The overall goal of this National Cooperative Drug Discovery Group (NCDDG) project is to develop telomere and telomerase-interactive agents that improve the survival and quality of life of patients with cancer. Telomeres are repetitive sequences (TTAGGG in humans) at the ends of chromosomes, which have been called """"""""chemical bookends."""""""" The integrity of telomeres is vital for cell survival. Unfortunately, as cells divide (age), the length of telomeres gradually decreases which leads to chromosome instability. When telomeres become very short, cells undergo a crisis. The cells that survive are immortal and have an increase in the enzyme telomerase. Telomerase is a reverse transcriptase that synthesizes and maintains telomeres. Important to this application are two observations: l) tumor cells have shorter telomeres than do normal cells (because the tumor cells have undergone more divisions); and 2) telomerase is produced in tumor cells (and not in normal cells). These two observations give us unique targets which are different in tumor cells versus normal cells and an opportunity to develop agents that affect tumor cells but not normal cells.
The Specific Aims of Program 4 include: l) to determine if telomeres are indeed shorter in primary and metastatic human tumors (versus normal cells); 2) to determine if the enzyme telomerase is present in primary and metastatic human tumors (versus normal cells); 3) to establish preclinical in vivo models relevant to potential clinical trials with telomere and telomerase-interactive agents and to test candidate agents in those models. This program works with human breast, lung, head and neck, colon and ovarian cancer specimens. Our team has already gathered preliminary information that tumor cells taken directly from patients have telomeres in tumors that are shorter than telomeres taken from normal cells from the same patient. In addition, we have documented that the enzyme telomerase is present in tumor cells taken directly from patients. These findings solidify the selection of telomeres/telomerase as drug development targets. This program will provide us with increased knowledge about our two targets: telomeres and telomerase in tumors taken directly from patients. That work should give us leads to improve the specificity of our telomere/telomerase-interactive agents (i.e., to maximize effectiveness/minimize toxicities). The program also includes the development of in vivo models as well as testing of our candidate compounds in those models. These models are designed to reflect true clinical situations that should lead to rapid clinical trials of compounds developed by this NCDDG.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067760-04
Application #
6269712
Study Section
Project Start
1998-09-30
Project End
1999-09-29
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Nishioka, David; Marcell, Vanessa; Cunningham, Meghan et al. (2003) The use of early sea urchin embryos in anticancer drug testing. Methods Mol Med 85:265-76
Kerwin, Sean M; Chen, Grace; Kern, Jonathan T et al. (2002) Perylene diimide G-quadruplex DNA binding selectivity is mediated by ligand aggregation. Bioorg Med Chem Lett 12:447-50
Kern, Jonathan T; Kerwin, Sean M (2002) The aggregation and G-quadruplex DNA selectivity of charged 3,4,9,10-perylenetetracarboxylic acid diimides. Bioorg Med Chem Lett 12:3395-8
Kern, Jonathan T; Thomas, Pei Wang; Kerwin, Sean M (2002) The relationship between ligand aggregation and G-quadruplex DNA selectivity in a series of 3,4,9,10-perylenetetracarboxylic acid diimides. Biochemistry 41:11379-89
Sun, Daekyu (2002) Biotinylated primer for detecting telomerase activity without amplification. Methods Mol Biol 191:165-71
Shi, D F; Wheelhouse, R T; Sun, D et al. (2001) Quadruplex-interactive agents as telomerase inhibitors: synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase. J Med Chem 44:4509-23
Duan, W; Rangan, A; Vankayalapati, H et al. (2001) Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects. Mol Cancer Ther 1:103-20
Sun, D; Hurley, L H (2001) Targeting telomeres and telomerase. Methods Enzymol 340:573-92
Izbicka, E; Barnes, L D; Robinson, A K et al. (2001) Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast. Anticancer Res 21:1899-903
Han, H; Langley, D R; Rangan, A et al. (2001) Selective interactions of cationic porphyrins with G-quadruplex structures. J Am Chem Soc 123:8902-13

Showing the most recent 10 out of 36 publications