Oligonucleotide inhibition of protein kinase C

• US 6,537,973 B1
• Filed: 12/18/2001
• Issued: 03/25/2003
• Est. Priority Date: 03/16/1992
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Holmlund, Jon T., Dorr, F. Andrew, Dean, Nicholas M., Bennett, C. Frank
• Primary Examiner(s): Wang, Andrew
• Assistant Examiner(s): SCHULTZ, JAMES
• Application Number:
  US10/025,139
• Time in Patent Office: 462 Days
• Field of Search: 514/44, 435/6, 435/325, 435/375, 536/24.3, 536/24.5, 536/24.32, 536/23.1
• US Class Current: 514/44.00A
• 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: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3527 Other alkyl chain
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Y 207/11013 Protein kinase C (2.7.11.13)

Abstract

Compositions and methods are provided for the treatment and diagnosis of diseases associated with protein kinase C. Oligonucleotides are provided which are targeted to nucleic acids encoding PKC. In preferred embodiments, the oligonucleotides contain one or more chemical modifications. Methods of modulating PKC expression and of treating animals suffering from disease amenable to therapeutic intervention by modulating protein kinase C expression using oligonucleotides targeted to PKC are disclosed.

Claims

1. A pharmaceutical composition comprising an oligonucleotide up to 50 nucleotide units in length comprising SEQ ID NO:

2, in combination with carboplatin and paclitaxel.

2. The pharmaceutical composition of claim 1, wherein said oligonucleotide comprises at least one phosphorothioate linkage.

3. The pharmaceutical composition of claim 1, wherein said oligonucleotide has the sequence shown in SEQ ID NO:

2.

13. A method of inhibiting PKC-α

expression in human cells comprising contacting the cells with the pharmaceutical composition of claims 1, 4, 7 or 10.

14. The method of claim 13 wherein the cells are cancer cells.

15. A method of treating a condition associated with expression of human PKC-α

comprising administering to an animal or cells, tissues or a bodily fluid thereof, a therapeutically effective amount of the pharmaceutical composition of claims 1, 4, 7 or 10.

16. The method of claim 15 wherein said condition is cancer.

17. A method of treating non small cell lung cancer (NSCLC) in a human in need thereof, comprising administering to said human the pharmaceutical composition of claim 1.

4. A pharmaceutical composition comprising an oligonucleotide up to 50 nucleotide units in length comprising SEQ ID NO:

2, in combination with docetaxel.

5. The pharmaceutical composition of claim 4, wherein said oligonucleotide comprises at least one phosphorothioate linkage.

6. The pharmaceutical composition of claim 4, wherein said oligonucleotide has the sequence shown in SEQ ID NO:

2.

7. A pharmaceutical composition comprising an oligonucleotide up to 50 nucleotide units in length comprising SEQ ID NO:

2, in combination with cisplatin and gemcitabine.

8. The pharmaceutical composition of claim 7, wherein said oligonucleotide comprises at least one phosphorothioate linkage.

9. The pharmaceutical composition of claim 7, wherein said oligonucleotide has the sequence shown in SEQ ID NO:

2.

10. A pharmaceutical composition comprising an oligonucleotide up to 50 nucleotide units in length comprising SEQ ID NO:

2, in combination with 5-fluorouracil and leucovorin.

11. The pharmaceutical composition of claim 10, wherein sad oligonucleotide comprises at least one phosphorothioate linkage.

12. The pharmaceutical composition of claim 10, wherein said oligonucleotide has the sequence shown in SEQ ID NO:

2.

18. A method of treating non-Hodgkin'"'"'s lymphoma in a human in need thereof, comprising administering to said human a pharmaceutical composition comprising an oligonucleotide up to 50 nucleotide units in length comprising SEQ ID NO:

2.