四氢尿苷作用机制 - Medchemexpress - MCE中国

1、Product Data SheetTetrahydrouridineCat. No.: HY-15345CAS No.: 18771-50-1分式: CHNO分量: 248.23作靶点: Others作通路: Others储存式: Pure form -20C 3 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 100 mg/mL (402.85 mM)H2O : 50 mg/mL (201.43 mM; Need ultrasonic)* means soluble, but saturation unknown.Solv

2、entMass1 mg 5 mg 10 mgConcentration制备储备液1 mM 4.0285 mL 20.1426 mL 40.2852 mL5 mM 0.8057 mL 4.0285 mL 8.0570 mL10 mM 0.4029 mL 2.0143 mL 4.0285 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 储存时，请在 6 个内使，-20C 储存时，请在 1 个内使。体内实验请根据您的实验动物和给药式选择适当的溶解

3、案。以下溶解案都请先按照 In Vitro 式配制澄清的储备液，再依次添加助溶剂：为保证实验结果的可靠性，澄 的储备液可以根据储存条件，适当保存；体内实验的作液，建议您现现配，当天使； 以下溶剂前显的百分 指该溶剂在您配制终溶液中的体积占；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的式助溶1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (10.07 mM); Clear solution此案可获得 2.5 mg/mL (10.07 mM，饱和度未知) 的澄清溶液。以 1 m

4、L 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (10.07 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (10.07 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的

5、澄 DMSO 储备液加到 900 L 20% 的 SBE-CD 理盐溶液中，混合均匀。3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (10.07 mM); Clear solution此案可获得 2.5 mg/mL (10.07 mM，饱和度未知) 的澄 溶液，此案不适于实验周 期在半个以上的实验。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIVITY物活性 Tetrahydrouridine种有效的胞苷脱氨酶 (CDA) 抑

6、制剂，竞争性阻断酶的活性位点。IC & Target cytidine deaminase (CDA)1体外研究 Tetrahydrouridine (THU) is a specific inhibitor of cytidine deaminase (CDA) which can suppress deamination in thecatabolism of cytotoxic deoxycytidine analogues like ara-C and Gemcitabine. To test how Tetrahydrouridine affectsthe Gemcitabine-m

7、ediated anti-neoplastic effect on pancreatic and lung carcinoma cells, a combination therapy isperformed. As expected, high CDA expression in BxPC-3 and H441 results in improved Gemcitabine sensitivity after a100 M Tetrahydrouridine treatment. The sensitivity of BxPC-3 and H441 cell lines increases

8、by as much asapproximately 2.1 and 4.4 fold respectively. On the other hand, MIAPaCa-2 and H1299 cells unexpectedly becomemore sensitive to Gemcitabine with low CDA expression. MIAPaCa-2 and H1299 cells show a change in IC50 of 2.2 and2.3 fold respectively. However, Panc-1 and H322 cells do not show

9、 significant changes in drug sensitivity. These datasuggested that Tetrahydrouridine can sensitize some pancreatic and lung carcinoma cells to Gemcitabine-inducedcell death regardless of CDA expression levels. Tetrahydrouridine inhibits S-phase without apoptosis1.体内研究 Administration of 167 mg/kg Tet

10、rahydrouridine (THU) followed by 1.0 mg/kg DAC results in death in one male andeight females. Animals surviving to scheduled termination are generally asymptomatic with no treatment relatedeffects observed in body weights, food consumption, clinical chemistry and urinalysis for a treatment up to 1.0

11、 mg/kgDAC in combination with 167 mg/kg Tetrahydrouridine in animals2.PROTOCOLCell Assay 1 Cell growth for pancreatic and lung carcinoma cell lines is carried out using the colorimetric methylene blue assay in96-well plates at a density of 5,000 cells/well. Cells are either exposed or not exposed to

12、 Tetrahydrouridine (100 M),counting the first 12 hrs as Day 0. Mean values are calculated from three different wells in triplicates for four days1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice2Administration 2 CD-1 mice (male 30-38 g and f

13、emale 24-31g) from are individually housed in polycarbonate cages suspended onstainless steel racks with SaniChip certified hardwood bedding. Mice are assigned to four dose groups and a vehiclecontrol group. Animals are gavaged with DAC or its vehicle 1 hour 5 minutes after administration of THU or

14、itsvehicle at a dose volume of 10 mL/kg. The DAC doses are selected based on the range finding study in which themice tolerated six oral doses (2x/week) of 0.1, 0.2 and 0.4 mg/kg DAC in combination with a fixed dose of 167 mg/kgTHU. A fixed Tetrahydrouridine dose (500 mg/m2) and the optimal timing b

15、etween Tetrahydrouridine and DACadministration (60 min) are selected. Conversion of milligrams per body surface area dose in mice into milligrams perkilogram body weight dose estimation is based on Michaelis constant (km) values for mice obtained from US Foodand Drug Administration published guideli

16、nes. In brief, the mouse dose in milligrams per body surface area (500Page 2 of 3 www.MedChemEmg/m2) is divided by the km of 3 to convert the dose to milligrams per kilogram body weight (167 mg/kg).MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFEREN

17、CES1. Funamizu N, et al. Tetrahydrouridine inhibits cell proliferation through cell cycle regulation regardless of cytidine deaminase expression levels. PLoS One.2012;7(5):e37424.2. Terse P, et al. Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice. Int J