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Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy
BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyz...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer-Verlag
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587684/ https://www.ncbi.nlm.nih.gov/pubmed/22983756 http://dx.doi.org/10.1007/s00384-012-1551-2 |
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author | Wehler, Thomas C. Hamdi, Swaantje Maderer, Annett Graf, Claudine Gockel, Ines Schmidtmann, Irene Hainz, Michael Berger, Martin R. Theobald, Matthias Galle, Peter R. Moehler, Markus Schimanski, Carl C. |
author_facet | Wehler, Thomas C. Hamdi, Swaantje Maderer, Annett Graf, Claudine Gockel, Ines Schmidtmann, Irene Hainz, Michael Berger, Martin R. Theobald, Matthias Galle, Peter R. Moehler, Markus Schimanski, Carl C. |
author_sort | Wehler, Thomas C. |
collection | PubMed |
description | BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. RESULTS: In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45β. In resistant cell lines, pp53 and GADD45β levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFRβ expression intensity. CONCLUSIONS: In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect. |
format | Online Article Text |
id | pubmed-3587684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-35876842013-03-07 Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy Wehler, Thomas C. Hamdi, Swaantje Maderer, Annett Graf, Claudine Gockel, Ines Schmidtmann, Irene Hainz, Michael Berger, Martin R. Theobald, Matthias Galle, Peter R. Moehler, Markus Schimanski, Carl C. Int J Colorectal Dis Original Article BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. RESULTS: In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45β. In resistant cell lines, pp53 and GADD45β levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFRβ expression intensity. CONCLUSIONS: In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect. Springer-Verlag 2012-09-15 2013 /pmc/articles/PMC3587684/ /pubmed/22983756 http://dx.doi.org/10.1007/s00384-012-1551-2 Text en © The Author(s) 2012 https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Article Wehler, Thomas C. Hamdi, Swaantje Maderer, Annett Graf, Claudine Gockel, Ines Schmidtmann, Irene Hainz, Michael Berger, Martin R. Theobald, Matthias Galle, Peter R. Moehler, Markus Schimanski, Carl C. Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title | Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title_full | Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title_fullStr | Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title_full_unstemmed | Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title_short | Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
title_sort | single-agent therapy with sorafenib or 5-fu is equally effective in human colorectal cancer xenograft—no benefit of combination therapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587684/ https://www.ncbi.nlm.nih.gov/pubmed/22983756 http://dx.doi.org/10.1007/s00384-012-1551-2 |
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