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.

Abstract

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.

MATERIALS AND 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.

• Authors: Bradford Siegele, Christopher Cefalu, Neal Holm, Guang Sun, Jesse Tubbs, Carol Meschonat, Yoshinobu Odaka, Arrigo DeBenedetti, G E Ghali, Quyen Chu, J Michael Mathis, Benjamin D L Li
• Journal: The Journal of surgical research (J Surg Res) Vol. 148 Issue 1 Pg. 83-9 (Jul 2008) ISSN: 0022-4804 [Print] United States
• PMID: 18570935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eukaryotic Initiation Factor-4E

Topics

• Animals
• Carcinoma, Squamous Cell (therapy)
• Cell Line, Tumor
• Disease-Free Survival
• Eukaryotic Initiation Factor-4E (genetics)
• Genes, Transgenic, Suicide
• Genetic Therapy (methods)
• Genetic Vectors
• Head and Neck Neoplasms (therapy)
• Mice
• Mice, Inbred C3H
• Neoplasm Metastasis (therapy)
• Neoplasms, Experimental