Diseases of the Colon & Rectum

, Volume 40, Issue 10, pp 1156–1169 | Cite as

Clinical and genomic influence of sulindac on rectal mucosa in familial adenomatous polyposis

  • Guenther Winde
  • Kurt W. Schmid
  • Burkhardt Brandt
  • Oliver Müller
  • Hans Osswald
Original Contributions
  • 19 Downloads

Abstract

PURPOSE: A study was performed to evaluate the antiproliferative effects of low doses of the nonsteroidal drug, sulindac, on adenomas and rectal mucosa in familial adenomatous polyposis and to analyze the influence on tumor-suppressor genes and on apoptosis. METHODS: This was a prospective, controlled, nonrandomized Phase II dose-finding study for sulindac. The study group (n=28) and control group (n=10) underwent colectomy and ileorectal anastomoses, with repeated proctoscopy with endoluminal ultrasound and biopsies every three months. Dose-reduction of sulindac according to adenoma reversion was predetermined. Proliferation marker, Ki-67 (MIB1 and 5), on frozen or paraffin sections evaluated the antiproliferative effects; mutant p21 ras ,pantropic p53, mutant p53, and anti -bcl-2 were performed as enzyme-linked immunosorbent assay procedures and/or immunohistochemistry on paraffin sections. RESULTS: All patients responded to sulindac after 24 weeks (at the latest). 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 percent partial reversions of adenomas at latest re-examination, and no influence on upper gastrointestinal tract adenomas. No influence was detected on repeated hemograms, liver, or renal function at high or low doses. There was a permanent antiproliferative effect (Ki-67) of low-dose sulindac, significant blocking ofrasmutation activation, and a significant difference of untreated and treated mucosa in mutant p53 content (Wilcoxon's or Kruskal-Wallis each,P<0.05). Reverse correlation of anti-bcl-2 and p53 immunostaining on mucosa sections was an indication of adenoma relapse. CONCLUSIONS: Low-dose antiproliferative sulindac therapy is highly effective in adenoma reversion in familial adenomatous polyposis patients. Sulindac shows influence on tumor-suppressor genes and on apoptosis markers. An immunostaining correlation indicates adenoma relapse in flat microadenomas in advance of macroscopic appearance. Low-dose sulindac treatment may develop into an additive permanent therapy for colectomized familial adenomatous polyposis patients.

Key words

Adenoma reversion Familial adenomatous polyposis Nonsteroidal anti-inflammatory drugs Sulindac Apoptosis p53 bcl-2 

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Copyright information

© American Society of Colon and Rectal Surgeons 1997

Authors and Affiliations

  • Guenther Winde
    • 1
  • Kurt W. Schmid
    • 2
  • Burkhardt Brandt
    • 3
  • Oliver Müller
    • 4
  • Hans Osswald
    • 5
  1. 1.Department of General Surgery of the Westfälische Wilhelms-University of MünsterMünsterGermany
  2. 2.Gerhard-Domagk-Institute of Pathology of the Westfälische Wilhelms-University of MünsterMünsterGermany
  3. 3.Institute of Clinical Chemistry and Laboratory Medicine of the Westfälische Wilhelms-University of MünsterMünsterGermany
  4. 4.Institute of Molecular PhysiologyDortmundGermany
  5. 5.German Cancer Research CenterHeidelbergGermany

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