SULINDAC CAUSES RAPID REGRESSION OF PREEXISTING TUMORS IN MIN + MICE INDEPENDENT OF PROSTAGLANDIN BIOSYNTHESIS/

Several lines of evidence strongly link prostaglandins (PGs) and leuko trienes (LTs) to cancer of the intestine, Several studies have reporte d a 40-50% reduction in mortality from colorectal cancer in individual s who routinely consume nonsteroidal anti-inflammatory drugs, possibly by inhibiting cyclooxygenase activity, However, the role of eicosanoi ds in this process is still unclear, The heterozygote Min/+ mouse mode l, like patients with familial adenomatous polyposis, carries a nonsen se 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 biosynthe sis, intestinal tumor load, and the chemotherapeutic effect of the non steroidal anti-inflammatory drug sulindac during early and preexisting phases of tumor growth and development as well as residual effects af ter drug withdrawal, Administration of sulindac (320 ppm) to Min/+ mic e reduced the tumor number by 95% but did not alter the levels of PGE( 2) and LTB4 in intestinal tissues, Increasing PGE(2) and LTB4 levels b y 44% with dietary arachidonic acid supplementation had no effect on t umor number or size, When sulindac was added to the arachidonic acid-s upplemented diet, tumor number was reduced by 82%, whereas eicosanoid levels remained elevated, In Min/+ mice with established tumors, treat ment with sulindac for 4 days reduced tumor number by 75%, and continu al administration of sulindac was necessary to maintain a reduced tumo r load, In summary, alterations in eicosanoid formation were not corre lated with tumor number or size in the Min/+ mouse model; thus, the an titumor effect of sulindac seems to be PG independent.