Reply to the Editor

Abstract

We thank Ates and colleagues for their thoughtful comments. We agree that there is an interrelationship between the cyclooxygenase-2 (COX-2) enzyme (and prostanoid products) and the epidermal growth factor receptor (EGFR) family. In an important article, Pai and colleagues1Pai R. Soreghan B. Szabo I.L. Pavelka M. Baatar D. Tarnawski A.S. Prostaglandin E2 transactivates EGF receptor a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.Nat Med. 2002; 8: 289-293Crossref PubMed Scopus (750) Google Scholar reported that COX-2/prostaglandin E2 transactivates the EGFR receptor, with resultant activation of downstream signaling.1Pai R. Soreghan B. Szabo I.L. Pavelka M. Baatar D. Tarnawski A.S. Prostaglandin E2 transactivates EGF receptor a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.Nat Med. 2002; 8: 289-293Crossref PubMed Scopus (750) Google Scholar Similarly it has been proposed that EGFR signaling can increase COX-2 activity. These findings have given cause for initiation of human trials of combination therapy with both EGFR receptor inhibitors and celecoxib in patients with non–small cell cancer, with some exciting initial results. However, the interaction between the two is complex and as yet incompletely understood. Recently, Richardson and colleagues2Richardson C.M. Richardson D. Swinson D.E. Swain W.A. Cox G. O’Byrne K.J. Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non–small cell lung cancer.Lung Cancer. 2005; 48: 47-57Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar found that COX-2 protein levels are independent of EGFR expression or activation in patients with non–small cell cancer.2Richardson C.M. Richardson D. Swinson D.E. Swain W.A. Cox G. O’Byrne K.J. Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non–small cell lung cancer.Lung Cancer. 2005; 48: 47-57Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar We have found that combination therapy (EGFR receptor blocker together with COX-2 blockade by celecoxib) are occasionally antagonistic (at least in one cell line) in an animal orthotopic lung cancer model. When understanding the interaction, though, it is important to realize that levels of the COX-2 enzyme (both messenger RNA and protein) are variably affected by celecoxib, but the activity of the enzyme is profoundly blocked even by low doses of the drug. With regard to final sentence of the letter, we would agree that celecoxib decreases PGE2 levels (but not COX-2 levels) and that interactions with the EGFR cascade probably account for some of the antineoplastic activity of the compound. Association between cyclooxygenase and epidermal growth factor receptor pathways in non–small cell lung cancerThe Journal of Thoracic and Cardiovascular SurgeryVol. 130Issue 5PreviewWe read with great interest the article by Sievers and associates.1 In their orthotopic murine model of lung cancer with adenocarcinoma, they showed inhibition of tumor growth with a low-dose cyclooxygenase-2 (COX-2) inhibitor, celecoxib. In their article, they discussed different mechanisms of association between COX-2 inhibition and attenuation of tumor growth in non–small cell lung cancer (NSCLC), and we want to propose another. COX (or prostaglandin endoperoxide synthase) catalyzes the conversion of arachidonic acid to prostaglandin (PG) H2. Full-Text PDF