U. Zangemeister-wittke et al., A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells, CLIN CANC R, 6(6), 2000, pp. 2547-2555
Bcl-2 and Bcl-xL are inhibitors of apoptosis frequently overexpressed in so
lid tumors, The bcl-2 and bcl-xL mRNAs share a region of homology comprisin
g nucleotides 605-624 and 687-706, respectively, which differs by only thre
e nucleotides. This sequence does not occur in the proapoptotic splice vari
ant bcl-xS, To test the possibility that oligonucleotides targeting this re
gion have the potential to down-regulate bcl-2 and bcl-xL expression simult
aneously, three 2'-O-methoxy-ethoxy-modified phosphorothioate oligonucleoti
des were designed. These oligonucleotides differed in the number of mismatc
hes to bcl-2 and bcl-xL and in the number of nucleotides to which the modif
ications were made. The effects of these oligonucleotides on bcl-2 and bcl-
xL expression, as well as their abilities to induce apoptosis, were assesse
d in small cell and non-small cell lung cancer cell lines expressing differ
ent basal levels of bcl-2 acid bcl-xL, Although all oligonucleotides down-r
egulated bcl-2 and bcl-xL expression, oligonucleotide 4625, which has no mi
smatching nucleotides to bcl-2 but three to bcl-xL, two of which were modif
ied by 2'-O-methoxy-ethoxy residues, showed the strongest bispecific activi
ty on the transcript and protein level, In all cell lines this bispecific a
ctivity induced apoptotic cell death, as demonstrated by increased uptake o
f propidium iodide, a 10-100-fold increase in caspase-3-like protease activ
ity, and nuclear condensation and fragmentation, This is the first report o
f a bcl-2/bcl-xL bispecific antisense oligonucleotide that deserves attenti
on as a therapeutic compound in lung cancer and other malignancies in which
bcl-2 and/or bcl-xL are overexpressed.