eIF4E-targeted suicide gene therapy in a minimal residual mouse model for metastatic soft-tissue head and neck squamous cell carcinoma improves disease-free survival.
BACKGROUND
Translation initiation factor eIF4E unwinds long 5'-untranslated regions of certain tightly regulated mRNAs and, thereby, facilitates their translation into proteins. eIF4E has been shown to be overexpressed in a majority of solid tumors, including head and neck cancers. To exploit this dysregulation, a long 5'-untranslated region was spliced upstream of a thymidine kinase (Tk) gene to enhance translation of this "suicide" gene within cells overexpressing eIF4E. We investigated the efficacy of therapy with an adenovirus incorporating this novel suicide gene (Ad-HSV-UTk) following cytoreductive tumor surgery in improving disease-free and overall survival in a mouse soft-tissue metastasis model for head and neck squamous cell carcinoma.


METHODS
SCC-7 (orally-derived mouse SCCa) cells were treated with Ad-HSV-Tk, Ad-HSV-UTk, Ad-null, or saline and characterized for eIF4E and Tk levels by Western blot analysis. Cytotoxicities for cells treated with Ad-HSV-Tk, Ad-HSV-UTk, or Ad-null were quantified by MTS assay. Mice bearing SCC-7-induced tumors received cytoreduction followed by Ad-HSV-UTk + ganciclovir (GCV) or control treatment and were followed for disease-free and overall survival.


RESULTS
SCC-7 cells showed uniformly high levels of eIF4E but elevated Tk for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells over Ad-null-treated cells. Cytotoxicities for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells were, correspondingly, observed to be 100-fold more sensitive than Ad-null-treated cells to GCV treatment. Cytoreduced mice receiving Ad-HSV-UTk + GCV treatment showed significantly longer disease-free survival (P = 0.0045) than control arm mice.


CONCLUSIONS
Ad-HSV-UTk suicide gene therapy prolonged disease-free survival in a mouse minimal residual soft-tissue head and neck squamous cell carcinoma metastasis model.
Department of Surgery, Louisiana State University Health Sciences Center and Feist-Weiller Cancer Center, Shreveport, Louisiana 71103, USA.
Bradford
B
Siegele
Christopher
C
Cefalu
Neal
N
Holm
Guang
G
Sun
Jesse
J
Tubbs
Carol
C
Meschonat
Yoshinobu
Y
Odaka
Arrigo
A
DeBenedetti
G E
GE
Ghali
Quyen
Q
Chu
J Michael
JM
Mathis
Benjamin D L
BD
Li
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis / Q000628:therapy*; D009374:Neoplasms, Experimental
D039561:Eukaryotic Initiation Factor-4E