Abstract
We summarize results on the experimental gene therapy of methylcholanthrene-induced tumors in transgenic mice with mutant p53. pTE50 transgenic mice were constructed with the mutant p53 cDNA carrying a 9 bp deletion in exon 6 obtained from a radiation-induced tumor. Fetus fibroblasts of the mouse exhibited the suppressed p21 induction after 5 Gy X-irradiation, indicating the dominant-negative activity of mutant p53 in the mice. Previously, the transgenic mice showed a 1.7 fold elevated tumor incidence (42% excess) as compared to wild-type mice after subcutaneous injection of 0.02 mg MCA. These tumors, after grown to 5 mm diameter, were treated by local injection of siRNA no.220 designed to suppress the promoter/enhancer of the mutant p53 with a delivery system using atelocollagen, 4 times with an interval of 2 days. The tumors responded with a frequency of 4 out of 23, including 3 cures without recurrence for 51-116 days, and 2 with growth suppression. These results indicate that the autochthonous tumors can be cured by the gene therapy. Combined with results on transplanted tumors, the total frequency of siRNA no.220-responsive tumors was 30%, corresponding to the estimated frequency of mutant p53-dependent tumors. Transplant line TT18 exhibited the induction of apoptosis after treatment with siRNA no.220. Tumors in wild-type mice did not respond to siRNA no.220. These results indicate that suppression of the mutant p53 with siRNA no.220 restored the apoptotic activity of wild-type p53 retained in the tumors. (Cancer Gene Therapy, in press; online June 26, 2009)
