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
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
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.