A novel suicide gene therapy targeting the overexpression of eukaryotic initiation factor 4E improves survival in a rat peritoneal carcinomatosis model.

Abstract

BACKGROUND:

Eukaryotic Initiation Factor 4E (eIF4E) is pivotal in translating mRNAs with complex 5' un-translated regions (UTRs). A target-specific gene therapy was developed by splicing a complex 5'UTR upstream of the herpes simplex virus thymidine kinase (TK) gene in an adenovirus vector (Ad-HSV-UTK). Translation of the suicide TK gene is restricted to cells that overexpress eIF4E. We investigated the efficacy of this novel therapy in a rat peritoneal carcinomatosis (PC) model.

METHODS:

A PC model was developed by implanting a syngeneic 0.25 cm(3) tumor into Fisher 344 rats' omentum. Rats were grouped as follow: No surgery (Ø CS), cytoreductive surgery alone (CS), and CS + Ad-HSV-UTK + gancyclovir (GCV). 10(9) Ad-HSV-UTK was injected intraperitoneally (i.p.) and GCV (50 mg/kg) was administered i.p. every other day, beginning on postoperative day 2. The Kaplan-Meier survival method and log-rank test were statistical tests used.

RESULTS:

Treated rats had a significantly longer median and overall survival than the Ø CS and CS groups (P = .012). The median survivals for the treated rats, Ø CS, CS were 18 days, 9 days, and 11 days, respectively.

CONCLUSIONS:

Treatment with a novel suicide gene therapy following cytoreductive surgery prolonged survival in a rat peritoneal carcinomatosis model.

• Authors: Kerry Byrnes, Benjamin D L Li, Neal Holm, Jie Li, Yoshi Okadata, Arrigo De Benedetti, A Nedeljkovic-Kurepa, Michael Mathis, Quyen D Chu
• Journal: Surgery (Surgery) Vol. 142 Issue 2 Pg. 270-5 (Aug 2007) ISSN: 0039-6060 [Print] United States
• PMID: 17689695 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Eukaryotic Initiation Factor-4E
• Ganciclovir

Topics

• Adenocarcinoma (surgery, therapy)
• Adenoviridae (genetics)
• Animals
• Antiviral Agents (pharmacology)
• Cell Line, Tumor
• Combined Modality Therapy
• Disease Models, Animal
• Eukaryotic Initiation Factor-4E (genetics)
• Female
• Ganciclovir (pharmacology)
• Gene Expression Regulation, Neoplastic
• Genes, Transgenic, Suicide
• Genetic Therapy (methods)
• Mammary Neoplasms, Animal (surgery, therapy)
• Neoplasm Transplantation
• Neoplasm, Residual (surgery, therapy)
• Omentum
• Peritoneal Neoplasms (surgery, therapy)
• Rats
• Rats, Inbred F344
• Survival Rate