A novel suicide gene therapy targeting the overexpression of eukaryotic initiation factor 4E improves survival in a rat peritoneal carcinomatosis model Kerry Byrnes, MD, a Benjamin D.L. Li, MD, a Neal Holm, MD, a Jie Li, MD, PhD, a Yoshi Okadata, PhD, b Arrigo De Benedetti, PhD, c A. Nedeljkovic-Kurepa, PhD, b Michael Mathis, PhD, b and Quyen D. Chu, MD, a Shreveport, Louisiana 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. (Surgery 2007;142:270-5.) From the Departments of Surgery, a Cellular Biology and Anatomy, b and Biochemistry and Molecular Biology, c Louisiana State University Health Sciences Center in Shreveport, and Feist-Weiller Cancer Center, Shreveport, Louisiana Following metastatic disease to the liver, peritoneal carcinomatosis (PC) is the second most frequent cause of death in patients with colorectal cancer. 1 Traditionally, patients were treated with systemic chemotherapy and palliative surgery was generally reserved for those who presented with complica- tions. The outcome for both options has been dis- mal. 2,3 Recent advances in oncologic surgery have dem- onstrated that in select patients with PC, long-term survival with cytoreductive surgery (CS) and intra- peritoneal chemotherapy is possible. 4,5 Despite such advances, however, recurrence is common and the majority of patients succumb to the dis- ease. Novel treatments, therefore, are needed. A novel approach is to use cancer suicide gene ther- apy, specifically modifying the herpes simplex virus type-1 thymidine kinase suicide gene (HSV-TK) to target cancer cells, based on characteristics that are specific to them. Eukaryotic initiation factor 4E (eIF4E) is a 24 kDa cap-binding protein involved in initiating pro- tein synthesis. It is a subunit of the RNA helicase complex and its binding facilitates the unwinding of the 5= untranslated region (UTR) of messenger RNAs. 6-9 This protein typically exists in small rate- limiting quantities. Messenger RNAs with a long/ Presented as an oral presentation at the 2nd Academic Surgical Congress. Accepted for publication April 19, 2007. Reprint requests: Quyen D. Chu, MD, FACS, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreve- port, LA 71130. E-mail: kbyrne@lsuhsc.edu. 0039-6060/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.04.009 270 SURGERY