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Cabozantinib

Cabozantinib

【 药品别名 】 卡博替尼 Cabozantinib

【药品简介】 卡博替尼抑制RET、肝细胞生长因子受体、血管内皮生成因子受体1(VEGFR-1 、VEGFR-2、VEGFR-3)、干细胞生长因子受体(KIT) 、酪氨酸激酶受体(TRKB) 、FMS样酪氨酸激酶3(FLT-3) 、AXL及上皮生长因子样域酪氨酸激酶2(TIE-2)的活性,以上激酶受体在肿瘤细胞生长过程中起着重要作用,包括抑制肿瘤细胞凋亡,参与肿瘤血管生成及侵袭等病理过程。卡博替尼通过抑制上述激酶活性而发挥抗肿瘤作用,杀死肿瘤细胞,减少转移并抑制肿瘤血管新生。

【适应症状】 不可手术切除的恶性局部晚期或转移性甲状腺髓样癌患者。 晚期肾细胞癌 晚期肝癌

印度Cabozantinib(卡博替尼 Cabozantinib)价格,正品图片,治疗肺癌药物, 购买Cabozantinib请到印度药房官方网站进行购买 【印度药房大全目录】

资料发布时间:2018-10-30 14:50:00 资料更新时间:2019-11-12 09:19:48

【印度Cabozantinib(卡博替尼 Cabozantinib)说明书】

【用法用量】

推荐用量:
 
1)甲状腺髓样癌:每次140mg,每日一次,轻度及中度肝损伤患者起始剂量为80mg
 
2)肾癌、肝癌:每次60mg,每日一次
 
3)骨转移:每次40mg,每日一次
 
4)服用方法:服用卡博替尼前至少2小时和后至少1小时不要进食
 
 
【注意事项】
 
1)服用卡博替尼前至少2小时和后至少1小时不要进食。
 
2)  继续治疗直至疾病进展或发生不能接受毒性。
 
3)  整个吞服卡博替尼胶囊。不要打开卡博替尼胶囊。
 
4)  如出现漏服则12小时内不要再次服用。
 
5)  服用卡博替尼期间不要摄取已知抑制细胞色素P450食物(如,葡萄柚,葡萄柚汁)或营养补充物。
 
【不良反应】
 
卡博替尼最常报道药物不良反应(≥25%)是腹泻,口腔炎,掌足红肿综合征(PPES),体重减轻,食欲不振,恶心,疲乏,口腔痛,发色变化,味觉障碍,高血压,腹痛,和便秘。
 
卡博替尼最常见实验室异常(≥25%)是增加AST,增加 ALT,淋巴细胞减少,碱性磷酸酶增加,低钙血症,中性粒细胞减少,血小板减少, 低磷血症,和高胆红素血症。
 Cabozantinib
 
【注意事项】
 
1)血栓形成事件:对心肌梗死,脑梗死,或其他严重动脉血栓栓塞事件终止卡博替尼。
 
2) 伤口并发症:对裂开或需要医学干预并发症不给予卡博替尼。
 
3)高血压:有规律地监视血压;对高血压危象终止卡博替尼。
 
4)颌骨骨坏死:终止卡博替尼。
 
5)掌足红肿综合征(PPES):中断卡博替尼,或减低卡博替尼剂量。
 
6)蛋白尿:监视尿蛋白;对肾病综合征终止卡博替尼。
 
7)可逆性后部白质脑病综合征(RPLS):终止卡博替尼。
 
8)胚胎胎儿毒性:卡博替尼可致胎儿危害。建议妇女卡博替尼对胎儿潜在风险。
 
【特殊人群使用】
 
当给予妊娠妇女卡博替尼可致胎儿危害。如妊娠期间使用此药或当用此药患者怀孕,应告知患者对胎儿的潜在危害。


Cabozantinib

生物活性

产品描述

Cabozantinib (XL184) is a potent pan-tyrosine kinases inhibitor that inhibits VEGFR2, c-Met, Kit, Axl, and Flt3 (IC50s: 0.035, 1.3, 4.6, 7 and 11.3 nM).

靶点活性

AXL,7 nM (cell free)

c-Met,1.3nM

Kit,4.6nM

VEGFR2/KDR,0.035nM

VEGFR3/FLT4,6.0nM

VEGFR2,0.035 nM (cell free)

MET,1.3 nM (cell free)

MET (Y1248H),3.8 nM (cell free)

RET,5.2 nM (cell free)

FLT3,11.3 nM (cell free)

实验溶液

30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL

体外活性

Cabozantinib (XL184) is a potent inhibitor of MET and VEGFR2 (IC50s: 1.3 and 0.035 nmol/L). MET-activating kinase domain mutations Y1248H, D1246N or K1262R were also inhibited by cabozantinib (IC50s: 3.8, 11.8, and 14.6 nmol/L). Cabozantinib displayed strong inhibition of several kinases that have also been implicated in tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 (IC50s: 4.6, 5.2, 7, 14.3, and 11.3 nmol/L). In cellular assays, cabozantinib inhibited phosphorylation of MET and VEGFR2, as well as KIT, FLT3, and AXL (IC50s: 7.8, 1.9, 5.0, 7.5, and 42 μmol/L). Cabozantinib inhibited tubule formation (IC50: 6.7 nmol/L) with no evidence of cytotoxicity. Cabozantinib also inhibited tubule formation in response to conditioned media derived from cultures of MDA-MB-231 (IC50: 5.1 nmol/L), A431 (IC50: 4.1 nmol/L), HT1080 (IC50: 7.7 nmol/L), and B16F10 (IC50: 4.7 nmol/L) cells [1]. Only minimal impact on growth was seen with low XL184 doses (0.1μM/48h). However, increased XL184 doses did elicit a significant MPNST cell growth inhibition; higher XL184 doses were needed to inhibit NSC growth [2].

