Treatment of prostate and breast tumors employing mono- and bi-specific antisense oligonucleotides targeting apoptosis inhibitory proteins clusterin and bcl-2.

Abstract

Antisense oligonucleotides (oligos) have demonstrated their efficacy in inhibiting the growth of prostate and breast tumor cells. Previous studies employed first generation, phosphorothioated, cDNA oligos synthesized complimentary to mRNA encoding transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR), the anti-apoptosis protein bcl-2, and the androgen receptor (AR). In an effort to construct oligos with greater than one mRNA binding site, bi-specifics have been developed which target combinations of the above proteins, and these have been shown at least as effective as the mono-specific oligos from which their sequences were derived. While all bi-specifics have inhibitory effects, which can be enhanced by the combined administration of an additional chemotherapeutic agent, those bi-specifics which target bcl-2 and EGFR were reported to be the most effective. The experiments presented here are an effort to evaluate a new group of bi-specifics whose targets include the chaperone protein clusterin, whose expression is up regulated in many tumors and activity is known to inhibit apoptosis. Of particular interest were those bi-specifics constructed to target both clusterin and bcl-2 (also an apoptosis inhibitory protein). Cell lines targeted included both prostate LNCaP and PC-3, as well as the breast derived MCF-7. In order to identify agents which enhance oligo activity, but contribute less toxicity, oligos were tested both alone and in combination with either the immune inhibitor Rapamycin, or the chemotherapeutic (and more toxic) Taxol. Results indicate that bi-specifics targeting clusterin are statistically effective, and are similarly enhanced by Rapamycin, or Taxol. When bi-specifics including clusterin as a target, were tested against LNCaP and MCF-7 cells, the level of activity was intermediate between that of the mono-specific compounds tested separately. In experiments which compared both, bi-specifics which included a target for clusterin had inhibitory activity similar to the previously described bi-specifics directed towards bcl-2 and EGFR.

• Authors: Marvin Rubenstein, Paulus Tsui, Patrick Guinan
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 27 Issue 3 Pg. 592-9 (Sep 2010) ISSN: 1559-131X [Electronic] United States
• PMID: 19533419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Clusterin
• Neoplasm Proteins
• Oligonucleotides, Antisense
• Phosphorothioate Oligonucleotides
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• RNA, Neoplasm
• Paclitaxel
• Sirolimus

Topics

• Adenocarcinoma (drug therapy, pathology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor (drug effects)
• Clusterin (antagonists & inhibitors)
• Drug Delivery Systems
• Drug Screening Assays, Antitumor
• Female
• Humans
• Male
• Neoplasm Proteins (antagonists & inhibitors)
• Oligonucleotides, Antisense (pharmacology)
• Paclitaxel (pharmacology)
• Phosphorothioate Oligonucleotides (pharmacology)
• Prostatic Neoplasms (drug therapy, pathology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• RNA, Messenger (antagonists & inhibitors)
• RNA, Neoplasm (antagonists & inhibitors)
• Sirolimus (pharmacology)
• Substrate Specificity