生物活性

• 描述Microtubules are the main constituent of mitotic apparatus in all eukaryotic cells, thus make it become an important pharmacological target for the treatment of tumor^[1]. Cabazitaxel can bound to unfractionated microtubules with KD 7.4 μM (measured by [14C]-labled binding stoichiometries). Cabazitaxel is used as a microtubule-targeted cancer chemotherapeutic agent for treatment of metastatic castrationresistant prostate cancer after failure of docetaxel treatment. Compared with docetaxel, cabazitaxel can suppress microtubule dynamic instability significantly more potently in the presence of βIII-tubulin than in its absence. This was supported by the study of βIIItubulin-deleted microtubule assembly experiment orβIII-tubulin-knockdown MCF7 cells. Also, it was found that mitotic arrest IC50 for cabazitaxel was significantly more potent in control-transfected cells (8 nM) than in βIII-tubulin- knockdown cells (18 nM, a 2.3-fold difference). Thus, The selective potency of cabazitaxel on βIII-tubulin-containing level may explain the superior anti-tumor efficacy of cabazitaxe in tumors overexpressing βIII-tubulin [a]. Specifically, cabazitaxel has the ability to cross the blood–brain barrier^[2]. Cabazitaxel is approved for use in combination with prednisone for treatment of metastatic hormone refractory prostate cancer previously treated with a docetaxel-containing regimen (see in FDA net).
• 作用机制Cabazitaxel can bind and stabilize microtubules and suppress microtubule dynamic instability significantly more potently in the presence of βIII-tubulin than in its absence^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A431 cells	-	Growth inhibition assay	-	Growth inhibition of human A431 cells by MTT assay, IC50=1.48 nM	24405702
  human A549 cells	-	Growth inhibition assay	-	Growth inhibition of human A549 cells by MTT assay, IC50=1.48 nM	24405702
  human DU145 cells	-	Growth inhibition assay	-	Growth inhibition of human DU145 cells by MTT assay, IC50=1.43 nM	24405702

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• 动物研究
  剂量	Mice (i.p.): min = 9 mg/kg[4], max = 33 mg/kg[5]
  给药途径	i.p.
  动物药代数据	Animal Rats[6] Dose 2.5 mg/kg Administration i.v. Cmax 477 ng/ml Tmax 1 h Tlast 10 h CL 4.79 L/(h·kg) Vss 22.7 L/kg AUC 522 ng·h/ml T1/2z 10.1 h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03419442	-	-	Not yet recruiting	February 28, 2019	United States, New Jersey ... more >> US database Not yet recruiting Whippany, New Jersey, United States, 07981 Collapse <<
  NCT01379339	Squamous Cell Carcinoma of the... more >> Head and Neck Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Icahn School of Medicine at Mount Sinai New York, New York, United States, 10029 Collapse <<
  NCT01447225	Solid Tumors	Phase 1	Completed	-	United States, Indiana ... more >> Lafayette, Indiana, United States, 47905 United States, New York Buffalo, New York, United States, 14263 United States, Ohio Cincinnati, Ohio, United States, 45267 United States, Pennsylvania Philadelphia, Pennsylvania, United States, 19111 France Villejuif, France Collapse <<

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• 参考文献

• [1] Fong KW, Leung JW, et al. MTR120/KIAA1383, a novel microtubule-associated protein, promotes microtubule stability and ensures cytokinesis. J Cell Sci. 2013 Feb 1;126(Pt 3):825-37.

  [2] Cisternino S, Bourasset F, et al. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 2003 Apr;138(7):1367-75.

  [3] Smiyun G, Azarenko O, et al. βIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel. Cancer Chemother Pharmacol. 2017 Jul;80(1):151-164.

  [4] Girard E, Ditzler S, et al. Efficacy of cabazitaxel in mouse models of pediatric brain tumors. Neuro Oncol. 2015 Jan;17(1):107-15.

  [5] van Soest RJ, de Morrée ES, et al. Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer. Eur Urol. 2015 Jun;67(6):981-985.

  [6] 201023s000PharmrR

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