Antisense oligonucleotide compositions and methods for the modulation of activating protein 1

Abstract

Compositions and methods for the treatment and diagnosis of diseases or disorders amenable to treatment through modulation of Activating Protein 1 (AP-1) expression are provided. In accordance with various embodiments of the present invention, oligonucleotides are provided which are specifically hybridizable with c-fos or c-jun, the genes encoding c-Fos or c-Jun, respectively. In a preferred embodiment, a method of modulating the metastasis of malignant tumors via modulation of one or more of the AP-1 subunits is provided; this method can be effected using the oligonucleotides of the invention or any other agent which modulates AP-1 or AP-1-mediated transcription.

What is claimed is:  
     
         1 . An oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein.  
     
     
         2 . The oligonucleotide of  claim 1 , wherein at least one of said covalent linkages is a modified covalent linkage.  
     
     
         3 . The oligonucleotide of  claim 2 , wherein said modified covalent linkage is selected from the group consisting of a phosphorothioate linkage, a phosphotriester linkage, a methyl phosphonate linkage, a methylene(methylimino) linkage, a morpholino linkage, an amide linkage, a polyamide linkage, a short chain alkyl intersugar linkage, a cycloalkyl intersugar linkage, a short chain heteroatomic intersugar linkage and a heterocyclic intersugar linkage.  
     
     
         4 . The oligonucleotide of  claim 1 , wherein at least one of said nucleotides has a modified sugar moiety.  
     
     
         5 . The oligonucleotide of  claim 4 , wherein said modified sugar moiety is a modification at the 2′ position of any nucleotide, the 3′ position of the 3′ terminal nucleotide or the 5′ position of the 5′ terminal oligonucleotide.  
     
     
         6 . The oligonucleotide of  claim 5 , wherein said modification is selected from the group consisting of a substitution of an azido group for a 3′ hydroxyl group and a substitution of a hydrogen atom for a 3′ or 5′ hydroxyl group.  
     
     
         7 . The oligonucleotide of  claim 5 , wherein said modification is a substitution or addition at the 2′ position of a moiety selected from the group consisting of —OH, —SH, —SCH 3 , —F, —OCN, —OCH 3 OCH 3 , —OCH 3 O(CH 2 ) n CH 3 , —O(CH 2 ) n NH 2  or —O(CH 2 ) n CH 3  where n is from 1 to about 10, a C 1  to C 10  lower alkyl group, an alkoxyalkoxy group, a substituted lower alkyl group, a substituted alkaryl group, a substituted aralkyl group, —Cl, —Br, —CN, —CF 3 , —OCF 3 , an —O-alkyl group, an —S-alkyl group, an N-alkyl group, an O-alkenyl group, an S-alkenyl group, an N-alkenyl group, —SOCH 3 , —SO 2 CH 3 , —ONO 2 , —NO 2 , —N 3 , —NH 2 , a heterocycloalkyl group, a heterocycloalkaryl group, an aminoalkylamino group, a polyalkylamino group, a substituted silyl group, an RNA cleaving group, a reporter group, a DNA intercalating group, a group for improving the pharmacokinetic properties of an oligonucleotide, a group for improving the pharmacodynamic properties of an oligonucleotide, a methoxyethoxy group and a methoxy group.  
     
     
         8 . The oligonucleotide of  claim 1 , wherein at least one of said nucleotides has a modified nucleobase.  
     
     
         9 . The oligonucleotide of  claim 8 , wherein said modified nucleobase is selected from the group consisting of hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, glycosyl 5-hydroxymethylcytosine, gentiobiosyl 5-hydroxymethylcytosine, 5-bromouracil, 5-hydroxymethyluracil, 6-methyladenine, N 6 -(6-aminohexyl)adenine, 8-azaguanine, 7-deazaguanine and 2,6-diaminopurine.  
     
