Effective Ablation of Pancreatic Cancer Cells in SCID Mice Using Systemic Adenoviral RIP-TK/GCV Gene Therapy

Shi He Liu, Alan Davis, Zhijun Li, Nikiforos Ballian, Elizabeth Davis, Xiao Ping Wang, William Fisher, F. Charles Brunicardi

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background: Studies have demonstrated that adenovirus subtype 5 mediated rat insulin promoter directed thymidine kinase (A-5-RIP-TK)/ganciclovir (GCV) gene therapy resulted in significant enhanced cytotoxicity to both PANC-1 and MIA PaCa2 pancreatic cancer cells in vitro. However, little is known about the effect in vivo. In this study we examine the in vivo safety and efficacy of intravenous A-5-RIP-TK/GCV gene therapy. Materials and methods: 1×106 Mia PaCa2 cells were injected intraperitoneally (i.p.) into SCID mice to create a mouse model of human pancreatic cancer. A-5-RIP-TK gene construct was administered intravenously (i.v.), followed by i.p. GCV administration. Intravenous injection of A-5-RIP-lacZ reporter gene constructs was used for evaluation of Ad-RIP-gene expression in tumors and other tissues. Optimal adenoviral and GCV doses and treatment duration were determined. Tumor volume, serum insulin, and glucose levels were measured. Immunohistochemical staining of pancreata and tumors were performed to assess morphology and hormone expression and apoptotic rates were determined. Results: All A-5-RIP-TK/GCV-treated mice had reduced tumor volume compared with controls, but maximal tumor volume reduction was observed with 108 vp followed by GCV treatment for 4 wk. A-5-RIP-TK/GCV gene therapy contributed to significant survival advantage in MIA PaCa2 bearing mice, and the greatest survival benefit was observed with 108 vp and was not affected by length of treatment of GCV. A-5-RIP-TK/GCV therapy increased PDX-1 expression and tumor cells apoptosis, and altered islet morphology. However, A-5-RIP-TK/GCV gene therapy caused diabetes associated with islet cell apoptosis, increased δ-cells and reduced pancreatic polypeptide (PP)-cell numbers. Conclusions: Systemically administered A-5-RIP-TK/GCV is an effective treatment of pancreatic cancer. A-5-RIP-TK/GCV cytotoxicity to malignant cells varies with adenoviral dose and length of GCV treatment. However, A-5-RIP-TK/GCV is associated with islet cell toxicity and diabetogenesis. The type of diabetes observed is distinct from Types 1 and 2 and is associated with islet cell apoptosis and reduced δ- and PP-cells.

Original languageEnglish (US)
Pages (from-to)45-52
Number of pages8
JournalJournal of Surgical Research
Volume141
Issue number1
DOIs
StatePublished - Jul 2007

Keywords

  • PDX-1
  • adenovirus
  • apoptosis
  • diabetes
  • gene therapy
  • pancreatic cancer
  • pancreatic polypeptide
  • rat insulin promoter

ASJC Scopus subject areas

  • Surgery

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