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p12^CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

Authors' Affiliations: ¹ Laboratory of Head and Neck Cancer Research, School of Dentistry and Dental Research Institute, and ² Department of Head and Neck Surgery, University of California Los Angeles, Los Angeles, California

Requests for reprints: David T.W. Wong, Laboratory of Head and Neck Cancer Research, Dental Research Institute, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-017 CHS, Los Angeles, CA 90095. Phone: 310-206-3048; Fax: 310-794-7109; E-mail: dtww{at}ucla.edu.

Purpose: To test the potential of p12^CDK2-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.

Key Words: gene therapy • CDK2-associated protein • squamous cell carcinoma • tumor growth inhibition • xenograft model