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Adenovirus‐mediated gene therapy for bladder cancer in an orthotopic model using a dominant negative H‐ ras mutant
Author(s) -
Watanabe Takafumi,
Shinohara Nobuo,
Sazawa Ataru,
Takimoto Masato,
Hashimoto Akira,
Koyanagi Tomohiko,
Kuzumaki Noboru
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20010601)92:5<712::aid-ijc1242>3.0.co;2-z
Subject(s) - genetic enhancement , bladder cancer , adenoviridae , cancer research , viral vector , biology , carcinogenesis , apoptosis , cancer , gene , recombinant dna , genetics , biochemistry
It has been suggested that abnormal Ras function is important in the carcinogenesis and progression of bladder cancer. Our aim was to investigate the efficacy of transurethral inoculation of an adenovirus expressing the dominant negative H‐ ras mutant N116Y against orthotopically implanted human bladder‐cancer cells in nude mice. We used a replication‐defective adenovirus vector containing the β‐galactosidase gene (AdCMV‐LacZ) as a control and the N116Y gene (AdCMV‐N116Y) as the therapeutic vector under the transcriptional control of the cytomegalovirus promoter. We initially investigated the in vitro growth‐suppressive effects of AdCMV‐N116Y on 2 human bladder‐cancer cell lines, KU‐7 and UMUC‐2. Thereafter, we examined the inhibitory effects of AdCMV‐N116Y on the 2 orthotopically implanted cell lines in nude mice. Intravesically created, orthotopic human bladder cancers were established in female KSN athymic nude mice with 1× 10 7 cancer cells. Then, 2, 3 and 4 days following implantation, 1 × 10 9 pfu of AdCMV‐LacZ or AdCMV‐N116Y were administered transurethrally. In vitro growth assays revealed significant growth suppression (>95%) with apoptosis of target cells treated with AdCMV‐N116Y compared to AdCMV‐LacZ. Transurethral inoculation of AdCMV‐N116Y into the bladder brought about a significant reduction in size (73% to 90%) and number (47% to 78%) of orthotopically implanted human bladder tumors compared to AdCMV‐LacZ or PBS. Normal mucosa in nude mice had minor inflammation with the infiltration of mononuclear cells. Our results suggest that gene therapy via transurethral inoculation of AdCMV‐N116Y holds promise for the treatment of human bladder cancer. © 2001 Wiley‐Liss, Inc.