The long-term goal for this project is to develop a triplex DNA-based anti-gene strategy for breast cancer treatment. The applicant's studies during the previous funding period have demonstrated a remarkable structural specificity effect of polyamine analogs in stabilizing triplex DNA, and in facilitating the uptake of a triplex forming oligonucleotide (TFO) in breast cancer cells. Their hypothesis is that the selective utilization of polyamine analogs is a viable strategy to increase the stability of triplex DNA, and enhance the therapeutic potential of TFOs. This hypothesis will be tested by: 1) Quantification of the ability of novel polyamine analogs to stabilize triplex DNA at the promoter site sequences of cmyc, her2, and cyclinD1 genes by spectroscopic techniques, fluorescence measurements, and electrophoretic mobility shift assay; 2) elucidation of the role of polyamine -induced TFO condensation in facilitating nuclear uptake of TFOs and determination of TFO accumulation and stability in breast cancer cells; 3) Evaluation of the biologic response of TFOs and polyamine analogs as single agents and in combination on breast cancer cells by Northern and Western blot analysis of target gene expression, and polyamine metabolism pathways; and 4) Elucidation of the mechanism of TFO/polyamine analog action in terms of transcription factors to targeted sites. Results of these studies will help to develop a new therapeutic modality for breast cancer, and advance our knowledge of the mechanism of triplex DNA stabilization in vitro.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073058-05
Application #
6376346
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
5
Fiscal Year
2001
Total Cost
$247,275
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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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
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Lewis, Joan S; Thomas, T J; Pestell, Richard G et al. (2005) Differential effects of 16alpha-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells. J Mol Endocrinol 34:91-105
Nair, S K; Thomas, T J; Greenfield, N J et al. (2005) Conformational dynamics of estrogen receptors alpha and beta as revealed by intrinsic tryptophan fluorescence and circular dichroism. J Mol Endocrinol 35:211-23
Lewis, Joan S; Vijayanathan, Veena; Thomas, T J et al. (2005) Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Oncol Res 15:113-28
Venkiteswaran, Sripriya; Vijayanathan, Veena; Shirahata, Akira et al. (2005) Antisense recognition of the HER-2 mRNA: effects of phosphorothioate substitution and polyamines on DNA.RNA, RNA.RNA, and DNA.DNA duplex stability. Biochemistry 44:303-12

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