The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells
| Autor: | Godefridus J. Peters, E. van Gelderop, Olaf H. Temmink, Henk-Jan Prins |
|---|---|
| Přispěvatelé: | Hematology laboratory, Medical oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Pyrrolidines Administration Oral Apoptosis Pharmacology Deoxycytidine Trifluridine chemistry.chemical_compound Mice Floxuridine Tumor Cells Cultured hollow fibre assay Enzyme Inhibitors Cytotoxicity Mice Inbred BALB C Cell Cycle Drug Synergism TAS-102 Flow Cytometry in vivo pharmacodynamics Drug Combinations Treatment Outcome Oncology colon cancer Colonic Neoplasms Fluorouracil Growth inhibition medicine.drug fluoropyrimidines Sensitivity and Specificity Capecitabine antimetabolites In vivo Cell Line Tumor medicine Animals Humans MTT assay Thymidine phosphorylase Uracil Thymidine Phosphorylase business.industry Xenograft Model Antitumor Assays chemistry Immunology business Translational Therapeutics Thymine |
| Zdroj: | British Journal of Cancer, 96(1), 61-66. Nature Publishing Group Temmink, O H, Prins, H J, Van Gelderop, E & Peters, G J 2007, ' The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells ', British Journal of Cancer, vol. 96, no. 1, pp. 61-66 . https://doi.org/10.1038/sj.bjc.6603507 British Journal of Cancer |
| ISSN: | 0007-0920 |
| DOI: | 10.1038/sj.bjc.6603507 |
| Popis: | The Hollow Fibre Assay (HFA) is usually applied as an early in vivo model for anti-cancer drug screening, but is potentially an excellent model for short-term in vivo pharmacodynamic studies. We used the model to study the in vivo role of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) in the cytotoxicity and pharmacodynamics of TAS-102 in colon cancer cells. TAS-102 is a new oral drug formulation, which is composed of trifluorothymidine (TFT) and thymidine phosphorylase inhibitor (TPI), which prevents TFT degradation. We compared the activity with Xeloda (capecitabine), which is activated by TP into 5FU. Hollow fibres filled with human Colo320 or Colo320TP1 colorectal cancer cells with deficient or high TP expression, respectively, were implanted subcutaneously (s.c.) at both flanks of BALB/c mice. The mice were treated orally over 5 days with TAS-102, TFT alone, 5′DFUR±TPI or capecitabine at their maximum tolerated dose (MTD). The cells were retrieved from the fibres and assayed for growth (MTT assay), cell cycle distribution (flow cytometry) and apoptosis induction (FragEL method). TAS-102 induced considerable growth inhibition (50%, P8-fold), which was more pronounced in Colo320 than in Colo320TP1. Again, omission of TPI neutralised the effect of TAS-102. Similarly, 5′DFUR and capecitabine induced a significant G2M-phase arrest (up to 45%) in the Colo320TP1 cell line, but less pronounced in the parental Colo320. Addition of TPI to 5′DFUR reduced this effect to control levels. Also induction of apoptosis was reduced in the presence of TPI. The data demonstrated that the HFA is excellently suited for studying short-term pharmacodynamic effects of fluoropyrimidines in vivo. TAS-102 is only effective in inducing cytotoxicity when systemic TPI is present, but acts against both low and high TP expressing colon cancer cells, while 5′DFUR needs cellular TP to exert significant activity. |
| Databáze: | OpenAIRE |
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