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

Akira Irie, Birgit Anderegg, Mohammed Kashani-Sabet, Tsukasa Ohkawa, Toshiya Suzuki, Meredith Halks-Miller, David T. Curiel, Kevin J. Scanlon

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Ras oncogenes are thought to play a critical role in cellular proliferation and tumorigenesis. Reversal of the malignant phenotype, inhibition of tumor growth, and decreased tumorgenicity have been demonstrated with the use of anti-H-ras ribozymes. In this study, the therapeutic efficacy of a hammerhead ribozyme targeting the mutated H-ras oncogene was investigated in an experimental 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 gene. The tumors were treated with intralesional injections of an adenovirus expressing an anti-H-ras ribozyme (rAd-Hras Rz) by different schedules at serial titers, and the tumor inhibition efficacy was analyzed. The viral infection efficacy and kinetics of ribozyme expression were also evaluated. Intralesional injection of rAd-Hras Rz resulted in significant antineoplastic 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 cytotoxicity in this cell line, complete regressions were not observed in the cases treated with control adenovirus vectors or vectors expressing an inactive anti-H-ras ribozyme or anti-H-ras antisense oligonucleotides. These results suggest the efficacy of a ribozyme-encoding adenovirus in the experimental gene therapy of human bladder cancer.

Original languageEnglish
Pages (from-to)341-349
Number of pages9
JournalAntisense and Nucleic Acid Drug Development
Volume9
Issue number4
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

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