Colorectal Cancer
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 28, 2006; 12(32): 5140-5147
Published online Aug 28, 2006. doi: 10.3748/wjg.v12.i32.5140
Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa™) and to the antiangiogenic agent ZD6474: Cytotoxic and biomolecular effects
Amalia Azzariti, Letizia Porcelli, Jian-Ming Xu, Grazia Maria Simone, Angelo Paradiso
Amalia Azzariti, Letizia Porcelli, Grazia Maria Simone, Angelo Paradiso, Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Italy
Jian-Ming Xu, Beijing 307 Hospital Cancer Center, Beijing 100039, China
Author contributions: All authors contributed equally to the work.
Supported by grants from the Italian Association for Cancer Research (AIRC-2004) and from the Italian Ministry of Health, Project ex art.12, Region of Emilia Romagna RF02
Correspondence to: Angelo Paradiso, MD, Head Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola 209, 70125 Bari, Italy.
Telephone: +39-80-5555561 Fax: +39-80-5555561
Received: July 6, 2005
Revised: July 20, 2005
Accepted: July 28, 2005
Published online: August 28, 2006

AIM: To analyze the biological effects of prolonged in vitro exposure of HT-29 and LoVo colon cancer cell lines to gefitinib (Iressa™), an inhibitor of epidermal growth factor receptor (EGFR) activity, and ZD6474, an inhibitor of both KDR and EGFR activities.

METHODS: Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent (4 d of drug exposure followed by 3 d of washout each week) schedule.

RESULTS: In both cell types, prolonged exposure (up to 14 d) to gefitinib or ZD6474 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule. The effects on cell growth were associated with a pronounced inhibition of p-EGFR and/or p-KDR expression. Treatment with gefitinib or ZD6474 also inhibited the expression of EGFR downstream signal molecules, p-Erk1/2 and p-Akt, although the magnitude of these effects varied between treatments and cell lines. Furthermore, expression of the drug resistance-related protein ABCG2 was shown to significantly increase after 14 d of continuous exposure to the two drugs.

CONCLUSION: We conclude that long-term exposure of colon cancer cells to gefitinib and ZD6474 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs.

Keywords: Gefitinib, ZD6474, Colon cancer, Tyrosine kinase, Chemo-resistance