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 deliver cytocidal polyunsaturated fatty acids (PUFA) such as gamma-linolenic (GLA) and eicosapentaenoic (EPA) acids. To assess the biodistribution and metabolism of these PUFA in immunodeficient mice bearing human pancreatic carcinomas (AsPC-1), gamma-linolenoyl-3-eicosapentaenoyl propane diol (GE diol) was provided in a fat-free diet (5% w:w) for 6 weeks or parentally administered as 14C-GE diol (1 or 3 consecutive doses of 1.66 g/kg/day) in an innovative non-ionic-digalactosyldiacylglycerol emulsion. In tumor, liver, brain, kidney, plasma and fat tissue of mice fed GE diol, PUFA were increased 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 fat tissue. The recovery of radioactivity from the i.v. infected 14C-GE diol was dose and time dependent. Ten days after the i.v. infusion, GLA was only detected in substantial concentrations in tumor and in fat tissue (21 and 202 micrograms/g, respectively). Overall, these studies 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 levels; EPA, competes with AA and probably inhibits the activity of delta 5 desaturase without affecting the elongation of GLA in the host and tumor tissue; the change in PUFA profile modifies the substrates for eicosanoid synthesis. In short, a potentially desirable cytotoxic PUFA pattern can be achieved in host tissues and, in particular, in a human pancreatic tumor by providing GLA and EPA in the form GE-diol. These findings guarantee further investigations in oncology with this neutral diol lipid.
De Antueno
R
R
Scotia Research Institute, Kentville, NS, Canada. r.deantueno@mailexcite.com
Bai
M
M
Elliot
M
M
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D003314:Corn Oil / Q000008:administration & dosage; D000090943:Delta-5 Fatty Acid Desaturase; D004041:Dietary Fats / Q000008:administration & dosage; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004655:Emulsions; D004750:Enteral Nutrition; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014781:Viscera / Q000378:metabolism; D017965:gamma-Linolenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D001095:Arachidonic Acids; D000090943:Delta-5 Fatty Acid Desaturase; D004041:Dietary Fats; D004655:Emulsions; D005231:Fatty Acids, Unsaturated; D009363:Neoplasm Proteins; C121195:gamma-linolenoyl-3-eicosapentaenoylpropanediol; D017965:gamma-Linolenic Acid; D003314:Corn Oil; D015118:Eicosapentaenoic Acid; D044943:Fatty Acid Desaturases