Activation of host antitumoral responses by cationic lipid/DNA complexes.
A model of lipoplex-induced peritonitis was used to characterize the inflammatory response to cationic lipid:DNA lipoplexes with respect to activation of host antitumoral effector mechanisms. Three different cationic lipids were used in these studies: N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N-(1-[2,3-dioleoyloxylpropyl)-N,N,N-trimethylammonium chloride (DOTAP), and N-(1-[2,3-dioleyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTMA). The DODAC and DOTMA lipoplexes exhibited similar transfection properties in vitro, whereas the DOTAP lipoplexes transfected quite poorly in all cell lines tested. Intraperitoneal injection of cationic lipoplexes into immunocompetent mice resulted in a profound infiltration of inflammatory cells, secretion of interferon-gamma, and increased natural killer activity within the peritoneal cavity. Both DODAC and DOTMA lipoplexes produced similar inflammatory responses, lasting at least 5 days. The inflammation induced by DOTAP lipoplexes peaked by day 3 and resolved to near-control levels by day 5. These data indicate that although cationic lipid DNA complexes may differ in their inflammatory properties, the natural killer activation and interferon-gamma secretion that follow lipoplex administration should provide a functional adjuvant for cancer gene therapies that benefit from immunostimulation.
Bramson
J L
JL
Inex Pharmaceuticals Corporation, Burnaby, British Columbia, Canada. bramsonj@FHS.mcmaster.ca
Bodner
C A
CA
Graham
R W
RW
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001202:Ascitic Fluid / Q000276:immunology / Q000378:metabolism; D002412:Cations; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008055:Lipids / Q000235:genetics / Q000494:pharmacology*; D008081:Liposomes / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002412:Cations; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; C015831:dimethyldioctadecylammonium; D004247:DNA; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane