Preclinical study for gene therapy against bladder cancer utilizing gelsolin gene and a dominant negative ras mutant

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We investigated the in vivo efficacy of gene therapy with the gelsolin gene in nude mice with human bladder cancer cell lines. This form of gene therapy, in which retrovirus producer cells were introduced, resulted in marked and reproducible tumor growth inbibition and prolonged survival time in the majority of animals tested.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. Initially, we examined suppressive effects of the N116Y on transformed phenotypes and Ras signaling pathways. These studies demonstrated that the N116Y was capable of suppressing the transformed phenotype in human bladder cancer cell line, even when its expression is relative low. To analyze the mechanism of suppressive effects of N116Y, we examined the expression of Grb2 and Sos proteins, which are probably affected by N116Y, in human bladder cancer cell lines. These results showed that expression of Grb2 and Sos proteins were significantly increased in human bladder cancer cell lines in comparison with cultured normal urothelial cells. Lastly, we examined the inhibitory effects of AdCMV-N116Y on orthotopically-implanted human bladder cancer cells in nude mice. The in vivo growth of implanted bladder cancer was significantly inhibited by transurethral inoculation of AdCMV-N116Y.These results suggest that the inoculation of AdCMV-N116Y into the bladder is highly effective for remission of bladder cancer, and this therapy would be very useful as a novel treatment of human bladder cancer.