Docetaxel

 

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Biological Activity

Description	Docetaxel, an analog of taxol, is an inhibitor of depolymerisation of microtubules by binding to stabilized microtubules.
Targets	Microtubules
IC50	[1]
In vitro	Docetaxel is a cytotoxic agent, especially for proliferating cells, which is related to its ability to promote the formation of microtubule bundles and induce sustained mitotic arrest, followed by apoptosis of mitotically arrested cells or permanent mitotic block. Docetaxel suppresses microtubule dynamic instability as well as tread-milling, resulting in the failure of chromosomes to segregate to the daughter cells, which in turn triggers premature exit from mitosis rather than a block at this phase of the cell cycle. [2] Docetaxel inhibits the clonogenic survival of Human cancer cell Hs746T (stomach), AGS (stomach), HeLa (cervix), CaSki (cervix), BxPC3 (pancreas), Capan-1 (pancreas) with IC50 of 1 nM, 1 nM, 0.3 nM, 0.3 nM, 0.3 nM and 0.3 nM respectively.[4] Docetaxel inhibits endothelial cell migration that does not affects microtubule gross morphology or inhibit cell proliferation, although they does produce more subtle effects on microtubule dynamics. Docetaxel inhibits HUVEC migration with an observed IC50 of 1 pM. HUVEC chemotaxis stimulated by either of two angiogenic factors, thymidine phosphorylase or VEGF, is inhibited by Docetaxel with IC 50 of 10 pM and is ablated at 1 nM.[7] Docetaxel induces human monocytes, but not RAW 264.7 murine macrophages, Prostaglandin H Synthase-2m (PGHS-2) expression. [8]
In vivo	Docetaxel (33 mg/kg/dose, given i.v. every 4 days for 3 injections) results in a tumor growth delay of 19.3 days in M2OL2 colon xenografts. Docetaxel also shows great antitumor activities in MX-1, SK-MEL-2, LX-1 and OVCAR-3 xenografts. Docetaxel inhibits the angiogenic response to fibroblast growth factor 2 with IC 50 of 5.4 mg/kg when injected twice weekly over a 14-day period, and angiogenesis is completely blocked in mice that receives 10 mg/kg Docetaxel. Docetaxel has selectivity for endothelial cell migration and/or microvessel formation because infiltration of inflammatory cells into the Matrigel plug is much less sensitive to inhibition by Docetaxel.[7]
Features

Protocol(Only for Reference)

Cell Assay: ^[5]

Cell lines	Human gastric cancer cell lines MKN-28
Concentrations	6 nM
Incubation Time	3 days
Method	2000 cells in 180 μL of medium are seeded in a 96-well plate, and 20 μL of drug solution is simultaneously added in triplicate to each well. The plate is incubated for 3 days at 37°C in a humidified atmosphere of 5% CO2. On day 3, 25 μL of MTT reagent is added to each well. After 4 h of incubation, the medium is removed by aspiration. 0.2 mL of dimethylsulphoxide (DMSO) is added to each well and thoroughly mixed by using a mechanical plate mixer to dissolve the resulting MTT-formazan crystals. Absorbance at 540 nm (OD) is measured by a reader.

Animal Study: ^[6]

Animal Models	Human colon carcinomas xenografts CX-1
Dosages	33 mg/kg
Administration	i.v. every 4 days for 3 injections
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01562301	Not yet recruiting	Chemotherapeutic Agent Toxicity|Lung Cancer	M.D. Anderson Cancer Center|National Cancer Institute (NCI)	2013-12	Phase 1
NCT01999673	Not yet recruiting	Non-Small-Cell Lung Cancer Stage IIIB|Non-Small-Cell Lung Cancer Stage IV|Non-Small-Cell Lung Cancer Metastatic|Carcinoma, Non-Small-Cell Lung|Non-Small Cell Lung Cancer|Non-Small-Cell Lung Carcinoma|	Peregrine Pharmaceuticals	2013-12	Phase 3
NCT02016417	Not yet recruiting	Nasopharyngeal Carcinoma	Cancer Hospital of Guangxi Medical University	2014-01	Phase 2
NCT02008227	Not yet recruiting	Non-Small Cell Lung Cancer	Hoffmann-La Roche	2014-01	Phase 3
NCT01972217	Not yet recruiting	Metastatic Castration-resistant Prostate Cancer	AstraZeneca	2014-01	Phase 2

Chemical Information

Download Docetaxel SDF

Chemical Name	Benzenepropanoic acid, β-[[(1,1-dimethylethoxy)carbonyl]amino]-α-hydroxy-, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester, (αR,βS)-

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.80788	8.0788	16.1576	24.2364

Product Citations (1)

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  Forkhead box transcription factor 1 expression in gastric cancer: FOXM1 is a poor prognostic factor and mediates resistance to docetaxel. [Li X, et al. J Transl Med 2013;11:204]