Reversal of transformed phenotypes by antisense fos.
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.
Bradley
M O
MO
Genetic MediSyn Corporation, Rockville, Maryland 20850.
Manam
S
S
Kraynak
A R
AR
Nichols
W W
WW
Ledwith
B J
BJ
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D016762:Genes, fos / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010957:Plasmids / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000302:isolation & purification; D016372:RNA, Antisense / Q000494:pharmacology*; D014162:Transfection
D016760:Proto-Oncogene Proteins c-fos; D016372:RNA, Antisense; D003907:Dexamethasone