Antitumor and Antimetastatic Activity of Ribozymes Targeting the Messenger RNA of Vascular Endothelial Growth Factor Receptors
Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-based oligonucleotides that selectively bind and cleave specific target RNAs. Due to their potential for specifically inhibiting gene expression, ribozymes are being investigated for therapeutic applications as well as for the el...
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Published in | Clinical cancer research Vol. 6; no. 5; pp. 2094 - 2103 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.05.2000
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Subjects | |
Online Access | Get full text |
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Summary: | Chemically
stabilized hammerhead ribozymes are nuclease-resistant, RNA-based
oligonucleotides that selectively bind and cleave specific target RNAs.
Due to their potential for specifically inhibiting gene expression,
ribozymes are being investigated for therapeutic applications as well
as for the elucidation of gene function. In particular, we have
investigated ribozymes that target the mRNA of the vascular endothelial
growth factor (VEGF) receptors because VEGF signaling is an important
mediator of tumor angiogenesis and metastasis. Here we report
pharmacodynamic studies testing anti- Flt-1 (VEGFR-1) and
anti- KDR (VEGFR-2) ribozymes in animal models of solid
tumor growth and metastasis. Ribozymes targeting either
Flt-1 or KDR significantly inhibited
primary tumor growth in a highly metastatic variant of Lewis lung
carcinoma. However, only treatment with the anti- Flt-1
ribozyme resulted in a statistically significant and dose-dependent
inhibition of lung metastasis in this model. The
anti- Flt-1 ribozyme was then tested in a xenograft model
of human metastatic colorectal cancer in which significant inhibition
of liver metastasis was observed. Taken together, these data represent
the first demonstration that synthetic ribozymes targeting VEGF
receptor mRNA reduced the growth and metastasis of solid tumors
in vivo . |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |