Treatment of MCF-7 breast cancer cells employing mono- and bispecific antisense oligonucleotides having binding specificity toward proteins associated with autocrine regulated growth and BCL-2
Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-α) (MR 1 ) and its binding site, the epidermal growth factor receptor (EGFR) (MR 2 ), are efficacious against the UACC 897 breast, PC-3 and LNCaP prostate, and T98G glioblastoma tumor lines in both in vitro and in vivo...
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Published in | Medical oncology (Northwood, London, England) Vol. 25; no. 2; pp. 182 - 186 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
New York
Humana Press Inc
01.06.2008
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-α) (MR
1
) and its binding site, the epidermal growth factor receptor (EGFR) (MR
2
), 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 (MR
4
) 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 MR
1
or MR
2
) 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-α and EGFR mRNA, but differed in 5′ to 3′ tandem orientation (TGF-α/EGFR [MR
12
] and EGFR/TGF-α [MR
21
] sequences); a second pair had binding sites associated with EGFR and bcl-2, also differing in orientation (EGFR/bcl-2 [MR
24
] and bcl-2/EGFR [MR
42
]). 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-α, 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 1357-0560 1559-131X |
DOI: | 10.1007/s12032-007-9018-y |