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

• Published in: Clinical cancer research Vol. 15; no. 8; pp. 2797 - 2807
• Main Authors: STEIN, C. A, SIJIAN WU, VOSKRESENSKIY, Anatoliy M, ZHOU, Jin-Feng, SHIN, Joongho, MILLER, Paul, SOULEIMANIAN, Naira, BENIMETSKAYA, Luba
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2009
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Proliferation - drug effects; Collagen Type I - metabolism; Cytoskeleton - drug effects; Cytoskeleton - metabolism; endothelial; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Fibroblast Growth Factor 2 - drug effects; Fibroblast Growth Factor 2 - metabolism; G3139; Humans; Medical sciences; oligonucleotide; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - metabolism; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Platelet-Derived Growth Factor - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-sis; Rats; Receptor, Fibroblast Growth Factor, Type 1 - drug effects; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Thionucleotides - genetics; Thionucleotides - metabolism; Thionucleotides - pharmacology; Vascular Endothelial Growth Factor A - metabolism; Morphogenesis; Cell proliferation; Fibroblast growth factor; Endothelial cell; Collagen type I; C-Onc gene; Oligomer; In vitro; Midkine; Protooncogene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2610

Purpose: 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. Experimental Design: 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.