Treatment of drug resistant proliferative diseases with telomerase mediated telomere altering compounds

Abstract

The described invention is directed toward pharmaceutical compositions and methods of using 6-mercaptopurine ribosides and analogues thereof for the treatment of cancer and other hyperproliferative diseases. The described compounds can be converted into telomere substrates in vivo and can be recognized by telomerase for incorporation into telomeres of telomerase active cells, leading to induction of cell death of the telomerase active cells.

What is claimed is: 
     
         1 . A method for treating a resistant or refractory cancer exhibiting pronounced telomerase activity, the patient population being characterized by relapse of the cancer within six months of a first line anti-cancer agent (resistant) or no response to the first-line anticancer agent treatment (refractory), the method comprising administering to the subject
 (a) a first amount or dose of a 6-mercaptopurine deoxyribonucleoside analogue selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       where R 1  is —C(O)(CH 2 ) n CH 3  where n=6-16, and pharmaceutically acceptable salts or polymorphs thereof; and 
       where R 2  is spermine or spermidine and pharmaceutically acceptable salts or polymorphs thereof; and
 (b) a second amount or dose of an anti-cancer agent, 
 
       wherein the first and second amounts or doses together comprise a therapeutically effective amount of a combination; 
       wherein the combination is effective to:
 (i) shorten telomere length; 
 (ii) reduce size of a tumor; 
 (iii) reduce growth rate of a tumor; 
 (iv) reduce incidence of metastasis; 
 (v) promote an immune response; 
 (vi) reduce progression of the cancer; 
 (vii) increase lifespan of the subject; or 
 (viii) a combination thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein the cancer is a carcinoma, a sarcoma, a leukemia, a lymphoma/myeloma or a brain/spinal cord cancer. 
     
     
         3 . The method according to  claim 1 , wherein the cancer comprises a solid tumor comprising tumor cells, a metastatic cancer comprising metastatic tumor cells, or a combination thereof. 
     
     
         4 . The method according to  claim 1 , wherein the 6-mercaptopurine ribonucleoside analogue is 6-thio-2′-deoxyguanosine. 
     
     
         5 . The method according to  claim 1 , wherein the amount or dose of the 6-mercaptopurine ribonucleoside analogue is about 0.5 mg/kg to about 3 mg/kg. 
     
     
         6 . The method according to  claim 1 , wherein the combination is administered intravenously or orally. 
     
     
         7 . The method according to  claim 1 , wherein the combination is administered by intratumoral injection. 
     
     
         8 . The method according to  claim 1 , wherein the subject is a human being. 
     
     
         9 . The method according to  claim 1 , wherein the anticancer agent of the second amount or dose is the first-line anticancer agent to which the cancer is refractory or resistant. 
     
     
         10 . The method according to  claim 1 , wherein the combination produces an additive effect. 
     
     
         11 . The method according to  claim 1 , wherein the combination produces a synergistic effect. 
     
     
         12 . The method according to  claim 1 , wherein the anti-cancer agent is selected from the group consisting of an alkylating agent, an antimetabolite agent, an anti-folate agent, a pyrmidine analog, a purine analog, an antimitotic agent, an epipodophyllotoxin agent; a camptothecin analog, an antibiotic agent, a biologic agent, an antiestrogen agent; a GnRH analog, an androgen analog, a somatostatin analog, a kinase inhibitor; an agent that forms a platinum coordination complex, and EDTA derivative; a platelet-reducing agent, a retinoid, and a histone deacetylase inhibitor. 
     
     
         13 . A method for treating a resistant or refractory cancer in a subject, the resistant or refractory cancer comprising one or more cells characterized by:
 (i) a less than a 4 fold change in one or more of the genes listed in TABLE III, relative to the level of expression in one or more of cell lines H1792, HCC44, HCC4017, H2887, H358, H2009, HCC827, H2347, H2291, H1975, H1373, H2258, H2250, HCC4006, H2087, HCC193, H820, H441, HCC1897, HCC2450, HCC1195, H1666, Calu3, H2122, H647, H1437, PC 9, H1770, HCC1359, HCC461, H157, H2882, H920, H1944, A549, H460, H2073, H1395, HCC2108, HCC15, H1651, HCC366, H1355, HCC1313, HCC2814, HCC95, HCC4018, H1755, H520, H661, Calu6, H125, H1299, HCC2429, H1155; and   (ii) a greater than −2 fold change in one or more of the genes listed in TABLE IV, relative to the level of expression in one or more of cell lines H1792, HCC44, HCC4017, H2887, H358, H2009, HCC827, H2347, H2291, H1975, H1373, H2258, H2250, HCC4006, H2087, HCC193, H820, H441, HCC1897, HCC2450, HCC1195, H1666, Calu3, H2122, H647, H1437, PC 9, H1770, HCC1359, HCC461, H157, H2882, H920, H1944, A549, H460, H2073, H1395, HCC2108, HCC15, H1651, HCC366, H1355, HCC1313, HCC2814, HCC95, HCC4018, H1755, H520, H661, Calu6, H125, H1299, HCC2429, H1155;   the method comprising administering to the subject:   (a) an amount or dose of a 6-mercaptopurine deoxyribonucleoside analogue selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       where R 1  is —C(O)(CH 2 ) n CH 3  where n=6-16, and pharmaceutically acceptable salts or polymorphs thereof; and 
       where R 2  is spermine or spermidine and pharmaceutically acceptable salts or polymorphs thereof; 
       wherein the amount or dose of the 6-mercaptopurine deoxyribonucleoside analogue is effective to:
 (i) shorten telomere length; 
 (ii) reduce size of a tumor; 
 (iii) reduce growth rate of a tumor; 
 (iv) reduce incidence of metastasis; 
 (v) promote an immune response; 
 (vi) reduce progression of the cancer; 
 (vii) increase lifespan of the subject; or 
 (viii) a combination thereof. 
 
     
     
         14 . The method according to  claim 13 , wherein the cancer is a carcinoma, a sarcoma, a leukemia, a lymphoma/myeloma or a brain/spinal cord cancer. 
     
     
         15 . The method according to  claim 13 , wherein the cancer comprises a solid tumor comprising tumor cells, a metastatic cancer comprising metastatic tumor cells, or a combination thereof. 
     
     
         16 . The method according to  claim 13 , wherein the 6-mercaptopurine ribonucleoside analogue is 6-thio-2′-deoxyguanosine. 
     
     
         17 . The method according to  claim 13 , wherein the amount or dose of the 6-mercaptopurine ribonucleoside analogue is about 0.5 mg/kg to about 3 mg/kg. 
     
     
         18 . The method according to  claim 13 , wherein the combination is administered intravenously or orally. 
     
     
         19 . The method according to  claim 13 , wherein the subject is a human being.