title: Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft--no benefit of combination therapy.
abstract: 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.
authors.affiliation: Third Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz, Mainz, Germany. thomas.wehler@unimedizin-mainz.de
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wehler
authors.forename: Swaantje
authors.initials: S
authors.lastname: Hamdi
authors.forename: Annett
authors.initials: A
authors.lastname: Maderer
authors.forename: Claudine
authors.initials: C
authors.lastname: Graf
authors.forename: Ines
authors.initials: I
authors.lastname: Gockel
authors.forename: Irene
authors.initials: I
authors.lastname: Schmidtmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hainz
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
authors.forename: Carl C
authors.initials: CC
authors.lastname: Schimanski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D020169:Caspases; D005472:Fluorouracil