Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1999-01-19
2000-11-28
Elliott, George C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 231, 536 243, 536 245, 435 6, 435 911, 435325, 435375, C07H 2104, A61K 4800, C12Q 168, C12N 500
Patent
active
061535990
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to compositions and methods for modulation of the expression of protein kinase C. In particular, this invention relates to antisense oligonucleotides specifically hybridizable with nucleic acids encoding protein kinase C. These oligonucleotides have been found to modulate the expression of protein kinase C. These compositions and methods can be used diagnostically or therapeutically.
BACKGROUND OF THE INVENTION
The phosphorylation of proteins plays a key role in the transduction of extracellular signals into the cell. The enzymes, called kinases, which effect such phosphorylations are targets for the action of growth factors, hormones, and other agents involved in cellular metabolism, proliferation and differentiation. One of the major signal transduction pathways involves the enzyme protein kinase C (PKC), which is known to have a critical influence on cell proliferation and differentiation. PKC is activated by diacylglycerols (DAGs), which are metabolites released in signal transduction.
Interest in PKC was stimulated by the finding that PKC is the major, and perhaps only, cellular receptor through which a class of tumor-promoting agents called phorbol esters exert their pleiotropic effects on cells (Gescher et al., Anti-Cancer Drug Design 4:93-105 (1989)). Phorbols capable of tumor production can mimic the effect of DAG in activating PKC, suggesting that these tumor promoters act through PKC and that activation of this enzyme is at least partially responsible for the resulting tumorigenesis (Parker et al., Science 233:853-866 (1986)).
Experimental evidence indicates that PKC plays a role in growth control in colon cancer. It is believed that specific bacteria in the intestinal tract convert lipids to DAG, thus activating PKC and altering cell proliferation. This may explain the correlation between high dietary fat and colon cancer (Weinstein, Cancer Res. (Suppl.) 51:5080s-5085s (1991)). It has also been demonstrated that a greater proportion of the PKC in the colonic mucosa of patients with colorectal cancer is in an activated state compared to that of patients without cancer (Sakanoue et al., Int. J. Cancer 48:803-806 (1991)).
Increased tumorigenicity is also correlated with overexpression of PKC in cultured cells inoculated into nude mice. A mutant form of PKC induces highly malignant tumor cells with increased metastatic potential. Sphingosine and related inhibitors of PKC activity have been shown to inhibit tumor cell growth and radiation-induced transformation in vivo (Endo et al., Cancer Research 51:1613-1618 (1991); Borek et al., Proc. Natl. Acad. Sci. 88:1953-1957 (1991)). A number of experimental or clinically useful anti-cancer drugs show modulatory effects on PKC. Therefore, inhibitors of PKC may be important cancer-preventive or therapeutic agents. PKC has been suggested as a plausible target for more rational design of conventional anti-cancer drugs (Gescher, A. and Dale, I. L., Anti-Cancer Drug Design, 4:93-105 (1989)).
Experiments also indicate that PKC plays an important role in the pathophysiology of hyperproliferative skin disorders such as psoriasis and skin cancer. Psoriasis is characterized by inflammation, hyperproliferation of the epidermis and decreased differentiation of cells. Various studies indicate a role for PKC in causing these symptoms. PKC stimulation in cultured keratinocytes can be shown to cause hyperproliferation. Inflammation can be induced by phorbol esters and is regulated by PKC. DAG is implicated in the involvement of PKC in dermatological diseases, and is formed to an increased extent in psoriatic lesions.
Inhibitors of PKC have been shown to have both antiproliferative and antiinflammatory effects in vitro. Some antipsoriasis drugs, such as cyclosporine A and anthralin, have been shown to inhibit PKC. Inhibition of PKC has been suggested as a therapeutic approach to the treatment of psoriasis (Hegemann, L. and G. Mahrle, Pharmacology of the Skin, H. Mukhtar, ed., p. 357-368, CRC Press, Boca Raton, Fla., 1992).
REFERENCES:
patent: 4511713 (1985-04-01), Miller et al.
patent: 4806463 (1989-02-01), Goodchild et al.
patent: 5004810 (1991-04-01), Draper
patent: 5034506 (1991-07-01), Summerton et al.
patent: 5087617 (1992-02-01), Smith
patent: 5098890 (1992-03-01), Gerwitz et al.
patent: 5135917 (1992-08-01), Burch
patent: 5138045 (1992-08-01), Cook et al.
patent: 5166195 (1992-11-01), Ecker
patent: 5194428 (1993-03-01), Agrawal et al.
patent: 5225326 (1993-07-01), Bresser et al.
patent: 5264423 (1993-11-01), Cohen et al.
patent: 5276019 (1994-01-01), Cohen et al.
patent: 5286717 (1994-02-01), Cohen et al.
patent: 5585479 (1996-12-01), Hoke et al.
patent: 5703054 (1997-12-01), Bennett et al.
patent: 5882927 (1999-03-01), Bennett et al.
patent: 5948898 (1996-02-01), Dean et al.
