Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally.
BACKGROUND
The poor prognosis associated with ovarian cancer is primarily the result of delayed diagnosis and the lack of an effective treatment for advanced disease. Use of novel immunotherapy strategies are being evaluated that work to enhance local and systemic immune responses against cancer cells and can possibly work together with traditional cytotoxic chemotherapy regimens to produce more effective treatment options.


METHODS
In the present study, we describe a gene-based therapy whereby the anticancer cytokine interleukin-12 gene (pmIL-12) is formulated with a synthetic polymeric delivery vehicle (PPC) and administered intraperitoneally into a mouse model of disseminated ovarian cancer.


RESULTS
The administration of pmIL-12/PPC in tumor-bearing mice was associated with a shift towards a Th1 immune state, including significant increases in murine IL-12 (mIL-12) and interferon (IFN)-gamma (mIFN-gamma) in ascites fluid, with little change in systemic levels of these proteins. The mIL-12 protein was detectable for several days and could be reintroduced with subsequent injections. We show that treatment delayed the onset of ascites formation and improved survival in a dose-dependent manner. A significant decrease in vascular endothelial growth factor was associated with pmIL-12/PPC delivery and believed to play a predominant role in inhibiting ascites accumulation. Administration of pmIL-12/PPC was associated with minimal toxicity and, when combined with standard chemotherapies, resulted in additive improvement in survival.


CONCLUSIONS
Taken together, these results suggest that pmIL-12/PPC may be an effective strategy for inhibiting progression of disseminated ovarian cancer and may offer a new option for treatment of advanced disease that can be used to complement standard therapies.
Fewell
Jason G
JG
EGEN, Inc., Huntsville, AL 35806, USA. jfewell@egeninc.com
Matar
Majed M
MM
Rice
Jennifer S
JS
Brunhoeber
Elaine
E
Slobodkin
Gregory
G
Pence
Casey
C
Worker
Miranda
M
Lewis
Danny H
DH
Anwer
Khursheed
K
D000818:Animals; D001201:Ascites / Q000378:metabolism; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000097:blood; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects; D014780:Viruses
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018664:Interleukin-12; D016190:Carboplatin; D017239:Paclitaxel