Mutant p53 increases chemical tumor induction and serves as a target of gene silencing therapy in transgenic mice

Abstract

Transgenic mice with the added mutant p53 cDNA containing 9 bp deletion in exon 6 cloned from a radiation-induced tumor and ligated to the promoter of expression vector were generated. These mice showed a tumor incidence 1.7 fold higher than in wild-type mice, i. e., 42% excess, after subcutaneous injection of 0.02 mg 3-methylcholanthrene. Tumors produced in the mice were further treated with a siRNA#220 targeting to the promoter in the expression vector of the mutant p53 transgene using a delivery system with atelocollagen. This treatment resulted in suppression of 30% of 44 tumors, including 4/23 cures of autochthonous tumors. siRNA#220 was ineffective to wild-type tumors. The cure effect in the siRNA#220-senstive transplanted tumors involved induction of apoptosis as observed by TUNEL assay.