体内活性

A single 100 mg/kg oral dose of cabozantinib resulted in inhibition of phosphorylation of MET 2 to 8 hours postdose in H441 tumors that harbor constitutively phosphorylated MET. In separate experiments, cabozantinib inhibited in vivo stimulation of MET phosphorylation by HGF in liver hepatocytes and VEGF-stimulated phosphorylation of FLK1 with inhibition of both targets sustained through 8 hours postdose [1]. XL184 (30mg/kg/d, p.o.) treated tumors exhibited significantly slower growth. Moreover, treatment with XL184 significantly reduced tumor size and weight compared to control; average tumor weights at study termination were 0.84 g and 0.11 g in control and XL184 groups, respectively [2]. Cabozantinib (60 mg/kg per os daily) inhibited tumor growth based on BLI. Cabozantinib decreased the Ace1luc-induced osteoblastic lesions based on both radiographs and micro CT and a decrease of BMC towards the normal baseline [3].

激酶实验

The inhibition profile of cabozantinib against a broad panel of 270 human kinases was determined using luciferase-coupled chemiluminescence, 33P-phosphoryl transfer, or AlphaScreen technology. Recombinant human full-length, glutathione S-transferase tag or histidine tag fusion proteins were used, and half maximal inhibitory concentration (IC50) values were determined by measuring phosphorylation of peptide substrate poly(Glu, Tyr) at ATP concentrations at or below the Km for each respective kinase. The mechanism of kinase inhibition was evaluated using the AlphaScreen Assay by determining the IC50 values over a range of ATP concentrations [1].

细胞实验

Receptor phosphorylation of MET, VEGFR2, AXL, FLT3, and KIT were, respectively, assessed in PC3, HUVEC, MDA-MB-231, FLT3-transfected BaF3, and KIT-transfected MDA-MB-231 cells. Cells were serum starved for 3 to 24 hours, then incubated for 1 to 3 hours in serum-free medium with serially diluted cabozantinib before 10-minute stimulation with ligand: HGF (100 ng/mL), VEGF (20 ng/mL), SCF (100 ng/mL), or ANG1 (300 ng/mL). Receptor phosphorylation was determined either by ELISA using specific capture antibodies and quantitation of total phosphotyrosine or immunoprecipitation and Western blotting with specific antibodies and quantitation of total phosphotyrosine. Total protein served as loading controls [1].

细胞系: ST88-14, STS26T, and MPNST724

动物实验

Female nu/nu mice were housed according to the Exelixis Institutional Animal Care and Use Committee guidelines. H441 cells (3 × 10^6) were implanted intradermally into the hind flank and when tumors reached approximately 150 mg, tumor weight was calculated using the formula: (tumor volume = length (mm) × width^2 (mm^2)]/2, mice were randomized (n = 5 per group) and orally administered a single 100 mg/kg dose of cabozantinib or vehicle. Tumors were collected at the indicated time points. Pooled tumor lysates were subjected to immunoprecipitation with anti-MET and Western blotting with anti-phosphotyrosine MET. After blot stripping, total MET was quantitated as a loading control. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of HGF (10 μg per mouse) 10 minutes before liver collection. Analysis of MET phosphorylation in liver lysates was as described above. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of VEGF (10 μg per mouse) 30 minutes before lung collection. Pooled lung lysates were subjected to immunoprecipitation with FLK1 and Western blotting with anti-phosphotyrosine. After blot stripping, total FLK1 was quantitated as a loading control [1].

动物模型:RIP-Tag2 transgenic mice in a C57BL/6 background with spontaneous pancreatic islet tumors

化学信息

分子量

501.50

分子式

C28H24FN3O5

CAS

849217-68-1

溶解度

DMSO: 93 mg/mL (185.4 mM)

Ethanol: <1 mg/mL

Water: <1 mg/mL

( < 1 mg/ml refers to the product slightly soluble or insoluble )

储存条件

store at -80°C

备注

For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

配制溶液

  1 mg 5 mg 10 mg
1 mM 1.994 ml 9.97 ml 19.94 ml
5 mM 0.399 ml 1.994 ml 3.988 ml
10 mM 0.199 ml 0.997 ml 1.994 ml
50 mM 0.04 ml 0.199 ml 0.399 ml


参考文献
 
1. Yakes FM, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011, 10(12), 2298-2308.
2. Torres KE, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011 Jun 15;17(12):3943-55.
3. Dai J, et al. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res. 2014 Feb 1;20(3):617-30.
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