A novel suicide gene therapy targeting the overexpression of eukaryotic initiation factor 4E improves survival in a rat peritoneal carcinomatosis model.
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.
Byrnes
Kerry
K
Department of Surgery, Louisiana State University Health Sciences Center in Shreveport, and Feist-Weiller Cancer Center, Shreveport, Louisiana, USA. kbyrne@lsuhsc.edu
Li
Benjamin D L
BD
Holm
Neal
N
Li
Jie
J
Okadata
Yoshi
Y
De Benedetti
Arrigo
A
Nedeljkovic-Kurepa
A
A
Mathis
Michael
M
Chu
Quyen D
QD
D000230:Adenocarcinoma / Q000601:surgery / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000601:surgery / Q000628:therapy*; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000601:surgery / Q000628:therapy; D009852:Omentum; D010534:Peritoneal Neoplasms / Q000601:surgery / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate
D000998:Antiviral Agents; D039561:Eukaryotic Initiation Factor-4E; D015774:Ganciclovir