G3139, an anti-Bcl-2 antisense oligomer that binds heparin-binding growth factors and collagen I, alters in vitro endothelial cell growth and tubular morphogenesis.
OBJECTIVE
We examined the effects of G3139 on the interaction of heparin-binding proteins [e.g., fibroblast growth factor 2 (FGF2) and collagen I] with endothelial cells. G3139 is an 18-mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. A randomized, prospective global phase III trial in advanced melanoma (GM301) has evaluated G3139 in combination with dacarbazine. However, the mechanism of action of G3139 is incompletely understood because it is unlikely that Bcl-2 silencing is the sole mechanism for chemosensitization in melanoma cells.


METHODS
The ability of G3139 to interact with and protect heparin-binding proteins was quantitated. The effects of G3139 on the binding of FGF2 to high-affinity cell surface receptors and the induction of cellular mitogenesis and tubular morphogenesis in HMEC-1 and human umbilical vascular endothelial cells were determined.


RESULTS
G3139 binds with picomolar affinity to collagen I. By replacing heparin, the drug can potentiate the binding of FGF2 to FGFR1 IIIc, and it protects FGF from oxidation and proteolysis. G3139 can increase endothelial cell mitogenesis and tubular morphogenesis of HMEC-1 cells in three-dimensional collagen gels, increases the mitogenesis of human umbilical vascular endothelial cells similarly, and induces vessel sprouts in the rat aortic ring model.


CONCLUSIONS
G3139 dramatically affects the behavior of endothelial cells. There may be a correlation between this observation and the treatment interaction with lactate dehydrogenase observed clinically.
Stein
C A
CA
Department of Oncology, Albert Einstein-Montefiore Cancer Center, Montefiore Medical Center, Bronx, New York 10467, USA. cstein@montefiore.org
Wu
Sijian
S
Voskresenskiy
Anatoliy M
AM
Zhou
Jin-Feng
JF
Shin
Joongho
J
Miller
Paul
P
Souleimanian
Naira
N
Benimetskaya
Luba
L
D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000187:drug effects / Q000378:metabolism*; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D024042:Collagen Type I; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D020574:Proto-Oncogene Proteins c-sis; D013873:Thionucleotides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; C408162:oblimersen; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1