     
         10 . The oligonucleotide of  claim 1  wherein said nucleic acid is an mRNA molecule encoding said c-Fos protein.  
     
     
         11 . The oligonucleotide of  claim 1  wherein said c-Fos protein is human c-Fos.  
     
     
         12 . The oligonucleotide of  claim 11  wherein said sequence comprises SEQ ID NO: 15, 17, 20 or 21.  
     
     
         13 . An oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein, and wherein said oligonucleotide comprises at least one lipophilic moiety which enhances the cellular uptake of said oligonucleotide.  
     
     
         14 . The oligonucleotide of  claim 13  wherein said lipophilic moiety is selected from the group consisting of a cholesterol moiety, a cholesteryl moiety, cholic acid, a thioether, a thiocholesterol, an aliphatic chain, a phospholipid, a polyamine chain, a polyethylene glycol chain, adamantane acetic acid, a palmityl moiety, an octadecylamine moiety and a hexylamino-carbonyl-oxycholesterol moiety.  
     
     
         15 . The oligonucleotide of  claim 13  wherein at least one of said linkages is selected from the group consisting of a phosphorothioate linkage, a phosphodiester linkage, a phosphotriester linkage, a methyl phosphonate linkage, a methylene(methylimino) linkage, a morpholino linkage, an amide linkage, a polyamide linkage, a short chain alkyl intersugar linkage, a cycloalkyl intersugar linkage, a short chain heteroatomic intersugar linkage and a heterocyclic intersugar linkage.  
     
     
         16 . The oligonucleotide of  claim 13  wherein at least one of said nucleotides has a modified sugar moiety.  
     
     
         17 . The oligonucleotide of  claim 16 , wherein said modified sugar moiety is a modification at the 2′ position of any nucleotide, the 3′ position of the 3′ terminal nucleotide or the 5′ position of the 5′ terminal oligonucleotide.  
     
     
         18 . The oligonucleotide of  claim 17 , wherein said modification is selected from the group consisting of a substitution of an azido group for a 3′ hydroxyl group and a substitution of a hydrogen atom for a 3′ or 5′ hydroxyl group.  
     
     
         19 . The oligonucleotide of  claim 17 , wherein said modification is a substitution or addition at the 2′ position of a moiety selected from the group consisting of —OH, —SH, —SCH 3 , —F, —OCN, —OCH 3 OCH 3 , —OCH 3 O(CH 2 ) n CH 3 , —O(CH 2 ) n NH 2  or —O(CH 2 ) n CH 3  where n is from 1 to about 10, a C 1  to C 10  lower alkyl group, an alkoxyalkoxy group, a substituted lower alkyl group, a substituted alkaryl group, a substituted aralkyl group, —Cl, —Br, —CN, —CF 3 , —OCF 3 , an —O-alkyl group, an —S-alkyl group, an N-alkyl group, an O-alkenyl group, an S-alkenyl group, an N-alkenyl group, —SOCH 3 , —SO 2 CH 3 , —ONO 2 , —NO 2 , —N 3 , —NH 2 , a heterocycloalkyl group, a heterocycloalkaryl group, an aminoalkylamino group, a polyalkylamino group, a substituted silyl group, an RNA cleaving group, a reporter group, a DNA intercalating group, a group for improving the pharmacokinetic properties of an oligonucleotide, a group for improving the pharmacodynamic properties of an oligonucleotide, a methoxyethoxy group and a methoxy group.  
     
     
         20 . The oligonucleotide of  claim 13 , wherein at least one of said nucleotides has a modified nucleobase.  
     
     
         21 . The oligonucleotide of  claim 20 , wherein said modified nucleobase is selected from the group consisting of hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, glycosyl 5-hydroxymethylcytosine, gentiobiosyl 5-hydroxymethylcytosine, 5-bromouracil, 5-hydroxymethyluracil, 6-methyladenine, N 6 -(6-aminohexyl)adenine, 8-azaguanine, 7-deazaguanine and 2,6-diaminopurine.  
     
