Reduction of Toxicity of Multi-Targeting Antifolates

Abstract

The use of tetrahydrofolate, methylene-tetrahydrofolate and/or methyl-tetrahydrofolate, and at least one multi-targeting antifolate, for the manufacture of a pharmaceutical composition for the treatment of cancer is disclosed. By combining the multi-targeting anti-folate with tetrahydrofolate, methylene-tetrahydrofolate and/or methyl-tetrahydrofolate, it is possible to remarkably reduce toxic side-effects without diminishing the anti-tumour action of the drugs. A pharmaceutical composition, a kit comprising the pharmaceutical composition as well as a method for the treatment of cancer are also disclosed.

1 . Use of at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate, and at least one multi-targeting antifolate, for the manufacture of a pharmaceutical composition for the treatment of cancer.  
   
   
       2 . Use according to  claim 1 , wherein at least 60% by weight of said THF, methyl-THF and/or methylene-THF is in the form of a biologically active isomer.  
   
   
       3 . Use according to  claim 1 , wherein said multi-targeting antifolate is selected from the group consisting of premetrexed, raltitrexed, and lometrexol.  
   
   
       4 . Use according to  claim 1 , wherein said pharmaceutical composition further comprises at least one chemotherapeutic agent selected from the group consisting of anthracyclines, platinum derivatives, topoisomerase inhibitors, and antimetabolites.  
   
   
       5 . Use according to  claim 1 , wherein said tetrahydrofolate, methylene-tetrahydrofolate and/or methyl-tetrahydrofolate, and said at least one multi-targeting antifolate, are formulated in different pharmaceutical compositions.  
   
   
       6 . Use according to  claim 1 , wherein said at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate, and said at least one multi-targeting antifolate, are formulated in a common pharmaceutical composition.  
   
   
       7 . Use according to  claim 1 , wherein said cancer is selected from the group consisting of breast cancer, gastric cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, head and neck cancer, and mesotheolioma cancer.  
   
   
       8 . A pharmaceutical composition comprising at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate, and at least one multi-targeting antifolate.  
   
   
       9 . A pharmaceutical composition according to  claim 8 , wherein at least 60% by weight of said at least one of THF, methyl-THF and methylene-THF is in the form of a biologically active isomer.  
   
   
       10 . A pharmaceutical composition according to  claim 8 , wherein said multi-targeting antifolate is selected from the group consisting of premetrexed, raltitrexed, and lometrexol.  
   
   
       11 . A pharmaceutical composition according to  claim 8 , further comprising at least one chemotherapeutic agent selected from the group consisting of anthracyclines, platinum derivatives, topoisomerase inhibitors, and antimetabolites.  
   
   
       12 . A pharmaceutical composition according to  claim 8 , wherein said at least one of tetrahydrofolate, said methylene-tetrahydrofolate and said methyl-tetrahydrofolate, and said at least one multi-targeting antifolate, are formulated in different pharmaceutical compositions.  
   
   
       13 . A pharmaceutical composition according to  claim 8 , wherein said at least one of tetrahydrofolate, said methylene-tetrahydrofolate and said methyl-tetrahydrofolate, and said at least one multi-targeting antifolate, are formulated in a common pharmaceutical composition.  
   
   
       14 . A kit comprising a pharmaceutical composition comprising at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate, and a pharmaceutical composition comprising at least one multi-targeting antifolate.  
   
   
       15 . A kit according to  claim 14 , wherein at least 60% by weight of said at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate is in the form of a biologically active isomer.  
   
   
       16 . A kit according to  claim 14 , further comprising a pharmaceutical composition comprising at least one chemotherapeutic agent selected from the group consisting of anthracyclines, platinum derivatives, topoisomerase inhibitors, and antimetabolites.  
   
   
       17 . A method for the treatment of cancer comprising administering to a patient a pharmaceutically active amount of at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate, and a pharmaceutically active amount of at least one multi-targeting antifolate.  
   
   
       18 . A method according to  claim 17 , wherein at least 60% by weight of said at least one of tetrahydrofolate, methylene-tetrahydrofolate and methyl-tetrahydrofolate is in the form of a biologically active isomer.  
   
   
       19 . A method according to  claim 17 , wherein said multi-targeting antifolate is selected from the group consisting of premetrexed, raltitrexed, and lometrexol.  
   
   
       20 . A method according to  claim 17 , further comprising administering a pharmaceutically active amount of a chemoterapeutic agent selected from the group consisting of anthracyclines, platinum derivatives, topoisomerase inhibitors, and antimetabolites.