Development of long-term expressing p53 protein transduction therapy and the trial of treatment for malignant gliomas

Abstract

Protein transduction therapy using poly-arginine peptide can deliver biologically active proteins, peptides and compounds. We showed that 11 poly-arginine fused p53 protein (11R-p53) effectively penetrates across the plasma membrane and inhibits the proliferation of cancer cells. However, the intracellular half-life of the delivered protein is less than 24 h. Therefore, development of a protein therapy to transduce stable protein or a method to stabilize the delivered protein is important to consider clinical trial of protein therapy. Here, we generated two kinds of p53 mutants,which were resistant to Mdm2-mediated ubiquitination and the expressions were more stable than wild-type 11R-p53. Moreover, the mutant 11R-p53s displayed a higher transcriptional activity and a more powerful inhibition of the proliferation of glioma cells compared with wild-type 11R-p53. These results suggest that long-expressing p53 mutant protein therapy may overcome the disadvantage of 11R-p53 and become a new effective cancer therapy. [Jpn J Physiol 54 Suppl:S250 (2004)]