Antisense oligonucleotides targeting cooperating oncogenes

• US 5,734,039 A
• Filed: 09/15/1994
• Issued: 03/31/1998
• Est. Priority Date: 09/15/1994
• Status: Expired due to Fees

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Skorski, Tomasz, Calabretta, Bruno
• Primary Examiner(s): Guzo, David
• Assistant Examiner(s): SCHWARTZMAN, ROBERT A
• Application Number:
  US08/306,691
• Time in Patent Office: 1,293 Days
• Field of Search: 435/91.1, 435/91.21, 435/91.41, 435/172.3, 435/320.1, 536/23.1, 536/24.5, 536/22.1, 514/44, 935/34
• US Class Current: 536/24.5
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/315 Phosphorothioates

Abstract

Therapeutic combinations of two or more antisense oligonucleotides are provided. At least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene are combined for treatment of a neoplastic disease. The first antisense oligonucleotide may be specific for, e.g., a ras or raf gene, or an oncogene which codes for a protein tyrosine kinase. The nuclear gene-targeting antisense oligonucleotide preferably may be specific for a nuclear oncogene or proto-oncogene which encodes a transcriptional factor. The combined oligonucleotides have enhanced activity against neoplastic disease.

Claims

1. A composition comprising at least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene selected from the group consisting of ras genes, raf genes, EGF-1, c-fms, c-ros, c-kit, c-met, c-trk, c-src, c-abl, bcr-abl, c-fgr and c-yes and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene selected from the group consisting of myc genes, jun genes, c-ets, c-fos, c-myb, B-myb, c-rel, c-vav, c-ski, c-spi, cyclin D1, PML/RARα

, AML1/MTG8, E2A/prl and ALL-1/AF-4.

2. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for an oncogene or proto-oncogene which encodes a protein tyrosine kinase.

3. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for bcr-abl.

4. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for a cytoplasmic oncogene or proto-oncogene selected from the group consisting of ras and raf genes.

5. The composition according to claim 1 wherein the second antisense oligonucleotide is specific for an oncogene or proto-oncogene which encodes a transcriptional factor.

6. The composition according to claim 1 wherein the second antisense oligonucleotide is specific for a myc gene.

7. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for a ras or raf gene, and the second antisense oligonucleotide is specific for a myc gene or a jun gene.

8. The composition according to claim 1 wherein the first antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript of a cytoplasmic oncogene or proto-oncogene, and the second antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript of a nuclear oncogene or proto-oncogene.

9. The composition according to claim 1 further comprising a pharmaceutically acceptable carrier.

10. The composition according to claim 3 wherein the second antisense oligonucleotide is specific for c-myc.

11. The composition according to claim 8 wherein the first antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript lying within about 50 nucleotides of the translation initiation codon of the cytoplasmic oncogene or proto-oncogene mRNA, and the second antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript lying within about 50 nucleotides of the translation initiation codon of the nuclear oncogene or proto-oncogene mRNA.

12. The composition according to claim 8 wherein the oligonucleotides comprise from 12-mers to 50-mers.