CLINICAL AND GENOMIC INFLUENCE OF SULINDAC ON RECTAL MUCOSA IN FAMILIAL ADENOMATOUS POLYPOSIS

PURPOSE: A study was performed to evaluate the antiproliferative effec ts of low doses of the nonsteroidal drug, sulindac, on adenomas and re ctal mucosa in familial adenomatous polyposis and to analyze the influ ence on tumor-suppressor genes and on apoptosis. METHODS: This was a p rospective, controlled, nonrandomized Phase II dose-finding study for sulindac. The study group (n = 28) and control group (n = 10) underwen t colectomy and ileorectal anastomoses, with repeated proctoscopy with endoluminal ultrasound and biopsies every three months. Dose-reductio n of sulindac according to adenoma reversion was predetermined. Prolif eration marker, Ki-67 (MIB1 and 5): on frozen or paraffin sections eva luated the antiproliferative effects; mutant p21(ras), pantropic p53, mutant p53, and anti-bcl-2 were performed as enzyme-linked immunosorbe nt assay procedures and/or immunohistochemistry on paraffin sections. RESULTS: All patients responded to sulindac after 24 weeks (at the lat est). There was a significant reduction of adenomas and dose reduction to 67 mg/day after three years of therapy (Mann's test for trend, P < 0.001). Results consisted of 78 percent complete reversions, 22 perce nt partial reversions of adenomas at latest re-examination, and no inf luence on upper gastrointestinal tract adenomas. No influence was dete cted on repeated hemograms, Liver, or renal function at high or low do ses. There was a permanent antiproliferative effect (Ki-67) of low-dos e sulindac, significant blocking of ras mutation activation, and a sig nificant difference of untreated and treated mucosa in mutant p53 cont ent (Wilcoxon's or Kruskal-Wallis each, P < 0.05). Reverse correlation of anti-bcl-2 and p53 immunostaining on mucosa sections was an indica tion of adenoma relapse. CONCLUSIONS: Low-dose antiproliferative sulin dac therapy is highly effective in adenoma reversion in familial adeno matous polyposis patients. Sulindac shows influence on tumor-suppresso r genes and on apoptosis markers. An immunostaining correlation indica tes adenoma relapse in flat microadenomas in advance of macroscopic ap pearance. Low-dose sulindac treatment may develop into an additive per manent therapy for colectomized familial adenomatous polyposis patient s.