TY - JOUR
T1 - Prostaglandin levels in human colorectal mucosa
T2 - Effects of sulindac in patients with familial adenomatous polyposis
AU - Giardiello, Francis M.
AU - Spannhake, Ernst W.
AU - Dubois, Raymond N.
AU - Hylind, Linda M.
AU - Robinson, C. Rahj
AU - Hubbard, Walter C.
AU - Hamilton, Stanley R.
AU - Yang, Vincent W.
N1 - Funding Information:
Manuscript received July 8, 1997; revise d manuscript received September 17, 1997; accepte d October 6, 1997. From the Departme nts of Medicine, Pathology, Biological Chemistry, Oncology Center, and Asthma and Allergy Center, The Johns Hopkins University School of Medicine; Department of Environmental Health Science s, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205; and the Departments of Medicine and Cell Biolog, Vyadenrbilt University Medical Center, Nashville, Tennessee 37232. Supported by the ClatonyFund and NIH grants CA62924, CA53801, CA63721.
PY - 1998
Y1 - 1998
N2 - Recent evidence suggests that nonsteroidal antiinflammatory drugs (NSAIDs) may prevent colorectal cancer. The mechanism of action of NSAIDs in chemoprevention is unknown but may be linked to their effect on mucosal prostaglandin levels. Levels of five major prostaglandin metabolites were measured by gas chromatography-mass spectrometry in biopsy specimens of flat rectal mucosa from four patients with familial adenomatous polyposis (FAP) before and after sulindac therapy and from five healthy individuals. The prostaglandin present at highest concentration in rectal mucosa from FAP and control subjects was prostaglandin E2. The concentration of thromboxane B2 alone was significantly elevated in FAP patients compared to controls (P = 0.016). In FAP patients treated with sulindac, all prostaglandin metabolite levels were significantly reduced compared to pretreatment levels (P < 0.05) except prostaglandin D2 (P = 0.07). Prostaglandins D2, E2, F(2α), and 6- keto-F(1α) levels also were significantly reduced in FAP patients on sulindac compared to healthy controls (P < 0.05). However, interpatient heterogeneity of response to sulindac was evident with changes ranging from +19% to -89%, and the patient with the greatest reductions after sulindac developed colorectal cancer after 35 months of therapy. Sulindac treatment, at drug doses shown to regress colorectal adenomas in FAP patients, has heterogeneous effects on the level of major prostaglandins in their rectal mucosa and may not prevent colorectal cancer due to uncoupling of prostaglandin levels and carcinogenesis.
AB - Recent evidence suggests that nonsteroidal antiinflammatory drugs (NSAIDs) may prevent colorectal cancer. The mechanism of action of NSAIDs in chemoprevention is unknown but may be linked to their effect on mucosal prostaglandin levels. Levels of five major prostaglandin metabolites were measured by gas chromatography-mass spectrometry in biopsy specimens of flat rectal mucosa from four patients with familial adenomatous polyposis (FAP) before and after sulindac therapy and from five healthy individuals. The prostaglandin present at highest concentration in rectal mucosa from FAP and control subjects was prostaglandin E2. The concentration of thromboxane B2 alone was significantly elevated in FAP patients compared to controls (P = 0.016). In FAP patients treated with sulindac, all prostaglandin metabolite levels were significantly reduced compared to pretreatment levels (P < 0.05) except prostaglandin D2 (P = 0.07). Prostaglandins D2, E2, F(2α), and 6- keto-F(1α) levels also were significantly reduced in FAP patients on sulindac compared to healthy controls (P < 0.05). However, interpatient heterogeneity of response to sulindac was evident with changes ranging from +19% to -89%, and the patient with the greatest reductions after sulindac developed colorectal cancer after 35 months of therapy. Sulindac treatment, at drug doses shown to regress colorectal adenomas in FAP patients, has heterogeneous effects on the level of major prostaglandins in their rectal mucosa and may not prevent colorectal cancer due to uncoupling of prostaglandin levels and carcinogenesis.
KW - Familial adenomatous polyposis
KW - Nonsteroidal antiinflammatory drugs
KW - Polyps
KW - Prostaglandins
KW - Sulindac
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U2 - 10.1023/A:1018898120673
DO - 10.1023/A:1018898120673
M3 - Article
C2 - 9512123
AN - SCOPUS:0031893036
SN - 0163-2116
VL - 43
SP - 311
EP - 316
JO - Digestive diseases and sciences
JF - Digestive diseases and sciences
IS - 2
ER -