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Departments of Nutrition [C-H. C., J. W.] and Pathology [M. F. M.], University of Tennessee College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996-1900
Several lines of evidence strongly link prostaglandins (PGs) and leukotrienes (LTs) to cancer of the intestine. Several studies have reported a 40–50% reduction in mortality from colorectal cancer in individuals who routinely consume nonsteroidal anti-inflammatory drugs, possibly by inhibiting cyclooxygenase activity. However, the role of eicosanoids in this process is still unclear. The heterozygote Min/+ mouse model, like patients with familial adenomatous polyposis, carries a nonsense mutation in the adenomatous polyposis coli (APC) gene that results in the spontaneous development of intestinal adenomas (100% incidence). This study investigated the association between eicosanoid biosynthesis, intestinal tumor load, and the chemotherapeutic effect of the nonsteroidal anti-inflammatory drug sulindac during early and preexisting phases of tumor growth and development as well as residual effects after drug withdrawal. Administration of sulindac (320 ppm) to Min/+ mice reduced the tumor number by 95% but did not alter the levels of PGE2 and LTB4 in intestinal tissues. Increasing PGE2 and LTB4 levels by 44% with dietary arachidonic acid supplementation had no effect on tumor number or size. When sulindac was added to the arachidonic acid-supplemented diet, tumor number was reduced by 82%, whereas eicosanoid levels remained elevated. In Min/+ mice with established tumors, treatment with sulindac for 4 days reduced tumor number by 75%, and continual administration of sulindac was necessary to maintain a reduced tumor load. In summary, alterations in eicosanoid formation were not correlated with tumor number or size in the Min/+ mouse model; thus, the antitumor effect of sulindac seems to be PG independent.
1 Supported by a grant from the American Institute for Cancer Research, a Hatch Grant from the Tennessee Agricultural Experiment Station, and private donations from Myron Pfeifer and supporters of the Arachidonic Acid Project.
2 To whom requests for reprints should be addressed, at Department of Nutrition, 229 Jessie Harris Building, University of Tennessee, Knoxville, TN 37996-1900. Phone: 423-974-6260; Fax: 423-974-3491; e-mail: jwhelan@utk.edu.
Received 6/ 4/97. Accepted 8/14/97.
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