Sulindac causes rapid regression of preexisting tumors in Min/+ mice independent of prostaglandin biosynthesis.
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.
Chiu
C H
CH
Department of Nutrition, University of Tennessee College of Veterinary Medicine, Knoxville 37996-1900, USA.
McEntee
M F
MF
Whelan
J
J
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004198:Disease Susceptibility; D017491:Genes, APC; D006579:Heterozygote; D007580:Jejunal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011453:Prostaglandins / Q000096:biosynthesis* / Q000502:physiology; D012074:Remission Induction; D013467:Sulindac / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D011453:Prostaglandins; D013467:Sulindac; D007975:Leukotriene B4; D016718:Arachidonic Acid; D015232:Dinoprostone