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An Adenovirus Expressing Mutant p27 Showed More Potent Antitumor Effects Than Adenovirus-p27 Wild Type¹

Department of Internal Medicine [K-H. P., J. Y. S., T-Y. K., C-G. Y., Y. W. K., S. K. H., Y-S. S., C-T. L.], Cancer Research Institute [T-Y. K.], Seoul National University College of Medicine, Lung Institute of Medical Research Center, Seoul National University [C-G. Y., Y. W. K., S. K. H., Y-S. S., C-T. L.], and Gene Therapy Laboratory of Clinical Research Institute, Seoul National University Hospital [K-H. P., J. Y. S., C-T. L.], Seoul 110-744, Korea

The main inhibitory action of p27, a cyclin-dependent kinase inhibitor (CDKI), arises from its binding with the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex that results in G₁-S arrest. Degradation of p27 is mediated by phosphorylation of Thr-187 of p27, which follows ubiquitination. In this study, we generated two adenoviruses expressing wild-type p27 (ad-p27wt) and mutant p27 (ad-p27mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which was produced with the belief that mutant p27 would bind cyclin E/CDK2 more stably and show more potent antitumor effects. Ad-p27wt and ad-p27mt expressed p27 proteins that were indistinguishable by anti-p27 antibody. A pulse chase experiment showed that p27mt was more resistant to degradation than p27wt. In human lung cancer cell lines, ad-p27mt showed stronger growth inhibition than ad-p27wt. Both types of ad-p27 induced G₁-S arrest and apoptosis; however, ad-p27mt induced stronger G₁-S arrest and apoptosis. Intratumoral injection of ad-p27mt induced partial regression of established tumors and inhibited the growth of human lung cancer xenografts more strongly than ad-p27wt. From these results, we conclude that ad-p27mt has the potential to become a novel and powerful gene therapy tool.

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