This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keller, J. J. Articles by Giardiello, F. M. Search for Related Content PubMed PubMed Citation Articles by Keller, J. J. Articles by Giardiello, F. M.

Molecular Analysis of Sulindac-resistant Adenomas in Familial Adenomatous Polyposis¹

Department of Pathology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands [J. J. K., G. J. A. O., P. D., E. C., A. M.]; Department of Pathology, Helsinki University Central Hospital and University of Helsinki, FIN-00014 Helsinki, Finland [A. R.]; and Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205 [F. M. G.]

Purpose: Sulindac causes the reduction of adenomas in familial adenomatous polyposis (FAP) patients, but complete regression is unusual, and breakthrough of colorectal carcinoma during sulindac treatment has been described. The molecular features related to sulindac resistance are unknown. Therefore, we investigated molecular alterations in adenomas from FAP patients with complete adenoma regression on sulindac (responsive patients) and from FAP patients with sulindac-resistant adenomas (resistant patients).

Design: Fourteen baseline adenomas (removed before sulindac treatment) from six responsive patients were studied. Also, 9 baseline adenomas and 34 resistant adenomas (removed during sulindac treatment) from three resistant patients were analyzed. Using immunohistochemistry, we evaluated the expression of ß-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q (APC locus), and microsatellite instability were studied with PCR-based techniques.

Results: There were no significant differences between baseline adenomas from sulindac-responsive and -resistant patients (P > 0.05). There was less loss of membranous ß-catenin staining and less nuclear ß-catenin accumulation in resistant adenomas compared with baseline adenomas from the same (sulindac-resistant) patients (P < 0.01) or baseline adenomas from responsive patients (P < 0.01). Epithelial Cox-2 expression was less, though not significant, in resistant adenomas compared with baseline adenomas from resistant patients, but was significantly less in baseline adenomas from responsive patients (P < 0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%) and in none of the baseline adenomas (P < 0.05). Stromal Cox-2 expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q were comparable in both groups. Loss of Bax staining and microsatellite instability were not found in any adenoma.

Conclusions: Sulindac-resistant adenomas display less alteration in ß-catenin staining and less epithelial Cox-2 expression when compared with adenomas removed before sulindac treatment. K-ras mutations may contribute to sulindac-resistance. Continued research is needed to investigate molecular alterations related to sulindac resistance.

This article has been cited by other articles:

				A. M. Carothers, A. E. Moran, N. L. Cho, M. Redston, and M. M. Bertagnolli Changes in Antitumor Response in C57BL/6J-Min/+ Mice during Long-term Administration of a Selective Cyclooxygenase-2 Inhibitor. Cancer Res., June 15, 2006; 66(12): 6432 - 6438. [Abstract] [Full Text] [PDF]

				L. A.A. Brosens, C. A. Iacobuzio-Donahue, J. J. Keller, S. R. Hustinx, R. Carvalho, F. H. Morsink, L. M. Hylind, G. J. Offerhaus, F. M. Giardiello, and M. Goggins Increased Cyclooxygenase-2 Expression in Duodenal Compared with Colonic Tissues in Familial Adenomatous Polyposis and Relationship to the -765G -> C COX-2 Polymorphism Clin. Cancer Res., June 1, 2005; 11(11): 4090 - 4096. [Abstract] [Full Text] [PDF]

				S. M. Lippman and B. Levin Cancer Prevention: Strong Science and Real Medicine J. Clin. Oncol., January 10, 2005; 23(2): 249 - 253. [Full Text] [PDF]

				P. A. Adegboyega, O. Ololade, J. Saada, R. Mifflin, J. F. Di Mari, and D. W. Powell Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas Clin. Cancer Res., September 1, 2004; 10(17): 5870 - 5879. [Abstract] [Full Text] [PDF]

				T. Zhang, J. Z. Fields, S. M. Ehrlich, and B. M. Boman The Chemopreventive Agent Sulindac Attenuates Expression of the Antiapoptotic Protein Survivin in Colorectal Carcinoma Cells J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 434 - 437. [Abstract] [Full Text] [PDF]

				J. M Herendeen and C. Lindley Use of NSAIDs for the Chemoprevention of Colorectal Cancer Ann. Pharmacother., November 1, 2003; 37(11): 1664 - 1674. [Abstract] [Full Text] [PDF]

				W. W. J. de Leng, A. M. Westerman, M. A. J. Weterman, F. W. M. de Rooij, H. v. Dekken, A. F. P. M. de Goeij, S. B. Gruber, J. H. P. Wilson, G. J. A. Offerhaus, F. M. Giardiello, et al. Cyclooxygenase 2 Expression and Molecular Alterations in Peutz-Jeghers Hamartomas and Carcinomas Clin. Cancer Res., August 1, 2003; 9(8): 3065 - 3072. [Abstract] [Full Text] [PDF]

				Y. Sun, X. M. Tang, E. Half, M. T. Kuo, and F. A. Sinicrope Cyclooxygenase-2 Overexpression Reduces Apoptotic Susceptibility by Inhibiting the Cytochrome c-dependent Apoptotic Pathway in Human Colon Cancer Cells Cancer Res., November 1, 2002; 62(21): 6323 - 6328. [Abstract] [Full Text] [PDF]

				I. Chau and D. Cunningham Cyclooxygenase Inhibition in Cancer -- A Blind Alley or a New Therapeutic Reality? N. Engl. J. Med., April 4, 2002; 346(14): 1085 - 1087. [Full Text] [PDF]