Compositions and methods for treating neoplastic diseases

Abstract

Disclosed herein are compositions and methods for treating neoplastic diseases. Included are compositions and methods that are effective against multiple myeloma cells resistant to conventional and bortezomib treatment. Furthermore, combination treatment with two different proteosome inhibitors is shown to be synergistic for treating multiple myeloma.

What is claimed is: 
     
         1 . A method of treating a neoplastic disease, comprising:
 administering to a patient inflicted with the neoplastic disease a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:   
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine, and 
         wherein the neoplastic disease is susceptible to resistance to at least one other chemotherapeutic agent. 
       
     
     
         2 . The method of  claim 1 , wherein X is chlorine. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) has the structure of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the neoplastic disease is cancer. 
     
     
         5 . The method of  claim 4 , wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. 
     
     
         6 . The method of  claim 5 , wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma. 
     
     
         7 . The method of  claim 6 , wherein the cancer is a multiple myeloma. 
     
     
         8 . The method of  claim 1 , wherein the patient is a human. 
     
     
         9 . The method of  claim 1 , wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide. 
     
     
         10 . The method of  claim 1 , wherein the other chemotherapeutic agent is a proteosome inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the other chemotherapeutic agent is bortezomib. 
     
     
         12 . A method of treating a neoplastic disease, comprising administering to a patient inflicted with the neoplastic disease a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine, in combination with at least one additional chemotherapeutic agent. 
       
     
     
         13 . The method of  claim 12 , wherein X is chlorine. 
     
     
         14 . The method of  claim 12 , wherein the compound of formula (I) has the structure of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 12 , wherein the neoplastic disease is cancer. 
     
     
         16 . The method of  claim 15 , wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma. 
     
     
         18 . The method of  claim 17 , wherein the cancer is a multiple myeloma. 
     
     
         19 . The method of  claim 12 , wherein the patient is a human. 
     
     
         20 . The method of  claim 12 , wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide. 
     
     
         21 . The method of  claim 12 , wherein the other chemotherapeutic agent is a proteosome inhibitor. 
     
     
         22 . The method of  claim 21 , wherein the other chemotherapeutic agent is bortezomib. 
     
     
         23 . The method of  claim 12 , wherein the combination is synergistic. 
     
     
         24 . The method of  claim 12 , wherein the combination is additive. 
     
     
         25 . A pharmaceutical composition, comprising:
 a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:   
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine; and
 at least one additional chemotherapeutic agent. 
 
     
     
         26 . The composition of  claim 25 , wherein X is chlorine. 
     
     
         27 . The composition of  claim 25 , wherein the compound of formula (I) has the structure of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         28 . The composition of  claim 25 , wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide. 
     
     
         29 . The composition of  claim 25 , wherein the other chemotherapeutic agent is a proteosome inhibitor. 
     
     
         30 . The composition of  claim 29 , wherein the other chemotherapeutic agent is bortezomib. 
     
     
         31 . A method of treating a neoplastic disease, comprising administering to a patient inflicted with the neoplastic disease a synergistic combination of at least two proteosome inhibitors. 
     
     
         32 . The method of  claim 31 , wherein the neoplastic disease is cancer. 
     
     
         33 . The method of  claim 32 , wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. 
     
     
         34 . The method of  claim 33 , wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma. 
     
     
         35 . The method of  claim 34 , wherein the cancer is a multiple myeloma. 
     
     
         36 . The method of  claim 31 , wherein the patient is a human. 
     
     
         37 . The method of  claim 31 , wherein at least one of the proteosome inhibitors is selected from the group consisting of bortezomib and the compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine.