The long-term objective of this research is to develop genetic therapies for non-Hodgkin's lymphoma (NHL). The initial target is the most common chromosomal translocation in NHL, t(14;18), which fuses the BCL-2 gene with the JH and constant regions of immunoglobulin (Ig) genes. The resultant BCL-2/Ig fusion mRNA leads to dysregulated BCL-2 expression that inhibits cell death, or apoptosis. BCL-2 overexpression also reduces sensitivity to chemotherapy-induced apoptosis. In the WSU-FSCCL NHL cell line antisense oligonucleotides (AS-ODN) targeted not only to the BCL-2 gene, but also to Ig sequences present in all t(14;18) fusion genes, decrease BCL-2 expression and induce apoptosis. While AS-ODN that target BCL-2 would be toxic to many normal cells, AS-ODN targeted to Ig sequences are predicted to be specifically cytotoxic to NHL cells. Because they target Ig constant regions, Ig AS-ODN need not be individually designed.
The specific aims of this application are: 1) to optimize Ig AS-ODN cytotoxicity in vitro and to test whether Ig AS-ODN sensitize cells to chemo- and/or radio-therapy; 2) to test the efficacy and toxicity of Ig AS-ODN in a SCID mouse/WSU-FSCCL model of in vivo therapy with Ig AS-ODN; and 3) to determine the frequency of expression of different Ig constant regions, e.g., C mu vs C gamma in t(14;18) positive fresh NHL samples to define which Ig AS-ODN sequences need to be developed clinically. Ig AS-ODN with therapeutic efficacy and acceptable toxicity will be candidates for development of clinical trials in NHL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071552-03
Application #
2895605
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1997-06-20
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2001-05-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111