Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA
Language: 
English
Abstract: 

PURPOSE: To test ribozymes targeting mouse telomerase RNA (mTER) for suppression of the progression of B16-F10 murine melanoma metastases in vivo. EXPERIMENTAL DESIGN: Hammerhead ribozymes were designed to target mTER. The ribozyme sequences were cloned into a plasmid expression vector containing EBV genomic elements that substantially prolong expression of genes delivered in vivo. The activity of various antitelomerase ribozymes or control constructs was examined after i.v. injection of cationic liposome:DNA complexes containing control or ribozyme constructs. Expression of ribozymes and mTER at various time points were evaluated by quantitative real-time PCR. Telomerase activity was examined using the telomeric repeat amplification protocol. RESULTS: Systemic administration of cationic liposome:DNA complexes containing a plasmid-expressed ribozyme specifically targeting a cleavage site at mTER nucleotide 180 significantly reduced the metastatic progression of B16-F10 murine melanoma. The antitumor activity of the anti-TER 180 ribozyme in mice was abolished by a single inactivating base mutation in the ribozyme catalytic core. The EBV-based expression plasmid produced sustained levels of ribozyme expression for the full duration of the antitumor studies. In addition to antitumor activity, cationic liposome:DNA complex-based ribozyme treatment also produced reductions in both TER levels and telomerase enzymatic activity in tumor-bearing mice. CONCLUSIONS: Systemic, plasmid-based ribozymes specifically targeting TER can reduce both telomerase activity and metastatic progression in tumor-bearing hosts. The work reported here demonstrates the potential utility of plasmid-based anti-TER ribozymes in the therapy of melanoma metastasis.

Author(s): 
Nosrati, Mehdi
Li, Shang
Bagheri, Sepideh
Ginzinger, David
Blackburn, Elizabeth H.
Debs, Robert J.
Kashani-Sabet, Mohammed
Item Type: 
Journal Article
Publication Title: 
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Journal Abbreviation: 
Clin. Cancer Res.
Publication Date: 
8/1/2004
Publication Year: 
2004
Pages: 
4983-4990
Volume: 
10
Issue: 
15
ISSN: 
1078-0432
DOI: 
10.1158/1078-0432.CCR-04-0134
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 15297398

Turabian/Chicago Citation

Mehdi Nosrati, Shang Li, Sepideh Bagheri, David Ginzinger, Elizabeth H. Blackburn, Robert J. Debs and Mohammed Kashani-Sabet. 8/1/2004. "Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA." Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 10: 15: 4983-4990. 10.1158/1078-0432.CCR-04-0134.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1158/1078-0432.CCR-04-0134 | issn = 1078-0432 | volume = 10 | pages = 4983-4990 | last = Nosrati | first = Mehdi | coauthors = Li, Shang, Bagheri, Sepideh, Ginzinger, David, Blackburn, Elizabeth H., Debs, Robert J., Kashani-Sabet, Mohammed | title = Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA | journal = Clinical Cancer Research: An Official Journal of the American Association for Cancer Research | date = 8/1/2004 | pmid = | pmc = }} </ref>