| 名稱 | Vandetanib |
| 描述 | Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 (IC50: 40 nM). It also inhibits VEGFR3 and EGFR. |
| 細胞實驗 | HUVEC proliferation in the presence and absence of growth factors was evaluated using [3H]thymidine incorporation. Briefly, HUVECs isolated from umbilical cords were plated (at passage 2–8) in 96-well plates (1000 cells/well) and dosed with ZD6474 ± VEGF or EGF (3 ng/ml) or bFGF (0.3 ng/ml). The cultures were incubated for 4 days (37°C; 7.5% CO2) and then pulsed with 1 μCi/well [3H]thymidine and reincubated for 4 h. Cells were harvested and assayed for the incorporation of tritium using a beta counter. IC50 data were interpolated as described above [1]. |
| 激酶實驗 | The ability of ZD6474 to inhibit the kinase activity associated with the VEGFRs KDR, Flt-1, and Flt-4 was determined using a previously described ELISA. Briefly, ZD6474 was incubated with enzyme, 10 mm MnCl2, and 2 μm ATP in 96-well plates coated with a poly(Glu, Ala, Tyr) 6:3:1 random copolymer substrate. Phosphorylated tyrosine was then detected by sequential incubation with a mouse IgG anti-phosphotyrosine 4G10 antibody, a horseradish peroxidase-linked sheep anti-mouse immunoglobulin antibody, and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid). Microcal Origin software was used to interpolate IC50 values by nonlinear regression. This methodology was adapted to examine selectivity versus tyrosine kinases associated with EGFR, PDGFRβ, Tie-2, FGFR1, c-kit, erbB2, IGF-IR, and FAK. All enzyme assays (tyrosine or serine-threonine) used appropriate ATP concentrations at or just below the respective Km (0.2–14 μm). Selectivity versus serine-threonine kinases (CDK2, AKT, and PDK1) was examined using a relevant scintillation proximity assay (SPA) in 96-well plates. CDK2 assays contained 10 mm MnCl2, 4.5 μm ATP, 0.15 μCi of [γ-33P]ATP/reaction, 50 mm HEPES (pH 7.5), 1 mm DTT, 0.1 mm sodium orthovanadate, 0.1 mm sodium fluoride, 10 mm sodium glycerophosphate, 1 mg/ml BSA fraction V, and a retinoblastoma substrate (part of the retinoblastoma gene, 792–928, expressed in a glutathione S-transferase expression system; 0.22 μm final concentration). Reactions were allowed to proceed at room temperature for 60 min before quenching for 2 h with 150 μl of a solution containing EDTA (62 mm final concentration), 3 μg of a rabbit immunoglobulin anti-glutathione S-transferase antibody and protein A SPA-polyvinyltoluene beads (0.8 mg/reaction). Plates were then sealed, centrifuged (1200 × g for 5 min), and counted on a Topcount NXT Microplate scintillation counter for 30 s [1]. |
| 動物實驗 | Methodology to enable blood pressure measurement in anesthetized rats was as described previously. Briefly, anesthesia was induced in male Alderley Park rats using α-chloralose by the i.v. route and then maintained with thiopentone via the i.p. route. Once surgical anesthesia was established, the carotid artery was cannulated to enable blood pressure recording using a pressure transducer and a Lectromed MT8P amplifier. The jugular vein was cannulated to allow growth factor administration. Body temperature was maintained with a thermostatically controlled heated blanket coupled to a rectal thermometer. Human VEGF165 (32 μg/kg) or bFGF (40 μg/kg) was administered as a bolus injection [0.1 ml/250 g body weight in 0.85% (w/v) sodium chloride], and a maximal blood pressure drop was recorded within 2 min (typically 26–30 mm Hg). These changes were sustainable for more than 20 min in control experiments. ZD6474 (2.5 mg/kg) or vehicle alone [25% (w/v) hydroxypropyl-β-cyclodextrin in Sorensons phosphate buffer (pH 5.5)] was administered i.v., and blood pressure was recorded 5 min later to determine the effect on growth factor-induced hypotension [1]. |
| 體外活性 | Vandetanib (ZD6474) 是一種強效的KDR/VEGFR2酪氨酸激酶活性抑制劑（IC50：40 nM），對VEGFR3（IC50：110 nM）和EGFR/HER1酪氨酸激酶活性（IC50：500 nM）也有一定抑制作用。ZD6474對KDR酪氨酸激酶的抑制作用能強效抑制VEGF激活的內皮細胞（人臍靜脈內皮細胞）增殖（IC50：60 nM）[1]。ZD6474能劑量依賴性抑制小鼠NIH-EGFR成纖維細胞和人MCF-10A ras乳腺癌細胞中EGFR的磷酸化，并在具有功能性EGFR但缺乏VEGFR-2的七種人類細胞系中，劑量依賴性抑制軟瓊脂生長。ZD6474與紫杉醇或多西他賽聯(lián)合治療在體外觀察到增長抑制和凋亡的劑量依賴性超加性效應[2]。Vandetanib和neratinib對基礎ABCG2-ATP酶活性表現(xiàn)出抑制效果，在相對高濃度（10-20 mM）時，vandetanib能抑制激活的ABCG2-ATP酶活性[3]。 |
| 體內活性 | 給予ZD6474 (2.5 mg/kg, 靜脈注射) 能夠逆轉由VEGF引起的低血壓變化(63%)，但對由基礎成纖維細胞生長因子引起的變化無顯著影響。每日一次口服50 mg/kg ZD6474給缺乏胸腺的小鼠（這些小鼠體內已經皮下植入了A549腫瘤細胞）同樣顯著抑制了由腫瘤引起的新血管生成（5天后抑制率達63%）。對于用50 mg/kg/day ZD6474處理24天的Calu-6腫瘤進行組織學分析顯示，非壞死區(qū)域內CD31（內皮細胞）染色顯著減少（>70%）[1]。ZD6474對攜帶可觸知GEO結腸癌異種移植瘤的裸鼠治療顯示出劑量依賴性的腫瘤生長抑制作用。ZD6474在GEO腫瘤異種移植瘤模型中的抗腫瘤活性，在與紫杉醇聯(lián)合應用時得到增強。所有使用ZD6474加紫杉醇治療的小鼠觀察到腫瘤退縮，并且伴隨著顯著增強的抗血管生成抑制作用[2]。Vandetanib (15 mg/kg) 對H1650/PTEN和H1650親本異種移植瘤的生長具有相似的效果[4]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 27.5 mg/mL (57.85 mM), Sonication is recommended.
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| 關鍵字 | ZD-6474 | ZD 6474 | VEGFR3 | VEGFR2 | VEGFR | Vascular endothelial growth factor receptor | Vandetanib | Inhibitor | inhibit | EGFR | Autophagy | Apoptosis |
| 相關產品 | Naringin | Guanidine hydrochloride | L-Glutamic acid | Gefitinib | Cysteamine hydrochloride | Alginic acid | Hydroxychloroquine | Stavudine | Dextran sulfate sodium salt (MW 4500-5500) | L-Ascorbic acid sodium salt | Paeonol | Sodium 4-phenylbutyrate |
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