0 to 12.0 months with chemotherapy vs. 2.5 to 5.0 months with BSC (4-9). For patients with advanced colorectal cancer with distant spread, 5-year survival

is only 11% (10). There is a clear need for alternative treatment options that are effective in advanced GI cancers. Increasing knowledge of the molecular events underlying carcinogenesis, tumor growth, and metastasis has provided new targets for therapy, including the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 Inhibitors,research,lifescience,medical (COX-2). Elevated levels of EGFR and COX-2, both of which mediate events involved in tumorigenic processes, were observed in GI tumors (11-15). Erlotinib chemical structure Increased EGFR expression was shown to correlate with more aggressive GI disease and poor survival in several Inhibitors,research,lifescience,medical studies (11,12,14-19). Similarly, COX-2 was found to be associated with poor sellekchem prognosis and tumor recurrence in GI tumors (20-24). Indeed, COX-2 was also shown to promote angiogenesis and inhibit apoptosis in gastric tumor biopsies (25). As such, it was hypothesized

that simultaneous inhibition of EGFR and COX-2 signaling pathways may be a novel treatment option capable of producing synergistic antitumor effects in patients with GI tumors. Gefitinib (IRESSA®; AstraZeneca, Macclesfield, UK) is an orally active EGFR tyrosine kinase inhibitor. Phase I trials of gefitinib Inhibitors,research,lifescience,medical monotherapy demonstrated some activity in advanced GI cancer (26-29), with stable disease observed in several patients with colorectal Inhibitors,research,lifescience,medical and esophageal tumors. A phase II study also found that treatment with gefitinib (250 or 500 mg/day) was associated with disease control in 13/75 (18.3%) patients with metastatic gastric adenocarcinoma (30). In another phase II study, gefitinib (250 or 500 mg/day) was associated with a median progression-free and overall survival of 1.9 and 6.3 months, respectively,

in patients with recurrent colorectal adenocarcinoma (31). Interestingly, an in vitro study conducted Inhibitors,research,lifescience,medical in human colon cancer cells showed Cilengitide that when gefitinib was combined with the COX-2 inhibitor SC-236, the two agents had a cooperative antiproliferative effect (32). This effect was accompanied by a reduction in the expression of COX-2 and angiogenic growth factors, such as vascular endothelial growth factor. Celecoxib (Celebrex®; Pfizer Inc., New York, NY, USA) is a selective COX-2 inhibitor that has demonstrated potent suppression of colon polyps, which can lead to the development of colorectal cancer. However, enrollment in follow-up trials was inadequate and, as a result, regulatory requirements were not fulfilled and celecoxib was withdrawn in the USA and Europe as an adjunct to standard care in patients with familial adenomatous polyposis (33).