Doctoral Dissertations

Date of Award

8-1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Human Ecology

Major Professor

Jay Whelan

Committee Members

James Bailey, Roger Carroll, Naima Moustaid Moussa, Michael Zemel

Abstract

Several lines of evidence strongly link prostaglandins (PGs) and leukotrienes (LTs) to cancers of the intestine. Epidemiological studies showed aspirin and aspirin-like compounds reduced the relative risk of intestinal cancer in humans by 40-50%. Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause regression of intestinal tumors in humans and laboratory animals as well. The precise mechanism of antitumor effect of these NSAIDs is uncertain, but it has been presumed the effect is due to their ability to inhibit prostaglandin biosynthesis. This dissertation is designed to investigate the effect of modifying eicosanoid biosynthesis by NSAIDs and dietary manipulation on tumor load in a mouse model (Min/+) containing a germline defect of the APC gene. Min/+ mice were treated with sulindac (320 ppm), aspirin (400 ppm) and indomethacin (9 ppm) to inhibit and dietary arachidonic acid (1.5 wt %) to augment eicosanoid biosynthesis. Sulindac treatment reduced tumor number by > 90%, with the recurrence of tumor load following removal of treatment. In mice with established tumors, sulindac reduced tumor number by 28% and 75% after 2 and 4 days treatment, respectively. Surprisingly, sulindac treatment did not alter the levels of eicosanoids. Both indomethacin and aspirin are potent inhibitors of prostaglandins; however, only indomethacin significantly reduced the tumor number. Elevating prostaglandin E2 by 44% following dietary arachidonic acid supplementation had no effect on tumor load. In summary, the data indicate a discordance between the impact of different NSAIDs on eicosanoid biosynthesis and their antitumor activity.

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