Antitumor and antimetastatic actions of eicosapentaenoic acid ethylester and its by‐products formed during accelerated stability testing

The aim of the present work was to compare the effects of eicosapentaenoic acid (EPA) ethylester and EPA derivatives (EPAD) on tumor growth and metastasis to the lung in tumor-bearing mice. Because EPA is very unstable during long-term storage, the EPAD were subjected to accelerated testing under storage conditions of 60 +/- 5% relative humidity at 37 degrees C for 30 days. EPAD are composed of a mixture of a newly identified EPA ethylester dimer and EPA hydroxyethylester, and known EPA and EPA ethylesters. The inhibitory effects of EPAD, the EPA ethylester dimer and EPA hydroxyethylester on Matrigel-induced capillary-like network formation were stronger than the effect of EPA ethylester. The oral administration of EPAD (300 or 1000 mg/kg) inhibited angiogenesis in gels containing Matrigel supplemented with vascular endothelial growth factor (VEGF) and heparin in an in vivo model, but EPA ethylester had no effect. EPA ethylester (300 or 1000 mg/kg) or EPAD (1000 mg/kg) inhibited tumor growth in mice with subcutaneously implanted LLC. Furthermore, EPAD inhibited metastasis to the lung in mice implanted with LLC subcutaneously, but EPA had no effect. EPAD increased the CD8(+) T-cell population in the spleen compared with mice with subcutaneously implanted LLC. EPA ethylester increased the natural killer cell population in the spleen. Thus, it is suggested that the mechanisms of the antitumor and/or antimetastatic actions of EPAD and EPA ethylester involve different immune functions, and that the EPA ethylester dimer and the EPA hydroxyethylester of EPAD may contribute to these actions.