Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis.
OBJECTIVE
Familial adenomatous polyposis is an inherited colorectal cancer syndrome characterized by the presence of multiple adenomatous colorectal polyps. Molecular studies have revealed that germline mutations in the APC gene are the underlying cause of the disease. The nonsteroidal anti-inflammatory agent sulindac has been shown to reduce the number of colorectal adenomas. Most sulindac trials in the large bowel have focused on the distal colon and relatively little is known about its effect on the proximal colon. Moreover, it is unknown whether the site of the APC mutation affects the efficacy of sulindac.


METHODS
This study investigated whether there were regional differences in the effect of sulindac on the colon and whether response to sulindac was dependent on the site of mutation in the APC gene. In an open prospective study 17 patients with familial adenomatous polyposis were treated with 300 mg oral sulindac daily for four months followed by a washout phase of six months. Ten of the patients had an intact colon and seven had rectal stumps only. The number, size, and the degree of dysplasia of the adenomas were evaluated by colonoscopy at entry, end of treatment and end of the study.


RESULTS
Overall, a statistically significant decrease in the number of adenomas was observed (120 +/- 112 to 28 +/- 64, P = 0.007). After cessation of sulindac treatment the number of adenomas increased to 48 +/- 44.5, but remained significantly lower than the values observed at baseline. In the ten patients with intact colons, adenomas decreased by sevenfold in the proximal colon (103 +/- 73 to 15.1 +/- 47.4, P = 0.011) and twofold in the distal colon (80 +/- 52 to 29.6 +/- 37.2, P = 0.005). The size of adenomas and the grade of dysplasia also decreased. No correlation could be seen between the APC mutation site and the response to treatment.


CONCLUSIONS
These data indicate that sulindac reduces the number of adenomas in the entire colon and that the effect seems to be more pronounced in the proximal colon.
Guldenschuh
I
I
Gastroenterology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
Hurlimann
R
R
Muller
A
A
Ammann
R
R
Mullhaupt
B
B
Dobbie
Z
Z
Zala
G F
GF
Flury
R
R
Seelentag
W
W
Roth
J
J
Meyenberger
C
C
Fried
M
M
Hoppeler
T
T
Spigelman
A D
AD
Scott
R J
RJ
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy / Q000235:genetics*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D003113:Colonoscopy; D005260:Female; D017491:Genes, APC / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013467:Sulindac / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D013467:Sulindac