Microtubules (binds to tubulin, inhibits microtubule polymerization).

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.

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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.

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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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Microtubule inhibitor that binds to tubulin and inhibits microtubule polymerization. Cytotoxic to cancer cells with potent antiproliferative activity. Specific IC50 values depend on the cancer cell line.

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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Antitumor activity in preclinical cancer models and in patients with advanced bladder cancer. Induces mitotic arrest and apoptosis in cancer cells.

Tubulin polymerization assays using purified tubulin to evaluate inhibition of microtubule assembly. Binding assays to determine tubulin binding affinity. The assay measures the polymerization of tubulin in the presence of varying concentrations of the compound.

Cell viability and proliferation assays in cancer cell lines to evaluate cytotoxic potency (IC50). Cell cycle analysis to assess mitotic arrest. Cells are treated with the compound, and cell viability, proliferation, and cell cycle distribution are measured.

Dissolved in in a saline solution (0.9% NaCl); 20 mg/kg; i.v. injectionLS174T tumor cells are injected into the spleen of BALB/C nude mice.

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Animal models of cancer (xenograft models) and clinical trials in patients with advanced bladder cancer. Endpoints include tumor growth inhibition, response rate, and survival.

Absorption, Distribution and Excretion
In cancer patients, vinflunine exhibits linear pharmacokinetic characteristics across the dose range (30 mg/m² to 400 mg/m²). Fecal excretion accounts for 2/3 of the total clearance of vinflunine and its metabolites, with the remaining 1/3 excreted in urine. The terminal volume of distribution is large, at 2422 ± 676 L (approximately 35 L/kg), indicating widespread distribution in tissues. The plasma concentration to whole blood concentration ratio is 0.80 ± 0.12. Based on a population pharmacokinetic analysis of 372 patients, the total blood clearance was 40 L/h. Both inter- and intra-individual variability were low, with coefficients of variation of approximately 25% and 8%, respectively. Metabolites/Metabolic Substances: The main metabolite of vinblastine is cytochrome P450 3A4, but 4-O-deacetylated vinblastine (DVFL) may also be slowly generated by various esterases. DVFL is the major metabolite and the only metabolite that retains pharmacological activity. Biological Half-Life: The average terminal half-life is approximately 40 hours. The half-life of the major metabolite DVFL is approximately 120 hours.

Protein Binding
Vinpocetine binds to human plasma proteins at a rate of 67.2 ± 1.1%. It primarily binds to high-density lipoprotein and serum albumin, and does not reach saturation within the range of concentrations observed in patients. Binding to α-1 acid glycoprotein and platelets is negligible (< 5%).

:Cancer Res.2000;60(18):5045-51;Biochemistry.2000;39(39):12053-62;Eur J Cancer.2006;42(16):2821-32.

Pharmacodynamics
The antitumor effect of vinblastine depends on drug concentration and exposure time. Vinblastine exerts its antimitotic effect by inhibiting microtubule assembly (micromolar concentration) and reducing the rate and extent of microtubule growth. In vivo experiments have shown that vinblastine has significant antitumor activity against various human xenograft tumors in mice, including prolonging survival and inhibiting tumor growth. Compared with other vinca alkaloids, vinblastine has a lower potency in inducing drug resistance in vitro.

C45H54F2N4O8

816.93

816.391

162652-95-1

10629256

Typically exists as solid at room temperature

1.39 g/cm3

1.652

5.019

133.87

2

13

10

59

1720

9

CC[C@@]1(C=CCN2CC3)[C@@]2([H])[C@@]3(C(C=C([C@](C4=C5C(C=CC=C6)=C6N4)(CC(C[C@@H](C(F)(F)C)C7)([H])CN7C5)C(OC)=O)C(OC)=C8)=C8N9C)[C@]9([H])[C@](C(OC)=O)(O)[C@@H]1OC(C)=O

NMDYYWFGPIMTKO-HBVLKOHWSA-N

InChI=1S/C45H54F2N4O8/c1-8-42-14-11-16-51-17-15-43(36(42)51)30-19-31(34(56-5)20-33(30)49(4)37(43)45(55,40(54)58-7)38(42)59-25(2)52)44(39(53)57-6)21-26-18-27(41(3,46)47)23-50(22-26)24-29-28-12-9-10-13-32(28)48-35(29)44/h9-14,19-20,26-27,36-38,48,55H,8,15-18,21-24H2,1-7H3/t26-,27-,36+,37-,38-,42-,43-,44+,45+/m1/s1

methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-4-[(12S,14R,16R)-16-(1,1-difluoroethyl)-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8-tetraen-12-yl]-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)