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


METHODS
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.
Figueiredo
Marxa L
ML
Laboratory of Head and Neck Cancer Research, School of Dentistry and Dental Research Institute, and Department of Head and Neck Surgery, University of California Los Angeles, Los Angeles, California, USA.
Kim
Yong
Y
St John
Maie A R
MA
Wong
David T W
DT
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology* / Q000662:veterinary; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000662:veterinary; D051379:Mice; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000494:pharmacology*
C096151:CDK2AP1 protein, human; D025521:Tumor Suppressor Proteins