Crook, S., Basic Principles of Antisense Therapeutics, Springer-Verlag Berlin Heidelberg New York, Jul. 1998.
Gura T., Antisense Has Growing Pains, Science, vol. 270, pp. 575-577, Oct. 1995.
Crooke, S. et al., Antisense '97: A roundtable on the state of the industry, Nature Biotechnology, vol. 15, p.522, Jun. 1997.
Branch, A., A Good antisense molecule is hard to find, TIBS vol. 23, pp 47-49, Feb. 1998.
Ahmad et al., "Antisense Expression of Protein Kinase C.alpha. Inhibits the Growth and Tumorigenicity of Human Glioblastoma Cells", Neurosurg., 1994, 35, 904-908.
Bacher, N. et al., "Isolation and Characterization of PKC-L, A New Member of the Protein Kinase C-Related Gene Family Specifically Expressed in Lung, Skin, and Heart", Mol. Cell. Biol., 1991, 11, 126-133.
Ballester, R. et al., "Fate of Immunoprecipitable Protein Kinase C in GH.sub.3 Cells Treated with Phorbol 12-Myristate 13-Acetate", J. Biol. Chem., 1985, 260(28),15194-15199.
Baxter et al., "PKC-episilon is involved in granulocyte-macrophage colong-stimulating factor signal transduction: Evidence from microphysiometry and antisense oligonucleotide experiments", Biochemistry, 1992, 31, 10950-10954.
Berkowitz, P.T. et al., "Synthesis of 1,2-Dihydro-1-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-2-oxopyrizine 4-Oxide, a Potent Analog of Deoxyuridine", J. Med. Chem., 1973, 16, 813-814.
Borek, C. et al., "Long-chain (sphingoid) bases inhibit multistage carcinogenesis in mouse C3H/10T1/2 cells treated with radiation and phorbol 12-myristate 13-acetate", Proc. Natl. Acad. Sci., 1991, 88, 1953-1957.
Brandt, S.J. et al., "Distinct Patterns of Expression of Different protein Kinase C mRNAs in Rat Tissues", Cell, 1987, 49, 57-63.
Coussens et al., "Multiple, Distinct Forms of Bovine and Human Protein Kinase C Suggest Diversity in Cellular Signaling Pathways", Science, 1986, 233, 859-866.
Endo, et al., "Cell Membrane Signaling as Target in Cancer Therapy: Inhibitory Effect of N,N-Dimethyl and N,N,N-Trimethyl Sphingosine Derivatives on In Vitro and In Vivo Growth of Human Tumor Cells in Nude Mice", Cancer Research, 1991, 51, 1613-1618.
Farese et al., "Antisense DNA downregulates protein kinase C isozymes (beta and alpha) and insulin-stimulated 2-deoxyglucose uptake in rat adipocytes", Antisense Res. Dev., 1991, 1(1), 35-42.
Finkenzeller, G., "Sequence of Human Protein Kinase C .alpha.", Nucleic Acids Research, 1990, 18(8), 2183.
Gescher, A. et al., "Protein Kinase C-A Novel Target for Rational Anti-Cancer Drug Design", Anti-Cancer Drug Design, 1989, 4, 93-105.
Godson, et al., "Inhibition of Expression of Protein Kinase C .alpha. by Antisense cDNA Inhibits Phorbol Ester-Mediated Archidonate Release", J. Biol. Chem., 1993, 268, 11946-11950.
Hackh's Chemical Dictionary, Grant, et al. (ed.), McGraw-Hill Book Company, New York, p. 312.
Hegemann, L. et al., Pharmacology of the Skin, H. Mukhtar (ed.), CRC press, Boca Raton, FL, 1992, pp. 357-368.
Hidaka, H. et al., "Pharmacology of the isoquinoline sulfonamide protein kinase C inhibitors", TIPS, 1987, 8, 162-164.
Maister, Bioworld Today, Apr. 29, 1994, p. 3.
Kubo, K. et al., "Primary structures of human protein kinase CBI and BII differ only in their C-terminal sequences", FEBS Letters, 1987, 223(1), 138-142.
Altmann Karl-Heinz
Dean Nicholas M.
Martin Pierre
Elliott George C.
Epps Janet
ISIS Pharmaceuticals Inc.
Novartis AG
LandOfFree
Methoxyethoxy oligonucleotides for modulation of protein kinase does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methoxyethoxy oligonucleotides for modulation of protein kinase , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methoxyethoxy oligonucleotides for modulation of protein kinase will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1725981