T.J. Thomas
Professor

Bionanotechnology and development of gene delivery vehicles. polyamine-DNA interactions. triplex DNA. gene therapy for breast cancer

The major focus of the Thomas Laboratory is to develop novel DNA delivery vehicles for gene therapy. The current focus is on breast cancer. although the technological developments in this area can be utilized for other forms of cancer. cardiovascular diseases. and autoimmunity. Gene therapy demands the facile transport of oligonucleotides and plasmid DNA through the cell membrane; however. DNA transport occurs through an inefficient process. the mechanism of which is largely unknown. Our approach is to develop agents that can condense DNA to nanoparticles in order to facilitate the transport of DNA. During the development of DNA condensation agents. we are also advancing the development of bionanotechnology as a means of targeted drug delivery.

The second focus of our research is to develop gene targeted therapeutic approaches using oligonucleotides. Research in progress utilizes anti-gene and antisense oligonucleotides for breast cancer. targeting the HER-2. c-myc. and cyclin D1 genes that are overexpressed in subsets of breast tumors. Cell culture and animal models of breast cancer have been used in our investigation.

Selected Publications

Sundaresan N, Suresh CH, Thomas T, Thomas TJ, Pillai CK. (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. May 30. [Epub ahead of print]

Vijayanathan V, Greenfield NJ, Thomas TJ, Ivanova MM, Tyulmenkov VV, Klinge CM, Gallo MA, Thomas T. (2007) Effects of estradiol and 4-hydroxytamoxifen on the conformation, thermal stability, and DNA recognition of estrogen receptor beta. Biochem Cell Biol. 85(1):1-10.

Nayvelt I, Thomas T, Thomas TJ. (2007) Mechanistic differences in DNA nanoparticle formation in the presence of oligolysines and poly-L-lysine. Biomacromolecules. 8(2):477-84.

Nair SK, Verma A, Thomas TJ, Chou TC, Gallo MA, Shirahata A, Thomas T. (2007) Synergistic apoptosis of MCF-7 breast cancer cells by 2-methoxyestradiol and bis(ethyl)norspermine.
Cancer Lett. 250(2):311-22.

Vijayanathan V. Thomas TJ. Nair SK. Shirahata A. Gallo MA. Thomas T. (2006) Bending of the estrogen response element by polyamines and estrogen receptors alpha and beta: a fluorescence resonance energy transfer study. Int J Biochem Cell Biol. 38(7):1191-1206.

Vijayanathan V. Venkiteswaran S. Nair SK. Verma A. Thomas TJ. Zhu BT. Thomas T. (2006) Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells. Clin Cancer Res. 12(7 Pt 1):2038-48.

Sundaresan N. Thomas T. Thomas TJ. Pillai CK. (2006) Lithium ion induced stabilization of the liquid crystalline DNA. Macromol Biosci. 6(1):27-32.

Lewis JS. Vijayanathan V. Thomas TJ. Pestell RG. Albanese C. Gallo MA. Thomas T. 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(3):113-28.

Vijayanathan V. Lyall J. Thomas T. Shirahata A. Thomas TJ. (2005) Ionic. structural. and temperature effects on DNA nanoparticles formed by natural and synthetic polyamines. Biomacromolecules. 6(2):1097-103.

Lewis JS. Thomas TJ. Pestell RG. Albanese C. Gallo MA. Thomas T. (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(1):91-105.

Venkiteswaran S. Vijayanathan V. Shirahata A. Thomas T. Thomas TJ. (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(1):303-12.

Balabhadrapathruni S. Santhakumaran LM. Thomas TJ. Shirahata A. Gallo MA. Thomas T. (2005) Bis(ethyl)norspermine potentiates the apoptotic activity of the pure antiestrogen ICI 182780 in breast cancer cells. Oncol Rep. 13(1):101-8.

Thomas T. Gallo MA. Thomas TJ. (2004) Estrogen receptors as targets for drug development for breast cancer. osteoporosis and cardiovascular diseases. Curr Cancer Drug Targets. 4(6):483-99.

Santhakumaran LM. Thomas T. Thomas TJ. (2004) Enhanced cellular uptake of a triplex-forming oligonucleotide by nanoparticle formation in the presence of polypropylenimine dendrimers. Nucleic Acids Res. 32(7):2102-12.

Vijayanathan V. Thomas T. Antony T. Shirahata A. Thomas TJ. (2004) Formation of DNA nanoparticles in the presence of novel polyamine analogues: a laser light scattering and atomic force microscopic study. Nucleic Acids Res. 32(1):127-34.

Thomas T. Thomas TJ. (2003) Polyamine metabolism and cancer. J Cell Mol Med. 7(2):113-26.

Vijayanathan. V.. Thomas. T.. and Thomas. T.J. (2002) DNA nanoparticles and development of DNA delivery vehicles for gene therapy. Biochemistry 41:14085-14094.

Vijayanathan. V.. Thomas. T.. Sigal. L.H.. and Thomas. T.J. (2002) Direct measurement of the association constant of HER2/neu antisense oligonucleotide to its target RNA sequence using a molecular beacon. Antisense Nucleic Acid Drug Dev. 12:225-233.

Thomas. T.. Balabhadrapathruni. S.. Gallo. M.A.. and Thomas. T.J. (2002) Development of polyamine analogs as cancer therapeutic agents. Oncology Res. 13:123-135.

Ramirez. F.J.. Thomas. T.J.. Antony. T.. Ruiz-Chica. J.. and Thomas. T. (2002) Effects of aminooxy analogues of biogenic polyamines on aggregation and stability of calf thymus DNA. Biopolymers 65:148-157.

Saminathan. M.. Thomas. T.. Shirahata. A.. Pillai. C.K.S.. and Thomas. T.J. (2002) Polyamine structural effects on the induction and stabilization of liquid crystalline DNA: Potential applications to DNA packaging. gene therapy and polyamine therapeutics. Nucleic Acids Res. 30:3722-3731.

Lewis. J.S.. Thomas. T.J.. Klinge. C.M.. Gallo. M.A.. and Thomas. T. (2001) Regulation of cell cycle and cyclins by 16a-hydroxyestrone in MCF-7 breast cancer cells. J. Mol. Endocrinol. 27: 293-307.

Vijayanathan. V.. Thomas. T.. Shirahata. A.. and Thomas. T.J. (2001) DNA condensation by polyamines: a laser light scattering study of structural effects. Biochemistry 40. 13644-13651.

Antony. T.. Thomas. T.. Sigal. L.H.. Shirahata. A.. and Thomas. T.J. (2001) A molecular beacon strategy for the thermodynamic characterization of triplex DNA: triplex formation at the promoter region of cyclin D1. Biochemistry 40: 9387-9395.

Greenfield. N.. Vijayanathan. V.. Thomas. T.J.. Gallo. M.A.. and Thomas. T. (2001) Increase in the stability and helical content of estrogen receptor a in the presence of the estrogen response element: analysis by circular dichroism spectroscopy. Biochemistry 40:6646-6652.

Shah. N.. Thomas. T.J.. Lewis. J.S.. Klinge. C.M.. Shirahata. A.. Gelinas. C.. and Thomas. T. (2001) Regulation of estrogenic and nuclear factor kB functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells. Oncogene 20:1715-1729.