Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer.
Development of potential cancer chemopreventive drugs involves the systematic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation.


OBJECTIVE
We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estradiol (E2) in individuals at high risk for colorectal cancer development similar to our prior observations in a young normal-risk population.


METHODS
Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subjects. Prostaglandin E2 and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment.


RESULTS
The mean prostaglandin E2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/microg (mean +/- SE) tissue protein and after aspirin treatment was 4.9 +/- 0.91 pg/microg tissue protein (P < 0.0001). In high-risk subjects, mean pretreatment prostaglandin E2 was 14.4 +/- 1.7 pg/microg tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/microg tissue protein (P < 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression.


CONCLUSIONS
Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E2, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.
Krishnan
K
K
Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University and Medical Service, James H. Quillen Veterans Affairs Medical Center, Johnson City, Tennessee 37604, USA.
Ruffin
M T
MT
Normolle
D
D
Shureiqi
I
I
Burney
K
K
Bailey
J
J
Peters-Golden
M
M
Rock
C L
CL
Boland
C R
CR
Brenner
D E
DE
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001241:Aspirin / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D002277:Carcinoma / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry* / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin