p12CDK2-AP1 gene therapy strategy inhibits tumor growth in an in vivo mouse model of head and neck cancer

Marxa L. Figueiredo, Yong Kim, Maie A.R. St. John, David T.W. Wong

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Purpose: To test the potential of p12CDK2-AP1 (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma (∼70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo. Experimental Design: We addressed the effect of p12 expression on tumor growth by using a well-established squamous cell carcinoma VII/SF floor of mouth xenograft mouse model. The effect of therapy on tumor growth was determined for: (a) no treatment, (b) PBS, (c) vehicle (1,2-dioleoyloxy-3-trimethylammonium propane:cholesterol liposomes / 5% dextrose), (d) empty vector controls, and (e) p12-encoding vector experimental groups. Results: p12 gene therapy significantly induced antitumor effects as compared with controls, including (a) size and weight of p12-treated tumors decreased by 51% to 72% compared with all controls (P < 0.02), (b) tumor growth rate post-therapy was inhibited by 55% to 64% compared with empty vector controls (P < 0.0001), and (c) p12 expression was higher in p12-treated than controls (P. < 0.002) by two-tailed t test analyses. Mechanistically, p12 treatment affected cell turnover kinetics as assessed by apoptotic and cell proliferation indices. p12 therapy significantly increased terminal nucleotidyl transferase - mediated nick end labeling (P < 0.05) and morphology-based apoptotic indices (P < 0.05) as well as significantly decreased Ki-67 cell proliferation indices (P < 0.001) compared with controls, resulting in a net cell turnover reduction in p12-treated tumors. Conclusions: We show that this novel therapeutic modality can significantly induce antitumor responses in vivo. These results support a role for p12 as a novel tumor growth suppressor gene therapy and suggest that optimization and/or combination with current therapies may hold considerable promise in preparation for clinical trials.

Original languageEnglish (US)
Pages (from-to)3939-3948
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number10
DOIs
StatePublished - May 15 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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