Tissue prostanoids as biomarkers for chemoprevention of colorectal neoplasia: correlation between prostanoid synthesis and clinical response in familial adenomatous polyposis.
Recent studies indicate that sulindac, a nonsteroidal anti-inflammatory drug (NSAID), lowers mucosal prostanoid levels and regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP). To determine whether they are biomarkers for sulindac-mediated chemoprevention of colorectal adenomas, levels of 5 prostanoids [prostaglandin (PG) D2, PGE2, PGF2alpha, thromboxane B2, and 6-keto-PGF1alpha] in the normal-appearing rectal mucosa from 7 FAP patients with a history of subtotal colectomy and ileorectal anastomosis and 4 FAP patients without surgery, were measured in the absence or presence of exogenously added arachidonic acid before the initiation and at the end of 3 months of sulindac treatment. The addition of arachidonic acid resulted in a uniform increase in the levels of all 5 prostanoids although this increase was selectively attenuated in patients with ileorectal anastomosis who took sulindac. In the latter patients, arachidonic acid also augmented the inhibition of prostanoid synthesis by sulindac. In contrast, sulindac failed to attenuate the increase in prostanoid levels resulting from arachidonic acid in patients without previous surgery. Importantly, when measured in the presence of arachidonic acid, the reduction in the levels of all 5 prostanoids due to sulindac was statistically correlated with a reduction in the size and number of adenomas in the two groups of patients combined. These results suggest that tissue prostanoids measured in the presence of arachidonic acid may serve as sensitive and reliable biomarkers in monitoring the clinical responsiveness of FAP patients undergoing chemoprevention for colorectal neoplasia with NSAIDs.
Yang
V W
VW
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. vyang@welch.jhu.edu
Geiman
D E
DE
Hubbard
W C
WC
Spannhake
E W
EW
Hylind
L M
LM
Hamilton
S R
SR
Giardiello
F M
FM
D011125:Adenomatous Polyposis Coli / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011453:Prostaglandins / Q000096:biosynthesis / Q000378:metabolism*; D013467:Sulindac / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014408:Biomarkers, Tumor; D011453:Prostaglandins; D013467:Sulindac