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 Citations (Scopus)

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
Externally publishedYes

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Head and Neck Neoplasms
Genetic Therapy
Growth
Neoplasms
Tumor Suppressor Genes
Therapeutics
Cell Proliferation
Cyclin-Dependent Kinase 2
Mouth Floor
Transferases
Heterografts
Liposomes
Squamous Cell Carcinoma
Cell Cycle
Research Design
Cholesterol
Clinical Trials
Weights and Measures
Glucose
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

p12CDK2-AP1 gene therapy strategy inhibits tumor growth in an in vivo mouse model of head and neck cancer. / Figueiredo, Marxa L.; Kim, Yong; St. John, Maie A R; Wong, David T W.

In: Clinical Cancer Research, Vol. 11, No. 10, 15.05.2005, p. 3939-3948.

Research output: Contribution to journalArticle

Figueiredo, Marxa L. ; Kim, Yong ; St. John, Maie A R ; Wong, David T W. / p12CDK2-AP1 gene therapy strategy inhibits tumor growth in an in vivo mouse model of head and neck cancer. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 10. pp. 3939-3948.
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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.",
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