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Evaluation of a tissue-specific RNA polymerase I-targeted ribozyme in prostate cancer gene therapy...

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Evaluation of a tissue-specific RNA polymerase I-targeted ribozyme in prostate cancer gene therapy and the development and analysis of genomic instability-based transgenic models of prostate cancer

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Title	Evaluation of a tissue-specific RNA polymerase I-targeted ribozyme in prostate cancer gene therapy and the development and analysis of genomic instability-based transgenic models of prostate cancer
Author	Voeks, Dale J.
Date	1998
Affiliation/College	College of Graduate Studies
Department	Microbiology and Immunology
Extent	xii, 163 leaves : illustrations; 29 cm
Source	WJ 752 V872e 1998
Subject.MeSH	Academic Dissertations Academic Dissertations--South Carolina Prostatic Neoplasms--therapy Prostatic Neoplasms Genetic Therapy RNA, Catalytic Epithelial Cells Genomic Instability
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd1998_voeks_dj
Abstract	(1) Use of ribozymes in prostate cancer gene therapy has been limited due to a lack of molecular knowledge and the biologic heterogeneity of the disease. Therefore, a universally cytotoxic target for ribozyme design is required. In this regard, a hammerhead ribozyme was targeted to RNA polymerase I (poll) (controls rDNA transcription) and inserted between cis-acting ribozymes to form a poll triple ribozyme (TR). The TR demonstrated efficient cleavage of itself and the poll target in vitro and in cell culture resulting in a significant reduction in cellular growth. The expression of the ribozyme was restricted to the tissue of interest by coupling to the prostate epithelial cell-specific probasin promoter (PB). PB-driven TR expression resulted in severely diminished cell populations in a mouse prostate tumor cell line. The construct exhibited highly restricted prostate epithelial cell killing following delivery to normal mouse prostate tissue and in PBTR transgenic mice. Delivery to tumor-bearing mice caused a marked decrease in tumor growth. These experiments implicate the prostate-specific poll TR construct as a potential therapeutic agent in prostate cancer. (2) To develop animal models representing the broad spectrum of human prostate cancer, we employed two genes (EcoRI and c-fos) implicated in the induction of genomic instability to create transgenic mice. The expression of these genes was restricted to prostate epithelial cells by coupling to PB. Two lines of PBEcoRI mice and one line of PBF os mice displayed prostatic trans gene expression. Prostate tissue was examined histologically at time points from 4 months to 2 years of age. The progressive presence of regions of mild-to-severe hyperplasia, low- and hi-grade PIN (prostatic intra-epithelial neoplasia), and well-differentiated adenocarcinoma was observed in all three lines. Relative levels of a number of markers of human prostate cancer progression and prognosis were evaluated at multiple time points in the lines. The genomic instability-based models can be used to study the mechanisms involved in the early stages of prostate carcinogenesis and the missing events necessary for the progression to advanced disease.

Evaluation of a tissue-specific RNA polymerase I-targeted ribozyme in prostate cancer gene therapy and the development and analysis of genomic instability-based transgenic models of prostate cancer

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