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

Abstract

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 ( approximately 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.

• Authors: Marxa L Figueiredo, Yong Kim, Maie A R St John, David T W Wong
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 10 Pg. 3939-48 (May 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15897596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CDK2AP1 protein, human
• Tumor Suppressor Proteins

Topics

• Animals
• Apoptosis
• Carcinoma, Squamous Cell (genetics, pathology, veterinary)
• Cell Proliferation
• Disease Models, Animal
• Disease Progression
• Genetic Therapy
• Head and Neck Neoplasms (genetics, pathology, veterinary)
• Mice
• Transplantation, Heterologous
• Tumor Suppressor Proteins (genetics, pharmacology)