Tissue distribution and metabolism of gamma-linolenoyl-3-eicosapentaenoyl propane diol enterally or intravenously administered to mice bearing human pancreatic carcinomas

Synthetic propane diol lipids have been proposed as novel compounds to deli ver cytocidal polyunsaturated fatty acids (PUFA) such as gamma-linolenic (G LA) and eicosapentaenoic (EPA) acids. To assess the biodistribution and met abolism of these PUFA in immunodeficient mice bearing human pancreatic carc inomas (AsPC-1), gamma-linolenoyl-3-eicosapentaenoyl propane diol (GE diol) was provided il;in a fat-free diet (5% w:w)for 6 weeks or parentally admin istered as C-14-GE diol (1 or 3 consecutive doses of 1.66 g/kg/day) in an i nnovative non-ionic-digalactosyldiacylglycerol emulsion. In tumor, liver, b rain, kidney, plasma and fat tissue of mice fed GE diol, PUFA were increase d over 25-fold, except for arachidonic acid (AA) levels, which were reduced or remained constant when compared to mice fed control corn oil diet. GLA and EPA were mainly stored in fed tissue. The recovery of radioactivity fro m the i.v injected C-14-GE diol was dose and time dependent. Ten days after the i.v infusion, GLA was only detected in substantial concentrations in t umor and in fat tissue (21 and 202 mu g/g, respectively). Overall, these st udies showed that: GE diol emulsions provide 640-fold higher doses of both GLA and EPA without causing hemolysis or adverse effects in the host mouse when compared to free PUFA infusions; GE diol is metabolized after oral or i.v administration; tumor concentrations of GLA and EPA from the enterally administered diol were 4 to 13-fold higher than the in vitro cytotoxic leve ls; EPA, competes with AA and probably inhibits the activity of Delta 5 des aturase without affecting the Elongation of GLA in the host and tumor tissu e; the change in PUFA profile modifies the substrates for eicosanoid synthe sis. In short, a potentially desirable cytotoxic PUFA pattern can be achiev ed in host tissues and, in particular, in a human pancreatic tumor by provi ding GLA and EPA in the form GE-diol. These findings guarantee further inve stigations in oncology with this neutral diol lipid.