The activity of c-myb antisense oligonucleotide to prevent intimal hyperplasia is nonspecific.
BACKGROUND
We sought to determine the efficacy and specificity of a new c-myb antisense by inhibiting neointimal hyperplasia in a rat abdominal aorta injury model. Using c-myb antisense oligonucleotides, inhibition of vascular smooth muscle cell proliferation has been reported.


METHODS
Sixty-six male Wistar rats had a de-endothelialization of the abdominal aorta. Following a double blind randomization protocol, F127 pluronic gel containing one of the five oligonucleotides or plain gel was applied around the aorta: 1) 18-mer c-myb antisense (AS18) with four contiguous guanosines (G-quartet); 2) 15-mer c-myb antisense (AS15) without G-quartet; 3) 1-bp mismatch AS15 without G-quartet (MM1); 4) an oligonucleotide with G-quartet (4G), whereas the other bases were chosen at random; 5) 1-bp mismatch 4G without G-quartet (MM2). After 21 days all rats were sacrificed and aortas harvested for histomorphometric evaluation. Four rats were given fluorescent-labeled oligonucleotides to study in vivo localization after local advential delivery.


RESULTS
Morphometric analysis showed significant suppression of neointimal hyperplasia in AS18 and 4G and MM2 groups compared with GEL, AS15 and MM1 groups (p<0.05). The oligonucleotide-labeled aortas showed penetration of the oligonucleotides into the media which increased with time.


CONCLUSIONS
Our findings pointed to the potential non specificity of the c-myb antisense oligonucleotide in vivo. Such results will minimize the importance of antisense strategy as a potential therapeutic for preventing neointimal hyperplasia. The two oligonucleotides with a G-quartet inhibited neointimal hyperplasia in our model. Exploring a non-antisense mechanism, G-quartet oligonucleotides as potential drugs to reduce neointimal hyperplasia is attractive.
Castier
Y
Y
Department of Cardiovascular Surgery, Broussais Hospital, Paris, France.
Chemla
E
E
Nierat
J
J
Heudes
D
D
Vasseur
M A
MA
Rajnoch
C
C
Bruneval
P
P
Carpentier
A
A
Fabiani
J N
JN
D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics*; D004311:Double-Blind Method; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology
D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators