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A recombinant defective adenoviral agent expressing anti‐bcl‐2 ribozyme promotes apoptosis of bcl‐2‐expressing human prostate cancer cells
Author(s) -
Dorai Thambi,
Perlman Harris,
Walsh Kenneth,
Shabsigh Ahmad,
Goluboff Erik T.,
Olsson Carl A.,
Buttyan Ralph
Publication year - 1999
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/(sici)1097-0215(19990909)82:6<846::aid-ijc13>3.0.co;2-c
Subject(s) - prostate cancer , recombinant dna , ribozyme , apoptosis , cancer research , biology , virology , cancer , gene , rna , genetics
Over‐expression of bcl‐2, a potent anti‐apoptosis protein, is likely to be one of the genetic mechanisms through which human prostate cancer cells develop resistance to hormonal and other forms of therapy. To develop a therapeutic agent for hormone‐resistant prostate cancer based on suppression of bcl‐2 expression, we had previously designed and synthesized a dual‐hammerhead ribozyme capable of recognizing and specifically cleaving human bcl‐2 mRNA in vitro as well as in vivo . To increase the efficiency by which the anti‐bcl‐2 ribozyme can be delivered to target cells, we have created a recombinant replication‐deficient (defective) adenoviral agent capable of expressing the anti‐bcl‐2 ribozyme upon infection. This viral agent effectively reduces intracellular levels of bcl‐2 mRNA and protein in cultured LNCaP prostate cancer cells following standard infection procedures. Likewise, the defective adenovirus‐anti‐bcl‐2 ribozyme induces extensive apoptosis in several androgen‐sensitive (LNCaP) and androgen‐insensitive (LNCaP/bcl‐2 and PC‐3) human prostate cancer cell lines that express differing amounts of bcl‐2 protein. One androgen‐insensitive prostate cancer cell line, DU‐145, lacking in bcl‐2 expression, was found to be completely refractory to the effects of the virus ribozyme, supporting the concept that the cytotoxic effects of the ribozyme are based solely on its effects on bcl‐2 expression. Our results support further development of this adenovirus/anti‐bcl‐2 ribozyme for potential gene therapeutic purposes in certain forms of hormone‐resistant prostate cancer where over‐expression of bcl‐2 proto‐oncogene is indicated. Int. J. Cancer 82:846–852, 1999. © 1999 Wiley‐Liss, Inc.