     
         22 . The oligonucleotide of  claim 13  wherein said nucleic acid is an mRNA molecule encoding said c-Fos protein.  
     
     
         23 . The oligonucleotide of  claim 13  wherein said c-Fos protein is human c-Fos.  
     
     
         24 . The oligonucleotide of  claim 23  wherein said sequence comprises SEQ ID NO: 15, 17, 20 or 21.  
     
     
         25 . A pharmaceutical composition comprising an oligonucleotide of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         26 . An oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein.  
     
     
         27 . The oligonucleotide of  claim 26 , wherein at least one of said covalent linkages is a modified covalent linkage.  
     
     
         28 . The oligonucleotide of  claim 27 , wherein said modified covalent linkage is selected from the group consisting of a phosphorothioate linkage, a phosphotriester linkage, a methyl phosphonate linkage, a methylene(methylimino) linkage, a morpholino linkage, an amide linkage, a polyamide linkage, a short chain alkyl intersugar linkage, a cycloalkyl intersugar linkage, a short chain heteroatomic intersugar linkage and a heterocyclic intersugar linkage.  
     
     
         29 . The oligonucleotide of  claim 26 , wherein at least one of said nucleotides has a modified sugar moiety.  
     
     
         30 . The oligonucleotide of  claim 29 , wherein said modified sugar moiety is a modification at the 2′ position of any nucleotide, the 3′ position of the 3′ terminal nucleotide or the 5′ position of the 5′ terminal oligonucleotide.  
     
     
         31 . The oligonucleotide of  claim 30 , wherein said modification is selected from the group consisting of a substitution of an azido group for a 3′ hydroxyl group and a substitution of a hydrogen atom for a 3′ or 5′ hydroxyl group.  
     
     
         32 . The oligonucleotide of  claim 30 , wherein said modification is a substitution or addition at the 2′ position of a moiety selected from the group consisting of —OH, —SH, —SCH 3 , —F, —OCN, —OCH 3 OCH 3 , —OCH 3 O(CH 2 ) n CH 3 , —O(CH 2 ) n NH 2  or —O(CH 2 ) n CH 3  where n is from 1 to about 10, a C 1  to C 10  lower alkyl group, an alkoxyalkoxy group, a substituted lower alkyl group, a substituted alkaryl group, a substituted aralkyl group, —Cl, —Br, —CN, —CF 3 , —OCF 3 , an —O-alkyl group, an —S-alkyl group, an N-alkyl group, an O-alkenyl group, an S-alkenyl group, an N-alkenyl group, —SOCH 3 , —SO 2 CH 3 , —ONO 2 , —NO 2 , —N 3 , —NH 2 , a heterocycloalkyl group, a heterocycloalkaryl group, an aminoalkylamino group, a polyalkylamino group, a substituted silyl group, an RNA cleaving group, a reporter group, a DNA intercalating group, a group for improving the pharmacokinetic properties of an oligonucleotide, a group for improving the pharmacodynamic properties of an oligonucleotide, a methoxyethoxy group and a methoxy group.  
     
     
         33 . The oligonucleotide of  claim 26 , wherein at least one of said nucleotides has a modified nucleobase.  
     
     
         34 . The oligonucleotide of  claim 33 , wherein said modified nucleobase is selected from the group consisting of hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, glycosyl 5-hydroxymethylcytosine, gentiobiosyl 5-hydroxymethylcytosine, 5-bromouracil, 5-hydroxymethyluracil, 6-methyladenine, N 6 -(6-aminohexyl)adenine, 8-azaguanine, 7-deazaguanine and 2,6-diaminopurine.  
     
     
         35 . The oligonucleotide of  claim 26  wherein said nucleic acid is an mRNA molecule encoding said c-Jun protein.  
     
     
         36 . The oligonucleotide of  claim 26  wherein said c-Jun protein is human c-Jun.  
     
