Method to inhibit cell growth using oligonucleotides

Abstract

Described are methods for treating hyperproliferative disorders, including cancers, by administering to the affected mammal (e.g., human) an effective amount of a composition comprising pTT or a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat. Methods of treatment or prevention of hyperproliferative diseases or pre-cancerous conditions affecting epithelial cells, such as psoriasis, atopic dermatitis, or hyperproliferative or UV-responsive dermatoses, hyperproliferative diseases of other epithelia and methods for reducing photoaging, or oxidative stress or for prophylaxis against or reduction in the likelihood of the development of skin cancer, are also disclosed.

1 . A method for treating a hyperproliferative disorder in a mammal, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         2 . The method of  claim 1 , wherein the mammal is a human.  
     
     
         3 . The method of  claim 1 , wherein the composition comprises one or more oligonucleotides selected from the group consisting of: 
 a) oligonucleotides 2-200 nucleotides long;    b) oligonucleotides 2-20 nucleotides long;    c) oligonucleotides 5-11 nucleotides long; and    d) oligonucleotides 2-5 nucleotides long.    
     
     
         4 . The method of  claim 1  wherein the composition comprises an oligonucleotide having nucleotide sequence pGAGTATGAG (SEQ ID NO:1), pGTTAGGGTTAG (SEQ ID NO:5), pGGGTTAGGGTT (SEQ ID NO:13), pTAGATGTGGTG (SEQ ID NO:14), or pTT.  
     
     
         5 . A method for inhibiting the growth of cancer cells in a human, comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         6 . The method of  claim 5  wherein the disorder is selected from the group consisting of lymphoma, osteosarcoma, melanoma, leukemia, cervical cancer, and squamous cell carcinoma.  
     
     
         7 . A method for promoting differentiation of malignant cells in a mammal, said method comprising administering to the mammal an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         8 . A method for enhancing the expression of one or more surface antigens indicative of differentiation of cancer cells in a human, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         9 . The method of  claim 8  wherein the cancer cells are melanoma cells.  
     
     
         10 . The method of  claim 8  wherein the antigen is MART-1, tyrosinase, TRP-1 or gp-100.  
     
     
         11 . The method of  claim 8  wherein the composition comprises pTT.  
     
     
         12 . The method of  claim 8  wherein the cancer cells are melanoma cells.  
     
     
         13 . A method for inducing apoptosis in cancer cells in a human, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         14 . The method of  claim 13  wherein the cancer cells are melanoma cells.  
     
     
         15 . A method for inhibiting the growth of cancer cells in a mammal, said method being independent of the presence or activity of telomerase in said cells, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         16 . A method for inhibiting the growth of cancer cells in a mammal, said method not requiring the presence or activity of p53 normal function in said cells, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n ,.  
     
     
         17 . A method for inhibiting the growth of cancer cells in a mammal, said method resulting in S-phase arrest in said cells, said method comprising administering to the human an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         18 . The method of  claim 17  wherein the composition comprises oligonucleotides less than 6 nucleotides long.  
     
     
         19 . A method for preventing spongiosis, blistering or dyskeratosis in the skin of a mammal, following exposure to ultraviolet light, said method comprising applying to the skin an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         20 . The method of  claim 19  wherein the composition comprises pGAGTATGAG (SEQ ID NO:1).  
     
     
         21 . The method of  claim 19  wherein the composition comprises pTT.  
     
     
         22 . A method for reducing the occurrence of skin cancer in a human, said method comprising applying to the skin an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         23 . The method of  claim 22  wherein the composition comprises pGAGTATGAG (SEQ ID NO:1).  
     
     
         24 . The method of  claim 22  wherein the composition comprises pTT.  
     
     
         25 . A method for reducing the occurrence of skin cancer in a human with xeroderma pigmentosum or other genetic predisposition to skin cancer, said method comprising administering to the skin an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         26 . The method of  claim 25  wherein the composition comprises pGAGTATGAG (SEQ ID NO:1).  
     
     
         27 . The method of  claim 25  wherein the composition comprises pTT.  
     
     
         28 . A method for enhancing repair of ultraviolet irradiation-induced damage to skin in a human, said method comprising applying to the skin an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         29 . The method of  claim 28  wherein the composition comprises pGAGTATGAG (SEQ ID NO:1).  
     
     
         30 . The method of  claim 28  wherein the composition comprises pTT.  
     
