Heterozygous C57BL/6J-Min (Minf+) mice are highly susceptible to spontaneous development of intestinal adenomas due to a germ-line mutation in one allele of the murine APC3 gene, with tumor initiation

Several lines of evidence strongly link prostaglandins (PGs) and leu kotrienes (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 in hlbiting cyclooxygenase activity. However, the role of eicosanoids in this process is still unclear. The heterozygote Min/+ mouse model, like pa tients with familial adenomatous polyposis, carries a nonsense mutation in the adenomatous polyposis coil (APC) gene that results in the spontaneous development of intestinal adenomas (100% incidence). This study inves ligated the association between elcosanoid biosynthesis, intestinal tumor load, and the chemotherapeutic effect of the nonsteroidal anti-inflamma tory drug sulindac during early and preexisting phases of tumor growth and development as well as residual effects after drug withdrawaL Ad ministration of sulindac (320 ppm) to Min/+ mice reduced the tumor number by 95% but did not alter the levels ofPGE2 and LTB4 in intestinal tissues. Increasing PGE2 and LTB4 levels by 44% with dietary arachi donic 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 ele vated In Min/+ mice with established tumors, treatment with sullndac for 4daysreducedtumornumberby75%,andcontinual administration of sulindac was necessary to maintain a reduced tumor load. In summary, alterations in eicosanoid formation were not correlated with tumor num ber or size in the Min/+ mouse model; thus, the antitumor effect of sulindac seems to be PG independent.