     
         37 . The oligonucleotide of  claim 26  wherein said sequence comprises SEQ ID NO: 3, 4, 5, 6, 7, 8 or 9.  
     
     
         38 . An oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein, and wherein said oligonucleotide comprises at least one lipophilic moiety which enhances the cellular uptake of said oligonucleotide.  
     
     
         39 . The oligonucleotide of  claim 38  wherein said lipophilic moiety is selected from the group consisting of a cholesterol moiety, a cholesteryl moiety, cholic acid, a thioether, a thiocholesterol, an aliphatic chain, a phospholipid, a polyamine chain, a polyethylene glycol chain, adamantane acetic acid, a palmityl moiety, an octadecylamine moiety and a hexylamino-carbonyl-oxycholesterol moiety.  
     
     
         40 . The oligonucleotide of  claim 38  wherein at least one of said linkages is selected from the group consisting of a phosphorothioate linkage, a phosphodiester linkage, a phosphotriester linkage, a methyl phosphonate linkage, a methylene(methylimino) linkage, a morpholino linkage, an amide linkage, a polyamide linkage, a short chain alkyl intersugar linkage, a cycloalkyl intersugar linkage, a short chain heteroatomic intersugar linkage and a heterocyclic intersugar linkage.  
     
     
         41 . The oligonucleotide of  claim 38  wherein at least one of said nucleotides has a modified sugar moiety.  
     
     
         42 . The oligonucleotide of  claim 41 , wherein said modified sugar moiety is a modification at the 2′ position of any nucleotide, the 3′ position of the 3′ terminal nucleotide or the 5′ position of the 5′ terminal oligonucleotide.  
     
     
         43 . The oligonucleotide of  claim 42 , wherein said modification is selected from the group consisting of a substitution of an azido group for a 3′ hydroxyl group and a substitution of a hydrogen atom for a 3′ or 5′ hydroxyl group.  
     
     
         44 . The oligonucleotide of  claim 42 , wherein said modification is a substitution or addition at the 2′ position of a moiety selected from the group consisting of —OH, —SH, —SCH 3 , —F, —OCN, —OCH 3 OCH 3 , —OCH 3 O(CH 2 ) n CH 3 , —O(CH 2 ) n NH 2  or —O(CH 2 ) n CH 3  where n is from 1 to about 10, a C 1  to C 10  lower alkyl group, an alkoxyalkoxy group, a substituted lower alkyl group, a substituted alkaryl group, a substituted aralkyl group, —Cl, —Br, —CN, —CF 3 , —OCF 3 , an —O-alkyl group, an —S-alkyl group, an N-alkyl group, an O-alkenyl group, an S-alkenyl group, an N-alkenyl group, —SOCH 3 , —SO 2 CH 3 , —ONO 2 , —NO 2 , —N 3 , —NH 2 , a heterocycloalkyl group, a heterocycloalkaryl group, an aminoalkylamino group, a polyalkylamino group, a substituted silyl group, an RNA cleaving group, a reporter group, a DNA intercalating group, a group for improving the pharmacokinetic properties of an oligonucleotide, a group for improving the pharmacodynamic properties of an oligonucleotide, a methoxyethoxy group and a methoxy group.  
     
     
         45 . The oligonucleotide of  claim 38 , wherein at least one of said nucleotides has a modified nucleobase.  
     
     
         46 . The oligonucleotide of  claim 45 , wherein said modified nucleobase is selected from the group consisting of hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, glycosyl 5-hydroxymethylcytosine, gentiobiosyl 5-hydroxymethylcytosine, 5-bromouracil, 5-hydroxymethyluracil, 6-methyladenine, N 6 -(6-aminohexyl)adenine, 8-azaguanine, 7-deazaguanine and 2,6-diaminopurine.  
     
     
         47 . The oligonucleotide of  claim 38  wherein said nucleic acid is an mRNA molecule encoding said c-Jun protein.  
     
