Methods and compositions for treating cancer

Abstract

Pharmaceutical compositions and kits useful for the treatment of cancer include certain alkyl esters of cystine and certain alkyl-substituted cystamine derived esters, including, for example, cystine dimethyl ester and a di-alkyl peptidyl cystamine ester, among others. These compounds may be employed in methods of treating cancers or methods of determining sensitivity of certain cancer cells to apoptosis alone, or in combination with other chemotherapeutic, radiological or apoptotic agents.

1 . A pharmaceutical composition useful for the treatment of cancer comprising a compound selected from the formula consisting of  
     
       
         
         
             
             
         
       
     
     wherein for either formula (a) and (b), R 1  is a substituted or unsubstituted lower alkyl of 1 to 10 carbon atoms, X is a naturally-occurring or non-naturally-occurring amino acid, and m is an integer of 0 to 20 and wherein for formula (b), n is an integer of 1 or 2, and q is an integer of 0 or 1, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.  
   
   
       2 . The composition according to  claim 1 , wherein X m  of formula (a) is  
     
       
         
         
             
             
         
       
     
     wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19.  
   
   
       3 . The composition according to  claim 1 , wherein X m  of formula (a) is  
     
       
         
         
             
             
         
       
     
     wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19.  
   
   
       4 . The composition according to  claim 1 , which is selected from the group consisting of: 
 i. said formula (a), wherein m is 0;    ii. said formula (a), wherein m is 0, said R 1  is a methyl group, and said compound is cystine dimethyl ester;    iii. said formula (a), wherein X m  of formula (a) is                          wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19, X is selected from the group consisting of D-Asp, L-Asp, D-Glu and L-Glu, and m is 1;    iv. said formula (b) wherein X m  of formula (a) is                          wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19, X is selected from the group consisting of D-Asp, L-Asp, D-Glu and L-Glu, and m is    v. said formula (a), wherein X m  of formula (a) is                          wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19, wherein X is selected from the group consisting of D-Asp, L-Asp, D-Glu and L-Glu, and m is 1,    vi. said formula (b), wherein X m , of formula (a) is                          wherein n is an integer of 1 or 2, and q is an integer of 0 or 1, and s is an integer of 0 to 19, wherein X is selected from the group consisting of D-Asp, L-Asp, D-Glu and L-Glu, and m is 1;    vii. said formula (b), wherein q is 1 and m is 0;    viii. said formula (b) wherein R 1  is a methyl group,    ix. said formula (b), wherein m is an integer from 1 to 10; and    x. said formula (b), wherein m is 1.    
   
   
       5 - 10 . (canceled)  
   
   
       11 . The composition according to  claim 1 , comprising at least one compound of formula (a) and at least one compound of formula (b).  
   
   
       12 . The composition according to  claim 1 , further comprising a cytotoxic compound.  
   
   
       13 . The composition according to  claim 12 , wherein said cytotoxic compound is an apoptotic compound or a chemotherapeutic compound.  
   
   
       14 . (canceled)  
   
   
       15 . The composition according to  claim 1 , wherein said compound of Formula (a) or (b) upon exposure to a susceptible cell increases the cell's intralysosomal cystine level above 0.5 nmol/mg cell protein.  
   
   
       16 . (canceled)  
   
   
       17 . A method of treating or preventing the development of cancer in a mammalian subject comprising treating cancer cells of said subject with a composition of  claim 1 .  
   
   
       18 . The method according to  claim 17 , wherein said treating comprises administering said composition in vivo or ex vivo.  
   
   
       19 - 20 . (canceled)  
   
   
       21 . The method according to  claim 17 , further comprising treating said subject, or exposing said subject to, a cytotoxic agent, at a time selected from the group consisting of before treatment with a pharmaceutical composition useful for the treatment of cancer comprising a compound selected from the formula consisting of  
     
       
         
         
             
             
         
       
     
     wherein for either formula (a) and (b), R 1  is a substituted or unsubstituted lower alkyl of 1 to 10 carbon atoms, X is a naturally-occurring or non-naturally-occurring amino acid, and m is an integer of 0 to 20 and wherein for formula (b), n is an integer of 1 or 2, and q is an integer of 0 or 1, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, after treatment with said pharmaceutical composition, and concurrently with treatment with said pharmaceutical composition.  
   
   
       22 . The method according to  claim 21 , wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, an apoptotogen and radiation.  
   
   
       23 . The method according to  claim 17 , wherein said treating comprises administering said composition to said subject at a dosage of from 1.0 μg to 500 mg/kg patient body weight.  
   
   
       24 . (canceled)  
   
   
       25 . The method according to  claim 17 , wherein said compound is selected from the group consisting of a compound of formula (a) which is a is cystine dimethyl ester and a compound of formula (b), which is aspartyl-cystamine dimethyl ester.  
   
   
       26 . (canceled)  
   
   
       27 . A method of determining sensitivity of cancer cells to apoptosis comprising: contacting said cancer cells in culture with a pharmaceutically effective amount of a composition of  claim 1  and measuring the rate of apoptosis in said culture.  
   
   
       28 . A pharmaceutical kit for the treatment of cancer comprising at least one composition of  claim 1  in a dosage unit.  
   
   
       29 . The kit according to  claim 28 , further comprising at least one compound of formula (a) and at least one compound of formula (b).  
   
   
       30 . The kit according to  claim 28 , wherein said compound of formula (a) is cystine dimethyl ester.  
   
   
       31 . The kit according to  claim 28 , wherein said compound of formula (b) is an aspartyl-cystamine dimethyl ester.  
   
   
       32 . The kit according to  claim 28 , further comprising a cytotoxic compound.