Antisense oligonucleotides (oligos) against
transforming growth factor-alpha (
TGF-alpha) (MR1) and its binding site, the
epidermal growth factor receptor (EGFR) (MR2), are efficacious against the UACC 897 breast, PC-3 and LNCaP prostate, and T98G
glioblastoma tumor lines in both in vitro and in vivo studies. Oligos against the anti-apoptosis
protein bcl-2 (MR4) are also efficient against PC-3 and LNCaP
tumors in similar in vitro experiments. To enhance activity, and also to introduce a derivative type of multifunctional oligo into this field, "bispecifics" were constructed containing two truncated
complementary DNA sequences (from either MR1 or MR2) designed to bind targeted
mRNA about their respective AUG
initiation codons, and/or a similar sequence adjacent to the AUG site of
mRNA encoding bcl-2. Tandem pairs of bispecifics were constructed: The first had complementary sequences for
TGF-alpha and EGFR
mRNA, but differed in 5' to 3' tandem orientation (
TGF-alpha/EGFR [MR12] and EGFR/
TGF-alpha [MR21] sequences); a second pair had binding sites associated with EGFR and bcl-2, also differing in orientation (EGFR/bcl-2 [MR24] and bcl-2/EGFR [MR42]). In studies targeting PC-3 and LNCaP cells, bispecifics demonstrated significant in vitro activity, and the second pair was significantly better than the original monospecifics. These studies are now extended to the MCF-7
breast cancer model in order to determine whether these particular bispecifics have similar anti-
breast cancer activity and if they are significantly better than monospecific oligos from which they were derived. We conclude that bispecific oligos significantly inhibit MCF-7 growth, however, in contrast to results obtained with PC-3 and LNCaP, the monospecific oligos directed against EGFR and bcl-2 have significantly greater activity than the bispecifics targeting a combination of
TGF-alpha, EGFR, or bcl-2. These data suggest that the relative activities of oligos, whether mono- or bispecific, change with
tumor type. Bispecific oligos which target different
proteins, possibly those which regulate
estrogen utilization, may be more effective against MCF-7 cells and warrant additional investigation, particularly if co-administered with traditional chemotherapeutics.