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

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

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)83-89
Number of pages7
JournalJournal of Surgical Research
Volume148
Issue number1
DOIs
StatePublished - 1 Jul 2008

Keywords

  • adenovirus
  • cytoreductive
  • eIF4E
  • head and neck cancer
  • squamous cell carcinoma

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