Background
Capecitabine (Xeloda) is an anti-cancer chemotherapy drug. Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidinecarbamate that is converted to 5-fluorouracil (5-FUra) by three enzymes located in the liver and tumors [1].
In vitro: In antiproliferative assays, both LS174T WT and LS174T-c2 cells were more sensitive to capecitabine when cultivated in the same plates as HepG2 hepatoma. In LS174T WT alone and cultivated with HepG2, IC50values of capecitabine were 890 ± 48 and 630 ± 14 μm respectively. The IC50fell from 330 ± 4 down to 89 ± 6 μmin LS174T-C2 subline when cultivated in the same plates as hepatoma cells.In the LS174T-c2 subclone, whereas little cell death occurred in cells exposed to capecitabine, both early and late apoptosis were increased by 244 and 262%, respectively [1]. Furthermore, Capecitabine induces apoptosis in a Fas-dependent manner, and shows a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (TP)-transfected LS174T-c2 cells [2].
In vivo:Capecitabine was effective in a wider dose range in CXF280, HCT116, COLO205, and WiDr human colon cancer xenograft models [2]. In highly metastatic nude mice model, capecitabine inhibited tumor growth and metastatic recurrence after resection of HCC attributed to the high expression of PD-ECGF in tumors [3].
参考文献:
[1].? Ishikawa T, Utoh M, Sawada N, et al. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[J]. Biochemical pharmacology, 1998, 55(7): 1091-1097.
[2].?Ishikawa T, Utoh M, Sawada N, et al. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[J]. Biochemical pharmacology, 1998, 55(7): 1091-1097.
[3].? Zhou J, Tang Z Y, Fan J, et al. Capecitabine inhibits postoperative recurrence and metastasis after liver cancer resection in nude mice with relation to the expression of platelet-derived endothelial cell growth factor[J]. Clinical cancer research, 2003, 9(16): 6030-6037.
Protocol
Cell experiment: | HCT 116, HCT8, HCT15, HT29, SW620 and COLO205 human colon cancer cells are used. Cells are plated on day 1 in 96-well plates at a density of 2500 cells/well for HCT 116, 3500 cells/well for HCT8 and HT29, 5000 cells/well for HCT15, 6000 cells/well for SW620 and 7000 cells/wells for COLO205 in a volume of 150 μL/well. All cell lines are treated on day 2 with increasing concentrations of Capecitabine (0.1-10 mM), 5′DFCR (10 nM-100 μM), 5′DFUR (2.5-500 μM) or 5-FU (0.5-250 μM) for 24 h. After drug exposure, cells are washed once with cold PBS and placed in 200 μL of drug-free medium for 72 h after the end of drug exposure. The cells are then fixed with trichloroacetic acid and stained with sulforhodamine B. Optical densities are measured at 540 nm with a Biohit BP-800. The results are based on three independent experiments performed in triplicate[2]. |
Animal experiment: | Mice[2] Six-week-old C57/Bl6 Nu/Nu mice are used. Bilateral HCT 116 xenografts are obtained by subcutaneous injection of 107 cells/flank. Animals bearing HCT 116 xenografts are treated with vehicle or Capecitabine 0.52 or 2.1 mmol/kg (563 and 2250 mg/m2, respectively) given once daily for 5 consecutive days/week by oral gavage for 3 weeks (days 0-4, 7-11, 14-18). Animals are culled on day 0 at 15, 30 min, 1, 2, 4, 8 and 24 h, and prior to planned treatment on days 7 and 14 after the start of treatment. Three animals per time-point are analysed. At the time of collection, blood is collected in heparin, and plasma isolated and stored at ?80°C. The liver is removed immediately and stored in RNAlater solution. Tumours are macro-dissected to remove fibrotic tissue and blood vessels and snap-frozen in liquid nitrogen. |
参考文献: [1]. PharmD CM, et al. Capecitabine: A review. Clinical Therapeutics. 2005 Jan; 27(1): 23-44.
[2]. Guichard SM, et al. Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity. Eur J Cancer. 2008 Jan;44(2):310-7. |
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