ABSTRACT
BACKGROUND: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26(+) cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26(+) CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26(+) CSCs in CRC patients. METHODS: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26(+) CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. RESULTS: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26(+) cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. CONCLUSIONS: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.
Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/metabolism , Imidazoles/pharmacology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Pyridines/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Self Renewal , Colorectal Neoplasms/pathology , Drug Evaluation, Preclinical , Extracellular Signal-Regulated MAP Kinases/metabolism , Fluorouracil/pharmacology , HCT116 Cells , HT29 Cells , Humans , Mice , Mitogen-Activated Protein Kinases/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: To examine the safety and efficacy of endovenous laser obliteration to treat varicose vein in a day surgery setting, using sedation and local anaesthesia. DESIGN: Prospective study. SETTING: Day surgery centre in a regional hospital in Hong Kong. PATIENTS: A total of 24 patients with duplex-confirmed long saphenous vein insufficiency underwent endovenous laser (940 nm) varicose vein treatment from July to November 2007 in a single day surgery centre. Adjuvant phlebectomy and injection sclerotherapy were performed in the same session if indicated. All patients had postprocedural venous duplex scan and clinic assessment on day 7 and day 10 respectively. MAIN OUTCOME MEASURES: Procedure success rate, unplanned hospital admissions and re-admissions, major complications, and long saphenous vein obliteration rate. RESULTS: A total of 31 limbs of the 24 patients were treated with endovenous laser varicose vein treatment under local anaesthesia and sedation. The procedural success rate was 100%. All but two patients were admitted on the day of treatment and none were re-admitted. The patients' mean visual analogue pain score for the whole procedure was 2.3 (standard deviation, 1.5; range, 0-5). Post-procedural duplex scans showed 100% thrombosis of the treated long saphenous veins with no deep vein thrombosis. There were no skin burns or instances of thrombophlebitis. Induration of the treated long saphenous vein was relatively common (54%). The majority of the patients (54%) experienced mild discomfort in the early postoperative period. CONCLUSION: Endovenous laser varicose vein treatment performed under local anaesthesia and sedation in a day surgery setting is safe, and yields satisfactory clinical and duplex outcomes.