti-angiogenic activities and induced marked effects against experimental metastases, all properties that support its ongoing clinical development.

Joaquim Bellmunt - One of the best experts on this subject based on the ideXlab platform.

  • a randomized phase ii iii study of cabazitaxel versus Vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium secavin
    Annals of Oncology, 2017
    Co-Authors: Joaquim Bellmunt, J M Kerst, Federico Vazquez, Rafael Moralesbarrera, Enrique Grande, Ana Medina, M Gonzalez B Graguera, Gustavo Rubio, Urbano Anido, Fernandez O Calvo
    Abstract:

    ABSTRACT Background Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus Vinflunine. Patients and methods This is a multicenter, randomized, open-label, phase II/III study, following a Simon’s optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. Results Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7–32.4) and six patients (30%) in the Vinflunine arm (95% CI 11.9–54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for Vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring Vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. Conclusion This phase II/III second line bladder study comparing cabazitaxel with Vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. Trial number NCT01830231.

  • a randomized phase ii iii study of cabazitaxel versus Vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium secavin
    Journal of Clinical Oncology, 2017
    Co-Authors: Joaquim Bellmunt, J M Kerst, Enrique Grande, Ana Medina, Gustavo Rubio, Urbano Anido, Rafael Morales, Federico Vazquez Mazon, Belen Gonzalez Gragera, Ovidio Fernandez Calvo
    Abstract:

    285Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs Vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to Vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival...

  • Vinflunine gemcitabine versus Vinflunine carboplatin as first line chemotherapy in cisplatin unfit patients with advanced urothelial carcinoma results of an international randomized phase ii trial jasint1
    Annals of Oncology, 2016
    Co-Authors: M De Santis, Joaquim Bellmunt, Pawel Wiechno, C Lucas, Laurence Albiges, C C Lin, Elzbieta Senkuskonefka, Aude Flechon, Loic Mourey, Andrea Necchi
    Abstract:

    Background: There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two Vinflunine-based cytotoxic regimens in this setting. Patients and methods: Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received Vinflunine 250 or 280 mg/m2 (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m2 escalated to 1000 mg/m2 in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, β = 20%). Results: Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. Conclusion: Both Vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study.

  • long term survival results of a randomized phase iii trial of Vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum based chemotherapy
    Annals of Oncology, 2013
    Co-Authors: Joaquim Bellmunt, Fabio A.b. Schutz, Jonathan E. Rosenberg, Stephane Culine, Ronan Fougeray, H Von Der Maase, Yacine Salhi, Toni K. Choueiri
    Abstract:

    Abstract Background To compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with Vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy. Patients and methods Three hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to Vinflunine (320 or 280 mg/m2) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of Vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454–4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m. Results Three hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for Vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of Vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570–0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61–0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death. Conclusions The updated OS data confirm the positive treatment effect of Vinflunine on survival that was previously reported. These results are consistent over time and confirm that Vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.

  • Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid
    Expert opinion on drug safety, 2011
    Co-Authors: Fabio A.b. Schutz, Joaquim Bellmunt, Jonathan E. Rosenberg, Toni K. Choueiri
    Abstract:

    Introduction: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, Vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry. Areas covered: The authors describe the development of the new vinca alkaloid Vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of Vinflunine. In vitro and in vivo studies have shown a superior efficacy of Vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of Vinflunine against different malignancies. Phase III trials showed that Vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the seco...

Bridget T Hill - One of the best experts on this subject based on the ideXlab platform.

