Vinflunine tartrate (formerly
BMS710485, F-12158, F12158, BMS-710485), the tartrate salt of Vinflunine, is a bi-fluorinated analog of the vinca alkaloid vinorelbine with potential antitumor activity. It acts as a mitotic or tubulin inhibitor that inhibits the dynamic instability of microtubules with anticancer, anti-angiogenic, vascular-disrupting and anti-metastatic properties.
理化性质和储存条件
| Molecular Weight (MW) | 967.02 |
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| Formula | C45H54F2N4O8.xC4H6O6 |
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| CAS No. | 1201898-17-0 (tartrate); |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 100 mg/mL (103.4 mM) |
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| Water: 66 mg/mL (68.3 mM) |
| Ethanol: 11 mg/mL (11.4 mM) |
| Solubility (In vivo) | Saline: 30 mg/mL |
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| Synonyms | Vinflunine; Vinflunine tartrate; vinflunine ditartrate; F 12158, BMS 710485, F-12158, BMS710485, F12158, BMS-710485 |
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实验参考方法
| In Vitro | In vitro activity: The major effects of Vinflunine on dynamic instability are a slowing of the microtubule growth rate, an increase in growth duration, and a reduction in shortening duration. The effects of Vinflunine on the readmilling rate is examined by following [3H]GTP incorporation into MAP-rich microtubules, and the IC50 is 0.42 μM. Vinflunine induced mitotic accumulation with IC50 with 18.8 nM, which decreases the centromere dynamicity by 44% and increases the time centromeres spent ina paused state by 63%. Vinflunine ditartrate exhibits microtubule inhibition (purified tubulin and MTP) and cytotoxicity in L1210 cells with IC50 of (0.49 μM and 3.5 μM) and 97 nM, respectively. Vinflunine induces apoptosis in neuroblastoma SK-N-SH cells through a postmitotic G1 arrest and a mitochondrial pathway in a concentration-dependent manner with an IC50 with 50 nM. sup> Treatment of Vinflunine induces a rapid change in endothelial cell shape: cells retracts and assumes a rounded morphology. Mean IC50 values are 9.9 × 10-5 M × 10-5 M for fibronectin and 5.0× 10-5 M × 10-5 M for type IV collagen. A short 4 hours exposure of endothelial cells to Vinflunine at 10-8-4 M results in an inhibition of endothelial cell motility response to NIH3T3 cells-derived angiogenic factors. Inhibition is dose dependent, with a mean IC50 value of 7.1 × 10-7 × 10-7 M.
Kinase Assay: Purified tubulin (17 μM) is polymerized into microtubules in the abence or presence of a range of vnflunine concentrations (35 minutes; 37 °C) in 75 mM PIPES, 1.8 mM MgCl2, 1.0 mM EGTA, and 1.5 mM GTP (pH 6.8) using sea urchin (Strongylocentrotus purpuratus) axonemes as seeds for assembly initiation. After incubation, polymerized microtubules are separated from unpolymerized tubulin by centrifugation (150,000 × g; 1 hour; 35 °C). The supernatant is aspirated, the sedimented microtubules are depolymerized in assembly buffer by incubation on ice (2 hours), and the protein content is determined.
Cell Assay: Effects of Vinflunine on L1210 cell proliferation are determined using a standard growth inhibition assay. Exponentially growing L1210 cells (1.5 × 105 cells/well) in a 24-well plate are exposed to a range of concentrations of test compounds for 48 hours, prior to determining cell numbers using an electronic particle counter based on linear interpolation between data points. |
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| In Vivo | Intravenous treatment of mice with Vinflunine, immediately before and 2 day after Matrigel implantation, results in a dose-dependent inhibition of the bFGF-induced angiogenic response, compared with vehicle-treated animals. Inhibition of haemoglobin content is significant at 1.25, 2.5 and 5 mg/kg, with no effect at 0.63 mg/kg (P> 0.05). An ID50 value (dose which inhibits 50% of bFGF-induced neovascularisation) is calculated as 1 mg/kg. Low doses of Vinflunine reduce the number of experimental liver metastases by human LS174T colon cancer cell. A slight overall decrease in liver metastatic foci is already observed at the very low dose of 0.16 mg/kg Vinflunine, although maximal overall inhibition is reached at the maximal tolerated dose (MTD) of 20 mg/kg. |
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| Animal model | LS174T tumor cells are injected into the spleen of BALB/C nude mice. |
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| Formulation & Dosage | Dissolved in in a saline solution (0.9% NaCl); 20 mg/kg; i.v. injection |
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| References | Cancer Res. 2000 Sep 15;60(18):5045-51; Biochemistry. 2000 Oct 3;39(39):12053-62; Eur J Cancer. 2006 Nov;42(16):2821-32. |
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