     
         48 . The oligonucleotide of  claim 38  wherein said c-Jun protein is human c-Jun.  
     
     
         49 . The oligonucleotide of  claim 38  wherein said sequence comprises SEQ ID NO: 3, 4, 5, 6, 7, 8 or 9.  
     
     
         50 . A pharmaceutical composition comprising the oligonucleotide of  claim 26  and a pharmaceutically acceptable carrier.  
     
     
         51 . A pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) the oligonucleotide of  claim 1;  and    (c) a pharmaceutically acceptable carrier.    
     
     
         52 . A pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) the oligonucleotide of  claim 26;  and    (c) a pharmaceutically acceptable carrier.    
     
     
         53 . A pharmaceutical composition comprising 
 (a) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein; and    (c) a pharmaceutically acceptable carrier.    
     
     
         54 . A pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein;    (c) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein; and    (d) a pharmaceutically acceptable carrier.    
     
     
         55 . A method of modulating the expression of a c-Fos protein in cells or tissues comprising contacting said cells or tissues with an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein.  
     
     
         56 . The method of  claim 55  wherein said modulating comprises inhibiting the expression of said c-Fos protein.  
     
     
         57 . A method of modulating the expression of a c-Jun protein in cells or tissues comprising contacting said cells or tissues with an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein.  
     
     
         58 . The method of  claim 57  wherein said modulating comprises inhibiting the expression of said c-Jun protein.  
     
     
         59 . A method of inhibiting tumor growth in an animal comprising administering to said animal a therapeutically effective amount of an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein.  
     
     
         60 . A method of inhibiting tumor growth in an animal comprising administering to said animal a therapeutically effective amount of an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein.  
     
     
         61 . A method of inhibiting tumor growth in an animal comprising administering to said animal a therapeutically effective amount of an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide modulates the expression of one or more matrix metalloproteinases.  
     
     
         62 . A method of modulating cell cycle progression in cultured cells or the cells of an animal comprising administering to said cells an effective amount of an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein.  
     
     
         63 . A method of modulating cell cycle progression in cultured cells or the cells of an animal comprising administering to said cells an effective amount of an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein.  
     
     
         64 . A prodrug of the oligonucleotide of  claim 1 .  
     
     
         65 . A pharmaceutical composition comprising the oligonucleotide prodrug of  claim 64  and a pharmaceutically acceptable carrier.  
     
     
         66 . A prodrug of the oligonucleotide of  claim 25 .  
     
     
         67 . A pharmaceutical composition comprising the oligonucleotide prodrug of  claim 66  and a pharmaceutically acceptable carrier.  
     
     
         68 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein and a pharmaceutically acceptable carrier.  
     
     
         69 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein and a pharmaceutically acceptable carrier.  
     
     
         70 . A method of treating-an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein; and    (c) a pharmaceutically acceptable carrier.    
     
     
         71 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein; and    (c) a pharmaceutically acceptable carrier.    
     
     
         72 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (a) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein; and    (c) a pharmaceutically acceptable carrier.    
     
     
         73 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (a) a chemotherapeutic agent;    (b) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein;    (c) an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Jun protein and said oligonucleotide modulates the expression of said c-Jun protein; and    (d) a pharmaceutically acceptable carrier.    
     
     
         74 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising the oligonucleotide prodrug comprising an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein and a pharmaceutically acceptable carrier.  
     
     
         75 . A method of treating an animal having, suspected of having or prone to having a hyperproliferative disease comprising administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising the oligonucleotide prodrug comprising an oligonucleotide comprising 8 to 30 nucleotides connected by covalent linkages, wherein said oligonucleotide has a sequence specifically hybridizable with a nucleic acid encoding a c-Fos protein and said oligonucleotide modulates the expression of said c-Fos protein and a pharmaceutically acceptable carrier.