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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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Detalles Bibliográficos
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
Descripción
Sumario: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.