     
         31 . A method for reducing oxidative damage in a mammal, said method comprising administering to the mammal an effective amount of a composition comprising one or more oligonucleotides which share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         32 . The method of  claim 31  wherein the composition is administered to the skin.  
     
     
         33 . The method of  claim 31  wherein the composition comprises pGTTAGGGTTAG (SEQ ID NO:5).  
     
     
         34 . The method of  claim 31  wherein the composition comprises pTT.  
     
     
         35 . A method for treating melanoma in a mammal, comprising administering to the mammal an effective amount of a composition comprising one or more oligonucleotides that share at least 50% nucleotide sequence identity with (TTAGGG) n .  
     
     
         36 . The method of  claim 35  wherein the mammal is a human.  
     
     
         37 . The method of  claim 35  wherein the composition comprises pGTTAGGGTTAG (SEQ ID NO:5).  
     
     
         38 . The method of  claim 35  wherein the composition comprises pTT.  
     
     
         39 . A method for reducing proliferation of keratinocytes in the skin of a human, said method comprising administering to the skin an effective amount of a composition comprising one or more oligonucleotides that share at least 50% nucleotide sequence identity with the human telomere overhang repeat.  
     
     
         40 . The method of  claim 39 , wherein the human has seborrheic keratosis, actinic keratosis, Bowen's disease, squamous cell carcinoma, or basal cell carcinoma.  
     
     
         41 . The method of  claim 39 , wherein the composition comprises pGTTAGGGTTAG (SEQ ID NO:5).  
     
     
         42 . The method of  claim 39 , wherein the composition comprises pTT.  
     
     
         43 . A composition comprising an oligonucleotide and a physiologically acceptable carrier, wherein the oligonucleotide is pGAGTATGAG (SEQ ID NO:1), pCATAC (SEQ ID NO:6), pGTTAGGGTTAG (SEQ ID NO:5), pGGGTTAGGGTT (SEQ ID NO:13), orpTAGATGTGGTG (SEQ ID NO:14).  
     
     
         44 . A method of inhibiting proliferation of epithelial cells in a mammal, comprising administering to the epithelial cells an effective amount of a composition comprising at least one oligonucleotide, wherein the oligonucleotide comprises a base sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12, and a contiguous portion of any of the foregoing sequences.  
     
     
         45 . The method of  claim 44 , wherein the oligonucleotide is single-stranded.  
     
     
         46 . The method of  claim 44 , wherein the oligonucleotide comprises a 5′ phosphate.  
     
     
         47 . The method of  claim 44 , wherein the composition comprises oligonucleotide is at a concentration of about 1 μM to about 500 μM.  
     
     
         48 . The method of  claim 44 , wherein said oligonucleotide is ultraviolet-irradiated.  
     
     
         49 . The method of  claim 44 , wherein the composition comprises oligonucleotide in liposomes.  
     
     
         50 . The method of  claim 44 , wherein the composition comprises propylene glycol.  
     
     
         51 . The method of  claim 44 , wherein the composition is administered orally.  
     
     
         52 . The method of  claim 44 , wherein the composition is administered by aerosol.  
     
     
         53 . The method of  claim 44 , wherein the mammal is a human.  
     
     
         54 . The method of  claim 44 , wherein the epithelial cells are carcinoma cells.  
     
     
         55 . A method of preventing or reducing DNA damage in cells of a mammal, wherein said DNA damage is caused by radiation or DNA-damaging chemicals, comprising contacting said cells with an effective amount of a composition comprising at least one oligonucleotide, wherein the oligonucleotide comprises a base sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQED NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12, and a contiguous portion of any of the foregoing sequences.  
     
     
         56 . The method of  claim 55 , wherein the cells are epithelial cells.  
     
     
         57 . The method of  claim 55 , wherein said oligonucleotide is single-stranded.  
     
     
         58 . The method of  claim 55 , wherein the oligonucleotide comprises a 5′ phosphate.  
     
     
         59 . The method of  claim 55 , wherein the composition comprises the oligonucleotide at a concentration of about 1 μM to about 500 μM.  
     
     
         60 . The method of  claim 55 , wherein the composition comprises a physiologically acceptable carrier.  
     
     
         61 . A composition comprising an oligonucleotide and a physiologically acceptable carrier, wherein the oligonucleotide comprises a base sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12.  
     
     
         62 . The composition of  claim 61 , wherein the oligonucleotide comprises a 5′ phosphate.  
     
     
         63 . The composition of  claim 61  which comprises more than one oligonucleotide.