Antisense oligonucleotides are potentially powerful tools for cancer therapy. The manipulation of gene expression using antisense technology is now well established in cell biological experimentation. However, the therapeutic utilization of antisense oligonucleotides in cancer has been impeded by (1) lack of understanding of the pharmacodynamic behavior of these compounds in vivo and (2) by the inefficient delivery of these compounds to their sites of action in the cytoplasm and nucleus of tumor cells. The overall goals of this application are (1) systematically identify and evaluate improved approaches for the efficient delivery of antisense oligonucleotides to the cytoplasm and nucleus of cells in culture (2) to establish a rational basis for antisense therapy of tumors by evaluating the kinetics accumulation and subsequent distribution of oligonucleotides in host and tumor tissues (3) to utilize this information to design approaches to efficiently deliver therapeutic antisense oligonucleotides to tumor cells in vivo. Initially the applicant will use simple reporter gene system in CHO cells to rapidly identify promising approaches for oligonucleotide therapy. The applicant will then test these approaches in more stringent cancer related cell culture models including multidrug resistant 3T3 cells and ras-transformed human colon carcinoma cells. Approaches that lead to efficient oligonucleotide delivery in vitro will be further evaluated in terms of pharmacokinetics, tumor tissue uptake and subcellular distribution in human colon carcinoma xenografts in nude mice. Finally delivery approaches that are promising in both in vitro and in vivo contexts will be evaluated for their ability to enhance the pharmacological and therapeutic efficacy of ant-Ki-ras oligonucleotides in the colon xenograft model. This integrated and systematic approach to transport and delivery problems and antisense oligonucleotides will hasten their development as useful chemotherapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA047044-08
Application #
2007702
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-06-01
Project End
2001-01-31
Budget Start
1997-04-10
Budget End
1998-01-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Yoo, H; Juliano, R L (2000) Enhanced delivery of antisense oligonucleotides with fluorophore-conjugated PAMAM dendrimers. Nucleic Acids Res 28:4225-31
DeLong, R K; Yoo, H; Alahari, S K et al. (1999) Novel cationic amphiphiles as delivery agents for antisense oligonucleotides. Nucleic Acids Res 27:3334-41
Yoo, H; Sazani, P; Juliano, R L (1999) PAMAM dendrimers as delivery agents for antisense oligonucleotides. Pharm Res 16:1799-804
Alahari, S K; DeLong, R; Fisher, M H et al. (1998) Novel chemically modified oligonucleotides provide potent inhibition of P-glycoprotein expression. J Pharmacol Exp Ther 286:419-28
Nolting, A; DeLong, R K; Fisher, M H et al. (1997) Hepatic distribution and clearance of antisense oligonucleotides in the isolated perfused rat liver. Pharm Res 14:516-21
Delong, R; Stephenson, K; Loftus, T et al. (1997) Characterization of complexes of oligonucleotides with polyamidoamine starburst dendrimers and effects on intracellular delivery. J Pharm Sci 86:762-4
Cheng, X; Boyer, J L; Juliano, R L (1997) Selection of peptides that functionally replace a zinc finger in the Sp1 transcription factor by using a yeast combinatorial library. Proc Natl Acad Sci U S A 94:14120-5
Cheng, X; Kay, B K; Juliano, R L (1996) Identification of a biologically significant DNA-binding peptide motif by use of a random phage display library. Gene 171:1-8
Alahari, S K; Dean, N M; Fisher, M H et al. (1996) Inhibition of expression of the multidrug resistance-associated P-glycoprotein of by phosphorothioate and 5' cholesterol-conjugated phosphorothioate antisense oligonucleotides. Mol Pharmacol 50:808-19
Daoud, S S; Forde, N H (1991) Synergistic cytotoxic actions of cisplatin and liposomal valinomycin on human ovarian carcinoma cells. Cancer Chemother Pharmacol 28:370-6

Showing the most recent 10 out of 16 publications