Clinical and Genomic Influence of Sulindac on Rectal Mucosa in Familial Adenomatous Polyposis

Dis Colon Rectum. 1997 Oct;40(10):1156-68; discussion 1168-9. doi: 10.1007/BF02055161.

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 p21ras, 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 of ras mutation 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 permnanent therapy for colectomized familial adenomatous polyposis patients.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II

MeSH terms

  • Adenomatous Polyposis Coli / drug therapy*
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / metabolism
  • Adenomatous Polyposis Coli / pathology
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cell Division
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / chemistry
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology*
  • Ki-67 Antigen / analysis
  • Male
  • Middle Aged
  • Prospective Studies
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Proto-Oncogene Proteins p21(ras) / analysis
  • Rectum / drug effects
  • Rectum / pathology*
  • Sulindac / administration & dosage
  • Sulindac / therapeutic use*
  • Tumor Suppressor Protein p53 / analysis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Ki-67 Antigen
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Sulindac
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)