Oligonucleotide inhibitors of bcl-xL

Abstract

This invention provides an antisense oligonucleotide or analog thereof comprising 10 or more contiguous bases or base analogs from the sequence of bases of sequence A, B, C, D, E, F, G, H, I, J, K, L, or M of FIG. 1 . This invention also provides the above-described antisense oligonucleotides, wherein the nucleotide sequence comprises nucleotide sequence A, A′, B, C, C′, D, E, E′, F, G, G′, H, H′, I, I′, J, K, K′, L, L′, M, or M′ of FIGS. 2 A and 2 B. This invention also provides the above-described antisense oligonucleotides, wherein the oligonucleotide is encapsulated in a liposome or nanoparticle. This invention also provides the above-described antisense oligonucleotides, wherein the phosphate backbone comprises phosphorothioate bonds. In addition, this invention provides a method of treating cancer, comprising introducing into a tumor cell an effective amount of the the above-described antisense oligonucleotide, thereby reducing the levels of bcl-xL protein produced and treating cancer. This invention also provides the above-described methods, wherein the introducing comprises using porphyrin or lipofectin as a delivery agent. This invention also provides the above-described pharmaceutical compositions, wherein the oligonucleotide is encapsulated in a liposome or nanoparticle. This invention further provides the above-described pharmaceutical compositions, wherein the pharmaceutical composition comprises tetra meso-(4-methylpyridyl)porphine or tetra meso-(anilinium)porphine or a combination thereof.

What is claimed is:  
     
         1 . An antisense oligonucleotide or analog thereof comprising 10 or more contiguous bases or base analogs from the sequence of bases of sequence A, B, C, D, E, F, G, H, I, J, K, L, or M of FIG. 1.  
     
     
         2 . An antisense oligonucleotide or analog thereof comprising a sequence having 90% of greater identity to sequence A, B, C, D, E, F, G, H, I, J, K, L, or M of FIG. 1.  
     
     
         3 . An antisense oligonucleotide or analog thereof comprising nucleotide sequence A, B, C, D, E, F, G, H, I, J, K, L, or M of FIG. 1.  
     
     
         4 . The antisense oligonucleotide of  claim 3 , wherein the nucleotide sequence comprises nucleotide sequence A, A′, B, C, C′, D, E, E′, F, G, G′, H, H′, I, I′, J, K, K′, L, L′, M, or M′of FIGS. 2A and 2B.  
     
     
         5 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is conjugated to a peptide.  
     
     
         6 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is encapsulated in a liposome or nanoparticle.  
     
     
         7 . The antisense oligonucleotide of  claim 3 , wherein the phosphate backbone comprises phosphorothioate bonds.  
     
     
         8 . The antisense oligonucleotide of  claim 3 , wherein the backbone is bonded to one or more lipid substituents.  
     
     
         9 . The antisense oligonucleotide of  claim 3 , wherein one or more of the oligonucleotide's sugars contain an —OMe group at their 2′ position.  
     
     
         10 . The antisense oligonucleotide of  claim 3 , wherein the phosphate backbone consists essentially of phosphorothioate bonds.  
     
     
         11 . The antisense oligonucleotide of  claim 7 , wherein the phosphorothioate is stereo regular.  
     
     
         12 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is linked to an intercalating agent, a cross-linker, an endonuclease, a lipophilic carrier, an alkylating agent, a coordination complex, or a peptide conjugate, or a combination thereeof  
     
     
         13 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is modified to reduce its ionic charge or increase its hydrophobicity.  
     
     
         14 . The antisense oligonucleotide of  claim 13 , wherein the oligonucleotide comprises one or more short chain alkyl structures that replace some of the oligonucleotide's phosphodiester bonds.  
     
     
         15 . The antisense oligonucleotide of  claim 13 , wherein the oligonucleotide is linked to one or more cholesteryl moieties.  
     
     
         16 . The antisense oligonucleotide of  claim 13 , wherein the oligonucleotide comprises one or more bases with a C-5 propynyl pyrimidine modification.  
     
     
         17 . A method of treating cancer, comprising introducing into a tumor cell an effective amount of the antisense oligonucleotide of  claim 3 , thereby reducing the levels of bcl-xL protein produced and treating cancer.  
     
     
         18 . The method of  claim 17 , wherein the cancer is epithelial cancer.  
     
     
         19 . The method of  claim 18 , wherein the epithelial cancer is prostate cancer.  
     
     
         20 . The method of  claim 18 , wherein the epithelial cancer is lung cancer.  
     
     
         21 . The method of  claim 18 , wherein the epithelial cancer is bladder cancer.  
     
     
         22 . The method of  claim 17 , wherein the introducing comprises using a lipid as a delivery agent.  
     
     
         23 . The method of  claim 17 , wherein the introducing comprises using porphyrin or lipofectin as a delivery agent.  
     
     
         24 . The method of  claim 17 , wherein the effective amount is between 0.1 μM and 4 μM.  
     
     
         25 . The method of  claim 17 , wherein the effective amount is between 0.4 μM and 1 μM.  
     
     
         26 . A method of promoting the regression of vascular lesions, comprising introducing into a vascular cell an amount of the antisense oligonucleotide of  claim 3  effective to reduce the levels of bcl-xL protein produced, thereby promoting the regression of vascular lesions.  
     
     
         27 . The method of  claim 26 , wherein the introducing comprises using a lipid as a delivery agent.  
     
     
         28 . The method of  claim 26 , wherein the introducing comprises using porphyrin or lipofectin as a delivery agent.  
     
     
         29 . The method of  claim 26 , wherein the effective amount is between 0.1 μM and 4 μM.  
     
     
         30 . The method of  claim 26 , wherein the effective amount is between 0.4 μM and 1 μM.  
     
     
         31 . A pharmaceutical composition comprising an effective amount of the antisense oligonucleotide or analog thereof of  claim 3  and a pharmaceutically acceptable carrier.  
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the effective amount is between 0.1 μM and 4 μM.  
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein the effective amount is between 0.4 μM and 1 μM.  
     
     
         34 . The pharmaceutical composition of  claim 31 , wherein the oligonucleotide is encapsulated in a liposome or nanoparticle.  
     
     
         35 . The pharmaceutical composition of  claim 31 , wherein the pharmaceutical composition comprises tetra meso-(4-methylpyridyl)porphine or tetra meso-(anilinium)porphine or a combination thereof.