Effect of aspirin on prostaglandin E2 and leukotriene B4 production in human colonic mucosa from cancer patients.

Results from epidemiological studies indicate that chronic administration of aspirin reduces the incidence of colon cancer. The mechanism that accounts for this reduction is not known, but it may be related to the decreased production of prostanoids that results from aspirin inhibition of cyclooxygenase. However, it is not known whether aspirin has a local effect on prostanoid production in the colonic mucosa and whether this effect is dose dependent. In this study, we determined the effect of oral administration of aspirin on the production of the prostanoid prostaglandin E2 (PGE2) in the intact human colonic mucosa. Inhibition of cyclooxygenase could result in an increased availability of arachidonic acid and a corresponding increase in production of other eicosanoids. To determine whether such an effect occurs, we also quantitated the concentration of leukotriene B4 (LTB4) in colonic mucosal samples. Mucosal samples were obtained during sigmoidoscopy from the colons of 17 subjects with a history of colonic cancer prior to and following 60 days of self-administration of 325 mg aspirin/day and again 60 days after administration of 650 mg aspirin/day. PGE2 and LTB4 concentrations were determined by enzyme immunoassay for tissue samples that were flash frozen after removal from the biopsy forceps and also in medium that was collected from tissue samples that were incubated for 4 h following removal from the subject. PGE2 concentrations were decreased significantly in samples collected after 60 days of consumption of 325 mg aspirin. An additional 60 days of consuming 650 mg aspirin/day did not result in a further significant decrease relative to that attained after consumption of 325 mg/day. Similar results were obtained using colonic explants, and the addition of aspirin to medium further reduced PGE2 production. LTB4 in tissue and medium was not significantly different in pre-versus post-aspirin samples, with the exception of an increased concentration in medium samples collected after consumption of 650 mg/day relative to pre-aspirin samples. The results indicate that aspirin affects eicosanoid production in the colonic mucosa of humans, but the effect is most likely restricted to products of the cyclooxygenase-dependent pathway. It appears that 325 mg of aspirin is sufficient to affect PGE2 production and that increasing the dosage to 650 mg daily provides an additional decrease in PGE2 synthesis. However, the higher dosage was associated with a considerable increase in complaints of gastric discomfort. Additional study is needed to establish whether doses less than 325 mg also provide a significant decrease in PGE2 production.