The overall goal of this project is to elucidate the mechanism of action of polyamine analogues in facilitating the uptake and function of antisense oligonucleotides (ODNs). The hypothesis is that the selectivity of polyamine analogues in DNA condensation and/or stabilization of RNA.DNA hybrids can be utilized to facilitate the cellular uptake and function antisense ODNs for breast cancer therapy. Antisense ODNs targeted to c-myc and HER-2 genes will be studied. To evaluate the structural specificity effects of polyamine analogues on RNA.DNA hybrid stabilization, association constants will be determined using a molecular beacon technique. The role of ODN nanoparticles in facilitating cellular uptake of ODNs will be quantified by dynamic light scattering as well as electron, scanning force and polarizing spectroscopy. Cellular uptake and function of ODNs will be measured using MCF-7 and SK-BR-3 breast cancer cells. ODN uptake will be determined using radioactive and fluorescent ODNs. Effects of polyamine analogue/ODN combinations on target gene expression, cell growth arrest, and apoptosis will be examined to demonstrate enhanced function of ODNs. Subsequently, HER-2 gene targeted ODN and selected polyamine analogues will be examined for in vivo ODN delivery and function using a transgenic mouse model of breast cancer. The effects of polyamine analogues and ODNs on natural polyamines will be quantified by HPLC. These studies will advance our knowledge of the mechanism of cellular uptake of ODNs, and help to develop novel approaches for breast cancer therapy.
| Dubeau, S; Bourassa, P; Thomas, T J et al. (2010) Biogenic and synthetic polyamines bind bovine serum albumin. Biomacromolecules 11:1507-15 |
| Nayvelt, Irina; Hyvonen, Mervi T; Alhonen, Leena et al. (2010) DNA condensation by chiral alpha-methylated polyamine analogues and protection of cellular DNA from oxidative damage. Biomacromolecules 11:97-105 |
| Chen, Alex M; Taratula, Oleh; Wei, Dongguang et al. (2010) Labile catalytic packaging of DNA/siRNA: control of gold nanoparticles ""out"" of DNA/siRNA complexes. ACS Nano 4:3679-88 |
| N'soukpoe-Kossi, C N; Ahmed Ouameur, A; Thomas, T et al. (2009) Interaction of tRNA with antitumor polyamine analogues. Biochem Cell Biol 87:621-30 |
| Todd, Brian A; Parsegian, V Adrian; Shirahata, Akira et al. (2008) Attractive forces between cation condensed DNA double helices. Biophys J 94:4775-82 |
| John, Shali; Nayvelt, Irina; Hsu, Hui-Chen et al. (2008) Regulation of estrogenic effects by beclin 1 in breast cancer cells. Cancer Res 68:7855-63 |
| Sundaresan, Neethu; Suresh, Cherumuttathu H; Thomas, Thresia et al. (2008) Liquid crystalline phase behavior of high molecular weight DNA: a comparative study of the influence of metal ions of different size, charge and binding mode. Biomacromolecules 9:1860-9 |
| N'soukpoe-Kossi, C N; Ouameur, A Ahmed; Thomas, T et al. (2008) DNA interaction with antitumor polyamine analogues: a comparison with biogenic polyamines. Biomacromolecules 9:2712-8 |
| Nayvelt, Irina; Thomas, Thresia; Thomas, T J (2007) Mechanistic differences in DNA nanoparticle formation in the presence of oligolysines and poly-L-lysine. Biomacromolecules 8:477-84 |
| Beauchemin, R; N'soukpoe-Kossi, C N; Thomas, T J et al. (2007) Polyamine analogues bind human serum albumin. Biomacromolecules 8:3177-83 |
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