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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer-Verlag 2012
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.
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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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