Over-expression of the anti-apoptotic protein bcl-xL is frequently found in
lung cancer where it potentially contributes to tumor development, progres
sion and drug resistance. To override the apoptotic block in lung-adenocarc
inoma and small-cell-lung-cancer (SCLC) cells caused by over-expression of
bcl-xL, an anti-sense oligodeoxynucleotide was designed targeting a sequenc
e unique to the bcl-xL coding region and not shared by the pro-apoptotic sp
lice variant bcl-xS. Moreover, to improve the biophysical properties of the
antisense compound, 2'-methoxy-ethoxy modifications were made to selected
deoxy-ribose residues. The resulting gap-mer oligonucleotide 4259 was teste
d on lung-adenocarcinoma and SCLC cell lines in vitro. Treatment of the ade
nocarcinoma cell lines A549 and NCI-H125 and the SCLC cell lines SW2 and NC
I-H69 with 600 nM 4259 reduced bcl-xL levels by 70 to 90%. In the lung-aden
ocarcinoma cell lines, apoptosis was induced, as indicated by caspase-3-lik
e protease activation and nuclear condensation and fragmentation. In contra
st, in the SCLC cell lines, no induction of apoptosis could be demonstrated
. These findings imply that bcl-xL is a more critical survival factor for l
ung adenocarcinomas than for SOLO, and suggest the use of oligonucleotide 4
259 for therapy of this major sub-type of lung cancer. Int. J. Cancer 86:57
0-576, 2000. (C) 2000 Wiley-Liss, Inc.