title: IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile.
abstract: We have evaluated whether i.p. murine ovarian tumors could be treated with an IL-2 plasmid DNA complexed with the cationic lipid, (+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2, 3-bis(tetradecyloxy)-1-propanaminium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). Reporter gene studies were initially conducted in which mice bearing i.p. murine ovarian teratocarcinoma (MOT) were injected i.p. with reporter gene plasmid DNA (pDNA):DMRIE/DOPE. Histochemical analyses revealed that transfection occurred primarily in the tumor cells of the ascites, with only a minority of other ascitic cells or surrounding tissues transfected. IL-2 levels in the MOT ascites were determined after i. p. injection of either IL-2 pDNA:DMRIE/DOPE or recombinant IL-2 protein. IL-2 was detected in tumor ascites for up to 10 days after a single i.p. injection of IL-2 pDNA:DMRIE/DOPE, but was undetectable 24 h after a single i.p. injection of IL-2 protein. In an antitumor efficacy study, MOT tumor-bearing mice injected i.p. with IL-2 pDNA:DMRIE/DOPE on days 5, 8, and 11 after tumor cell implant had a significant inhibition of tumor ascites (p = 0.001) as well as a significant increase in survival (p = 0.008). A cytokine profile of the MOT tumor ascites revealed that mice treated with IL-2 pDNA:DMRIE/DOPE had an IL-2-specific increase in the levels of IFN-gamma and GM-CSF. Taken together, these findings indicate that i. p. treatment of ovarian tumors with IL-2 pDNA:DMRIE/DOPE can lead to an increase in local IL-2 levels, a change in the cytokine profile of the tumor ascites, and a significant antitumor effect.
authors.affiliation: Vical, Inc., San Diego, CA 92121, USA. hhorton@vical.com
authors.forename: H M
authors.initials: HM
authors.lastname: Horton
authors.forename: O
authors.initials: O
authors.lastname: Dorigo
authors.forename: P
authors.initials: P
authors.lastname: Hernandez
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: J S
authors.initials: JS
authors.lastname: Berek
authors.forename: S E
authors.initials: SE
authors.lastname: Parker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D001201:Ascites / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis*; D004269:DNA, Bacterial / Q000008:administration & dosage / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D008055:Lipids / Q000008:administration & dosage; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000235:genetics; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D018243:Teratocarcinoma / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004269:DNA, Bacterial; D006131:Growth Inhibitors; D007376:Interleukin-2; D008055:Lipids; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium; C094877:dioleoyl phosphatidylethanolamine