Abstract |
The therapeutic use of antisense DNA has started a revolution in pharmacology. As a model system for demonstrating the therapeutic power of the antisense concept, we sought to interrupt signal transduction in H-ras transformed cells to attempt to down-regulate their oncogenic phenotype. We hypothesized that down-regulation of c-fos translation by antisense-fos expression would decrease oncogenic signal transduction through the fos pathway and thus reverse the tumorigenic phenotype of these cells. To test this hypothesis, we transfected H-ras cells with a plasmid containing an 84-base sequence antisense to the 5' end of the mouse c-fos gene. The antisense-fos was under the transcriptional control of the MMTV promoter and inducible by dexamethasone. Two of the antisense-fos clones grew in a density-dependent manner, exhibiting both a flat morphology and a quiescence in low serum medium unlike the sense-fos controls. Antisense-fos also inhibited soft agar growth to 1% of control values and dramatically reduced tumor growth in nude mice. Antisense-fos had no effect on ras expression but greatly reduced c-fos protein levels as assayed by immunofluorescence. These findings suggest that down-regulation of signal transduction pathways by antisense therapeutic compounds might have major therapeutic benefits against malignant cells transformed by ras or other oncogenes.
|
Authors | M O Bradley, S Manam, A R Kraynak, W W Nichols, B J Ledwith |
Journal | Annals of the New York Academy of Sciences
(Ann N Y Acad Sci)
Vol. 660
Pg. 124-35
(Oct 28 1992)
ISSN: 0077-8923 [Print] United States |
PMID | 1340116
(Publication Type: Journal Article)
|
Chemical References |
- Proto-Oncogene Proteins c-fos
- RNA, Antisense
- Dexamethasone
|
Topics |
- 3T3 Cells
- Animals
- Cell Transformation, Neoplastic
(drug effects)
- Dexamethasone
(pharmacology)
- Dose-Response Relationship, Drug
- Fluorescent Antibody Technique
- Genes, fos
(genetics)
- Genes, ras
(genetics)
- Mice
- Mice, Nude
- Neoplasms, Experimental
(drug therapy)
- Plasmids
(genetics)
- Proto-Oncogene Proteins c-fos
(biosynthesis, isolation & purification)
- RNA, Antisense
(pharmacology)
- Transfection
|