SENSITIZATION OF COLORECTAL AND PANCREATIC-CANCER CELL-LINES TO THE PRODRUG 5-(AZIRIDIN-1-YL)-2,4-DINITROBENZAMIDE (CB1954) BY RETROVIRAL TRANSDUCTION AND EXPRESSION OF THE ESCHERICHIA-COLI NITROREDUCTASE GENE

Citation
Nk. Green et al., SENSITIZATION OF COLORECTAL AND PANCREATIC-CANCER CELL-LINES TO THE PRODRUG 5-(AZIRIDIN-1-YL)-2,4-DINITROBENZAMIDE (CB1954) BY RETROVIRAL TRANSDUCTION AND EXPRESSION OF THE ESCHERICHIA-COLI NITROREDUCTASE GENE, Cancer gene therapy, 4(4), 1997, pp. 229-238
Citations number
44
Categorie Soggetti
Oncology,"Biothechnology & Applied Migrobiology
Journal title
ISSN journal
09291903
Volume
4
Issue
4
Year of publication
1997
Pages
229 - 238
Database
ISI
SICI code
0929-1903(1997)4:4<229:SOCAPC>2.0.ZU;2-S
Abstract
Expression of genes encoding prodrug-activating enzymes can increase t he susceptibility of tumor cells to prodrugs, and may ultimately achie ve a better therapeutic index than conventional chemotherapy. CB1954 i s a weak, monofunctional alkylating agent which can be activated by Es cherichia coli nitroreductase to a potent difunctional alkylating agen t which crosslinks DNA. We have inserted the nitroreductase gene into an LNCX-based retroviral vector, to allow efficient gene transfer and expression in colorectal (LS174T) and pancreatic (SUIT2, BxPC3, and As PC1) cancer cell lines. A clone of LS174T cells expressing nitroreduct ase showed >50-fold increased sensitivity to CB1954, and nitroreductas e-expressing, clones of pancreatic tumor lines were up to similar to 5 00-fold (SUIT2) more sensitive than parental cells. Concentrations of CB1954 minimally toxic to nontransduced cells achieved 100% cell death in a 50:50 mix of parental cells with SUIT2 cells expressing nitrored uctase; and marked ''bystander'' cell killing was seen with just 10% o f cells expressing nitroreductase. Significant bystander cell killing was dependent on a high cell density. In conjunction with regional del ivery of vectors and tumor selectivity of cell entry and/or gene expre ssion, nitroreductase and CB1954 may be an attractive combination for prodrug-activating enzyme gene therapy of colorectal and pancreatic ca ncer.