IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile.
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.
Horton
H M
HM
Vical, Inc., San Diego, CA 92121, USA. hhorton@vical.com
Dorigo
O
O
Hernandez
P
P
Anderson
D
D
Berek
J S
JS
Parker
S E
SE
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*
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