The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis.
OBJECTIVE
The mechanism by which sulindac causes regression of adenomas in patients with familial adenomatous polyposis (FAP) is unclear. Conflicting data on the drug's effects on colorectal epithelial proliferation have been reported. An alternative mechanism, and one not previously studied, is via induction of colorectal epithelial cell apoptosis (programmed cell death). This hypothesis was tested by studying the effects of sulindac on colorectal epithelial proliferation and apoptosis in patients with FAP.


METHODS
Cell proliferation was studied via immunohistochemistry for cell nuclear antigen in a group of 22 patients randomized to either sulindac (150 mg twice a day) or placebo in a previously published trial. The rectal epithelium from 7 additional patients with FAP treated with sulindac was examined by flow cytometry to assess changes in cell-cycle distribution and apoptosis.


RESULTS
Although sulindac caused a significant decrease in polyp size and number, there was no significant change in cytokinetic variables or cell cycle distribution 3 months after treatment. However, the subdiploid apoptotic fraction was increased significantly 3 months after treatment with sulindac (31.3% +/- 4.8% compared with 10% +/- 4.3% at baseline; P = 0.01).


CONCLUSIONS
Our findings suggest that sulindac does not affect colorectal epithelial proliferation and that its effects in patients with FAP may instead result from induction of apoptosis.
Pasricha
P J
PJ
Department of Medicine, Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland, USA.
Bedi
A
A
O'Connor
K
K
Rashid
A
A
Akhtar
A J
AJ
Zahurak
M L
ML
Piantadosi
S
S
Hamilton
S R
SR
Giardiello
F M
FM
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000328:Adult; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004311:Double-Blind Method; D004848:Epithelium / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012007:Rectum / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D012074:Remission Induction; D013467:Sulindac / Q000627:therapeutic use*
D018809:Proliferating Cell Nuclear Antigen; D013467:Sulindac