EFFECT OF ASPIRIN ON PROSTAGLANDIN E-2 AND LEUKOTRIENE B-4 PRODUCTIONIN HUMAN COLONIC MUCOSA FROM CANCER-PATIENTS

Results from epidemiological studies indicate that chronic administrat ion of aspirin reduces the incidence of colon cancer, The mechanism th at accounts for this reduction is not known, but it may be related to the decreased production of prostanoids that results from aspirin inhi bition of cyclooxygenase. However, it is not known whether aspirin has a local effect on prostanoid production in the colonic mucosa and whe ther this effect is dose dependent, In this study, we determined the e ffect of oral administration of aspirin on the production of the prost anoid prostaglandin E-2 (PGE(2)) in the intact human colonic mucosa, I nhibition of cyclooxygenase could result in an increased availability of arachidonic acid and a corresponding increase in production of othe r eicosanoids. To determine whether such an effect occurs, we also qua ntitated the concentration of leukotriene B-4 (LTB4) in colonic mucosa l samples. Mucosal samples were obtained during sigmoidoscopy from the colons of 17 subjects with a history of colonic cancer prior to and f ollowing 60 days of self-administration of 325 mg aspirin/day and agai n 60 days after administration of 650 mg aspirin/day, PGE(2) and LTB4 concentrations were determined by enzyme immunoassay for tissue sample s that were flash frozen after removal from the biopsy forceps and als o in medium that was collected from tissue samples that were incubated for 4 h following removal from the subject, PGE(2) concentrations wer e decreased significantly in samples collected after 60 days of consum ption of 325 mg aspirin. An additional 60 days of consuming 650 mg asp irin/day did not result in a further significant decrease relative to that attained after consumption of 325 mg/day. Similar results were ob tained using colonic explants, and the addition of aspirin to medium f urther reduced PGE(2) production, LTB4 in tissue and medium was not si gnificantly different in pre-versus post-aspirin samples, with the exc eption of an increased concentration in medium samples collected after consumption of 650 mg/day relative to pre-aspirin samples, The result s indicate that aspirin affects eicosanoid production in the colonic m ucosa of humans, but the effect is most likely restricted to products of the cyclooxygenase-dependent pathway. It appears that 325 mg of asp irin is sufficient to affect PGE(2) production and that increasing the dosage to 650 mg daily provides an additional decrease in PGE(2) synt hesis. However, the higher dosage was associated with a considerable i ncrease in complaints of gastric discomfort. Additional study is neede d to establish whether doses less than 325 mg also provide a significa nt decrease in PGE(2) production.