  • anti angiogenic vascular disrupting and anti metastatic activities of Vinflunine the latest vinca alkaloid in clinical development
    European Journal of Cancer, 2006
    Co-Authors: Anna Kruczynski, Bridget T Hill, Maura Poli, Romina Dossi, Eric Chazottes, Geraldine Berrichon, Christel Ricome, Raffaella Giavazzi, Giulia Taraboletti
    Abstract:

    Abstract The aim of this study was to investigate the anti-angiogenic, vascular-disrupting and anti-metastatic properties of Vinflunine, the latest vinca alkaloid in phase III clinical development. The effects of Vinflunine on in vitro endothelial cell functions relevant to the performance of an already formed vasculature and to the angiogenic process were evaluated. The in vivo anti-angiogenic properties of Vinflunine were also investigated, as were its activity against a model of experimental metastasis. In vitro Vinflunine induced a rapid change in the morphology of endothelial cells and disrupted the network of capillary-like structures, indicating potential vascular-disrupting activity. Furthermore, Vinflunine showed anti-angiogenic properties, since it inhibited endothelial cell migration and the capacity of these cells to organise into a network of capillary-like structures. All these effects were observed under conditions that only marginally affect endothelial cell proliferation. In vivo , Vinflunine inhibited bFGF-induced angiogenesis in Matrigel implants at doses 40–20-fold lower than its maximal therapeutic dose (MTD). Treatment of mice with Vinflunine reduced the number of liver metastases induced by intrasplenic injection of LS174T cells, with significant effects also observed at low doses; i.e. 16-fold lower than the MTD. This study demonstrates that Vinflunine expresses both vascular-disrupting and anti-angiogenic activities and induced marked effects against experimental metastases, all properties that support its ongoing clinical development.

  • the effects of Vinflunine vinorelbine and vinblastine on centromere dynamics1
    Molecular Cancer Therapeutics, 2003
    Co-Authors: Tatiana Okouneva, Bridget T Hill, Leslie Wilson, Mary Ann Jordan
    Abstract:

    Vinflunine is a novel fluorinated Vinca alkaloid currently in Phase II clinical trials, which in preclinical studies exhibited superior antitumor activity to that of two clinically useful Vinca alkaloids, vinorelbine and vinblastine. All three of the drugs block mitosis at the metaphase/anaphase transition, leading to apoptosis. The mechanism of the mitotic block is not known. On the basis of results with purified microtubules and in living interphase cells, we hypothesized that it involves suppression of spindle microtubule dynamics. Here we measured the effects of the three Vinca alkaloids on dynamics of centromeres and spindle kinetochore-microtubules by a novel approach involving quantitative time-lapse confocal microscopy in living mitotic human U2OS cells. Green fluorescent protein-labeled centromere-binding protein B was used to mark centromeres and kinetochore-microtubule plus ends. In controls, pairs of centromeres on sister chromatids alternated under tension between increasing and decreasing separation (stretching and relaxing). All three of the Vinca alkaloids suppressed centromere dynamics similarly at concentrations that block mitosis. At concentrations approximating the IC50s for mitotic accumulation (18.8 nm Vinflunine, 7.3 nm vinorelbine, and 6.1 nm vinblastine), centromere dynamicity decreased by 44%, 25%, and 26%, respectively, and the time centromeres spent in a paused state increased by 63%, 52%, and 36%, respectively. Centromere relaxation rates, stretching durations, and transition frequencies all decreased. Thus all three of the drugs decreased the normal microtubule-dependent spindle tension at the centromeres/kinetochores, thereby preventing the signal for mitotic checkpoint passage. The strong correlation between suppression of kinetochore-microtubule dynamics and mitotic block indicates that the primary mechanism by which the Vinca alkaloids block mitosis is suppression of spindle microtubule dynamics.

  • Vinflunine the latest vinca alkaloid in clinical development a review of its preclinical anticancer properties
    Critical Reviews in Oncology Hematology, 2001
    Co-Authors: Anna Kruczynski, Bridget T Hill
    Abstract:

    Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of Vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of Vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of Vinflunine in combination therapy have revealed a high level of synergy when Vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although Vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that Vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for Vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of Vinflunine have been completed in Europe and phase II clinical trials are now ongoing.

  • Vinflunine a second generation novel vinca alkaloid with a distinctive pharmacological profile now in clinical development and prospects for future mitotic blockers
    Current Pharmaceutical Design, 2001
    Co-Authors: Bridget T Hill
    Abstract:

    The pharmacological profile of Vinflunine, a novel bi-fluorinated derivative of vinorelbine is summarised. Detailed comparisons, based on in vitro and in vivo experimental preclinical data, of Vinflunine with its parent molecule and the classic Vinca alkaloids, exemplified by vincristine or vinblastine, have revealed certain qualitative and quantitative differences between these first and second generation Vincas. Evidence is gradually accruing indicating that certain more subtle mechanistic differences exist in relation to the precise interactions of these individual molecules with cellular microtubules involving, for example, their suppression of microtubule dynamics. It is tempting, but premature, to suggest that these may be associated with the markedly superior in vivo antitumour activity of Vinflunine documented in a series of murine and human xenografted tumour models. The in vivo antivascular effects of Vinflunine, identified at doses below those required for optimal antitumour activity, coupled with the demonstrated potential value of Vinflunine as a component of combination regimens, together with the finding that resistance to Vinflunine was generated far less readily than to vinorelbine, augur well for the ongoing clinical development of this new agent. Finally, it is proposed that as our knowledge of the basic events involved in initiation and completion of mitosis and in defining the precise, yet multifaceted, functions of microtubules increases, alternative intracellular targets will be identified. Such targets may prove suitable for pharmacological exploitation and more effective antimitotic antitumour agents will undoubtedly emerge. However, whether these will be third generation Vincas or molecules with quite different structures remains an open question.

  • mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic vinca alkaloids vinorelbine and its newer derivative Vinflunine
    Molecular Pharmacology, 2001
    Co-Authors: Vivian K Ngan, Bridget T Hill, Leslie Wilson, Krista Bellman, Mary Ann Jordan
    Abstract:

    The two second-generation Vinca alkaloids, vinorelbine and Vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and Vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC50 values for inhibition of HeLa cell proliferation for Vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC50 value was highest for Vinflunine (4.2 ± 0.2 μM), intermediate for vinorelbine (1.3 ± 0.1 μM), and more than 10-fold lower for vinblastine (130 ± 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for Vinflunine's high efficacy and minimal side effects. * PIPES : piperazine- N , N ′-bis(2-ethanesulfonic acid)

Begona Mellado - One of the best experts on this subject based on the ideXlab platform.

Albert Font - One of the best experts on this subject based on the ideXlab platform.

  • maintenance therapy with Vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first line chemotherapy maja sogug 2011 02 a multicentre randomised controlled open l
    Lancet Oncology, 2017
    Co-Authors: Jesus Garciadonas, Albert Font, Begona Perezvalderrama, Jose Antonio Virizuela, Miquel Angel Climent, Susana Hernandopolo, Jose Angel Arranz, Maria Del Mar Llorente, Nuria Lainez, Jose Carlos Villaguzman
    Abstract:

