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Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy
Author(s) -
Hioki Masayoshi,
Kagawa Shunsuke,
Fujiwara Toshiya,
Sakai Ryo,
Kojima Toru,
Watanabe Yuichi,
Hashimoto Yuuri,
Uno Futoshi,
Tanaka Noriaki,
Fujiwara Toshiyoshi
Publication year - 2008
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/ijc.23438
Subject(s) - oncolytic virus , oncolytic adenovirus , telomerase reverse transcriptase , virotherapy , genetic enhancement , combination therapy , cancer research , biology , adenoviridae , telomerase , cancer cell , cancer , viral vector , gene , pharmacology , tumor cells , biochemistry , genetics , recombinant dna
Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP‐301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral E1 genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP‐301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP‐301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed E1A protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo , for the Bax gene expression to avoid interference with production of the oncolytic virus. © 2008 Wiley‐Liss, Inc.