Familial adenomatous polyposis (FAP) is a
genetic disorder characterized by the development of hundreds of
polyps throughout the colon. Without prophylactic
colectomy, most individuals with FAP develop
colorectal cancer at an early age. Treatment with EPA in the
free fatty acid form (EPA-FFA) has been shown to reduce
polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of
magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of
TP-252 on intestinal
tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA.
TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of
TP-252 significantly reduced
tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the
cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total
fatty acid composition and
eicosanoid metabolites. Treatment with
TP-252 significantly decreased the levels of
arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of
fatty acids, including EPA and
docosahexaenoic acid (DHA), and their downstream metabolites, including
PGE3 and 14-hydroxy-docosahexaenoic
acid (HDoHE), were strongly associated with
antineoplastic activity. These results indicate that
TP-252 warrants further clinical development as a potential strategy for delaying
colectomy in adolescent FAP patients.