Establishment of gene therapy against bladder cancer utilizing gelsolin gene and a dominant negative ras mutant

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Initially, we investigated the in vivo efficacy of gene therapy with the gelsolin gene in nude mice with human bladder cancer cell lines. In this analysis, we used orthotopically-implanted human bladder cancer cells in nude mice. By transurethral inoculation of adenovirus-containing Gelsolin gene, cellular growth was strongly suppressed in human bladder cancer cell lines (UMUC-2, KU-7), compared to the inoculation of control vector. With regard to the basic mechanism of the expression of gelsolin gene in human bladder cancer, deacethylation of the nuclear histone in the promoter lesion of the gelsolin gene is shown to be important and administration of trycostatin to the human bladder cancer induced the enhanced expression of gelsolin gene in human bladder cancer cells.We also examined whether N116Y, which derived from the v-H-ras oncogene by substituting the asparagine-116 with tyrosine, can also inhibit the growth of human bladder cancer cell lines. In this analysis, we used the N116Y ras mutant in vivo via an N116Y-containing adenoviral vector (AdCMV-N116Y). Using this adenoviral vector system, we investigated the growth suppressive effects of N116Y on orthotopically implanted bladder cancer cells in vivo. The results demonstrated that inoculation of AdCMV-N116Y caused significant growth suppression of orthotopically implanted bladder cancer cells (UMUC-2, KU-7).Although this is still in preclinical stage, gene therapy via transurethral inoculation of AdCMV-N116Y or AdCMV-Gelsolin might hold promise for the treatment of human bladdder cancer.