    Summary Background Maintenance therapy improves outcomes in various tumour types, but cumulative toxic effects limit the choice of drugs. We investigated whether maintenance therapy with Vinflunine would delay disease progression in patients with advanced urothelial carcinoma who had achieved disease control with first-line chemotherapy. Methods We did a randomised, controlled, open-label, phase 2 trial in 21 Spanish hospitals. Eligible patients had locally advanced, surgically unresectable, or metastatic transitional-cell carcinoma of the urothelial tract, adequate organ function, and disease control after four to six cycles of cisplatin and gemcitabine (carboplatin allowed after cycle four). Patients were randomly assigned (1:1) to receive Vinflunine or best supportive care until disease progression. We initially used block randomisation with a block size of six. Four lists were created for the two stratification factors of starting dose of Vinflunine and presence of liver metastases. After a protocol amendment, number of cisplatin and gemcitabine cycles was added as a stratification factor, and eight lists were created, still with a block size of six. Finally, we changed to a minimisation procedure to reduce the risk of imbalance between groups. Vinflunine was given every 21 days as a 20 min intravenous infusion at 320 mg/m 2 or at 280 mg/m 2 in patients with an Eastern Cooperative Oncology Group performance status score of 1, age 75 years or older, previous pelvic radiotherapy, or creatinine clearance lower than 60 mL/min. The primary endpoint was median progression-free survival longer than 5·3 months in the Vinflunine group, assessed by modified intention to treat. Comparison of progression-free survival between treatment groups was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01529411. Findings Between April 12, 2012, and Jan 29, 2015, we enrolled 88 patients, of whom 45 were assigned to receive Vinflunine and 43 to receive best supportive care. One patient from the Vinflunine group was lost to follow-up immediately after randomisation and was excluded from the analyses. One patient in the best supportive care group became ineligible for the study and did not receive treatment due to a delay in enrolment, but was included in the intention-to-treat efficacy analysis. After a median follow-up of 15·6 months (IQR 8·5–26·0), 29 (66%) of 44 patients in the Vinflunine group had disease progression and 24 (55%) had died, compared with 36 (84%) of 43 patients with disease progression and 32 (74%) deaths in the best supportive care group. Median progression-free survival was 6·5 months (95% CI 2·0–11·1) in the Vinflunine group and 4·2 months (2·1–6·3) in the best supportive care group (hazard ratio 0·59, 95% CI 0·37–0·96, p=0·031). The most common grade 3 or 4 adverse events were neutropenia (eight [18%] of 44 in the Vinflunine group vs none of 42 in the best supportive care group), asthenia or fatigue (seven [16%] vs one [2%]), and constipation (six [14%] vs none). 18 serious adverse events were reported in the Vinflunine group and 14 in the best supportive care group. One patient in the Vinflunine group died from pneumonia that was deemed to be treatment related. Interpretation In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with Vinflunine maintenance therapy. Moreover, progression-free survival was longer with Vinflunine maintenance therapy than with best supportive care. Vinflunine maintenance had an acceptable safety profile. Further studies of the role of Vinflunine are warranted. Funding Pierre-Fabre Medicament.

  • randomized placebo controlled phase ii trial maja efficacy results of maintenance Vinflunine after cisplatin chemotherapy ct in patients with advanced urothelial carcinoma uc sogug 2011 02
    Journal of Clinical Oncology, 2016
    Co-Authors: Albert Font, Begona Perezvalderrama, Jose Antonio Virizuela, Maria Del Mar Llorente, Nuria Lainez, Jose Angel Arranz Arija, Susana Hernando Polo, Miguel Angel Climent, Jose Carlos Villa Guzman, Begona Mellado
    Abstract:

    4529Background: Vinflunine (VFL) is a microtubule inhibitor approved by EMA as treatment after platinum progression in metastatic UC. We evaluated whether maintenance VFL delays progression after r...

  • Vinflunine maintenance therapy versus best supportive care after platinum combination in advanced bladder cancer a phase ii randomized open label study maja study sogug 2011 02 interim analysis on safety
    Journal of Clinical Oncology, 2014
    Co-Authors: Susana Hernando Polo, Albert Font, Begona Perezvalderrama, Nuria Lainez, Begona Mellado, Miguel Angel Climent, Jose Carlos Villa Guzman, Aranzazu Gonzalez Del Alba, Ignacio Duran, Daniel Castellano
    Abstract:

    359 Background: Vinflunine (VFL) is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. We evaluated whether maintenance Vinflunine delays progression after response to CT. Methods: Multicenter, randomized, open label, proof-of-concept study that is being performed in 21 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects are randomized to receive (arm A) VFL 320 mg/m2 (280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min) every 21 days plus best supportive care (BSC) vs. (arm B) BSC alone until disease progression. Main inclusion criteria: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease whith radiological response or stabilization after 4 to 6 cy of a cisplatin-containing doublet for metastasic/advanced disease (carboplatin allowed on cy 5-6). Primary ...

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