Tumor radiosensitization and /or chemopotentiation using isocoumarin derivatives

Abstract

A method for enhancing the efficacy of chemotherapy and/or radiation in the treatment of cancer in animals, particularly humans, is provided wherein certain isocoumarin derivatives which exhibit unique radiosensitization activity and/or chemopotentiation properties are employed in a combination treatment with ionizing radiation and/or chemotherapy.

1 . A method for inhibiting the growth of an endothelial cell comprising a contacting said endothelial cell with an isocoumarin derivative of the formula:  
       
         
           
           
               
               
           
         
         wherein each of X 1 , X 2  and X 3  is independently sulfur or oxygen; X 4  is sulfur, oxygen or an —NH— group; R 1  is hydrogen or C 1-6  alkyl; and R 2  and R 3  may be the same or different and each represents C 1-6  alkyl, and C 7-10  alkaryl, hydroxy or hydrogen; and n is zero on a whole integer of 1 to 3; and  
         (b) further contacting said tumor cell with a chemotherapeutic agent,  
         wherein said dose of isocoumarin derivative, when combined with said dose chemotherapeutic agent is effective to inhibit the growth of said endothelial cell in an enhanced effect relative to administration of said isocoumarin derivative or said chemotherapeutic agent alone.  
       
     
     
         2 . The method of  claim 1 , 
 wherein the isocoumarin derivative comprises a compound of the formula given in  claim 1 , wherein X 1 , X 2  and X 3  each are oxygen; X 4  is oxygen or sulfur; R 1  is C 1-3  alkyl; R 2  and R 3  are each independently selected from hydrogen and C 1-6  alkyl and n is 0, 1 or 2.    The method of  claim 2 ,    wherein the isocoumarin derivative has the formula:                          wherein R 1  is C 1-3  alkyl and R 2  and R 3  each represents hydrogen or C 1-6  alkyl and n is 0 or 1.    
     
     
         3 . The method of  claim 1 , 
 wherein the tumor cell is contacted with the isocoumarin derivative and a chemotherapeutic agent selected from a Tubulin interactive or a DNA-interactive agent or an antimetabolite.    
     
     
         4 . The method of  claim 3 , 
 wherein the chemotherapeutic agent is a Tubulin interactive agent.    
     
     
         5 . The method of  claim 4 , 
 wherein the Tubulin interactive agent is a Paclitaxel.    
     
     
         6 . The method of  claim 3 , 
 wherein the chemotherapeutic agent is a DNA-interactive agent.    
     
     
         7 . The method of  claim 6 , 
 wherein the DNA-interactive agent is cyclophosphamide.    
     
     
         8 . The method of  claim 3 , 
 wherein the chemotherapeutic agent is an antimetabolite.    
     
     
         9 . The method of  claim 8 , 
 wherein the antimetabolite is 5-fluorouracil.    
     
     
         10 . A method for treating cancer in a human patient comprising administering an isocoumarin derivative of the formula given in  claim 1  to said human patient and administering a chemotherapeutic agent as a second treatment modality, wherein said cancer is sensitive to the administration of said isocoumarin derivative when combined with the second treatment modality, and wherein such administration effects an enhanced treatment of said cancer relative to either said isocoumarin derivative or said shemotheraputic agent as a single modality.  
     
     
         11 . The method of  claim 10 , 
 wherein the isocoumarin derivative comprises a compound of the formula given in  claim 1 , wherein X 1 , X 2  and X 3  each are oxygen; X 4  is oxygen or sulfur, R 1  is C 1-3  alkyl; and R 2  and R 3  are each dependently selected from hydrogen and C 1-6  alkyl.    
     
     
         12 . The method of  claim 11 , 
 wherein the isocoumarin derivative has the formula:                          wherein R 1  is C 1-3  alkyl and R 2  and R 3  each represents hydrogen or C 1-6  alkyl and n is 0 or 1.    
     
     
         13 . The method of  claim 10 , 
 wherein the chemotherapeutic agent is selected from a Tubulin interactive agent, a DNA-interactive agent, and an antimetabolite.    
     
     
         14 . The method of  claim 13 , 
 wherein the chemotherapeutic agent is a Tubulin interactive agent.    
     
     
         15 . The method of  claim 14 , 
 wherein the Tubulin interactive agent is a Paclitaxel.    
     
     
         16 . The method of  claim 10 , 
 wherein the chemotherapeutic agent is a DNA-interactive agent.    
     
     
         17 . The method of  claim 16 , 
 wherein the DNA-interactive agent is cyclophosphamide.    
     
     
         18 . The method of  claim 10 , 
 wherein the chemotherapeutic agent is an antimetabolite.    
     
     
         19 . The method of  claim 18 , 
 wherein the antimetabolite is 5-fluorouracil.    
     
     
         20  The method of  claim 10 , wherein said tumor is selected from the group consisting of skin cancer, prostate cancer, lung cancer, brain cancer cell, breast cancer, ovarian cancer, cervical cancer, liver cancer, pancreatic cancer, colon cancer, stomach cancer and leukemia.