TY - JOUR
T1 - Therapeutic efficacy of an adenovirus-mediated anti-H-ras ribozyme in experimental bladder cancer
AU - Irie, Akira
AU - Anderegg, Birgit
AU - Kashani-Sabet, Mohammed
AU - Ohkawa, Tsukasa
AU - Suzuki, Toshiya
AU - Halks-Miller, Meredith
AU - Curiel, David T.
AU - Scanlon, Kevin J.
PY - 1999/1/1
Y1 - 1999/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032817549&partnerID=8YFLogxK
U2 - 10.1089/oli.1.1999.9.341
DO - 10.1089/oli.1.1999.9.341
M3 - Article
C2 - 10463078
AN - SCOPUS:0032817549
SN - 1087-2906
VL - 9
SP - 341
EP - 349
JO - Antisense and Nucleic Acid Drug Development
JF - Antisense and Nucleic Acid Drug Development
IS - 4
ER -