Original Article

International Journal of Colorectal Disease

, Volume 28, Issue 3, pp 385-398

Open Access This content is freely available online to anyone, anywhere at any time.

Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy

  • Thomas C. WehlerAffiliated withThird Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
  • , Swaantje HamdiAffiliated withFirst Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
  • , Annett MadererAffiliated withFirst Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
  • , Claudine GrafAffiliated withThird Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
  • , Ines GockelAffiliated withDepartment of General and Abdominal Surgery, Johannes Gutenberg University Hospital of Mainz
  • , Irene SchmidtmannAffiliated withInstitute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University Hospital of Mainz
  • , Michael HainzAffiliated withInstitute of Pathology, Johannes Gutenberg University Hospital of Mainz
  • , Martin R. BergerAffiliated withToxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ)
  • , Matthias TheobaldAffiliated withThird Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
    • , Peter R. GalleAffiliated withFirst Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz
    • , Markus MoehlerAffiliated withFirst Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz Email author 
    • , Carl C. SchimanskiAffiliated withFirst Department of Internal Medicine, Johannes Gutenberg University Hospital of MainzDepartment of Internal Medicine, Marienhospital

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.

Keywords

Colorectal cancer TKI Sorafenib