Therapeutic efficacy of an adenovirus-mediated anti-H-ras ribozyme in experimental bladder cancer

Ras oncogenes are thought to play a critical role in cellular proliferation and tumorigenesis. Reversal of the malignant phenotype, inhibition of tumo r growth, and decreased tumorgenicity have been demonstrated with the use o f anti-H-ras ribozymes, In this study, the therapeutic efficacy of a hammer head ribozyme targeting the mutated H-ras oncogene was investigated in an e xperimental bladder cancer model using a recombinant adenovirus as delivery vehicle. Tumors were established in nude mice by subcutaneous injection of EJ human bladder carcinoma cells harboring a point mutation of the H-ras g ene. The tumors were treated with intralesional injections of an adenovirus expressing an anti-a-ras ribozyme (rAd-Hras Rz) by different schedules at serial titers, and the tumor inhibition efficacy was analyzed, The viral in fection efficacy and kinetics of ribozyme expression were also evaluated, I ntralesional injection of rAd-Hras Rz resulted in significant antineoplasti c effects in a dose-dependent fashion. Complete regression of the tumor was achieved by rAd-Hras Rz in several cases without recurrence during the 50- day observation period. Although there was moderate vector-associated cytot oxicity in this cell line, complete regressions were not observed in the ca ses treated with control adenovirus vectors or vectors expressing an inacti ve anti-a-ras ribozyme or anti-H-ras antisense oligonucleotides, These resu lts suggest the efficacy of a ribozyme-encoding adenovirus in the experimen tal gene therapy of human bladder cancer.