Treatment for cancer

Abstract

The present invention provides methods for the treatment of tumors, comprising administration of an effective amount of at least one taxoid and an effective amount of at least one benzimidazol carbamate compound of formula (I). The invention also provides a method for the treatment of tumors insensitive to one or more anti-mitotic drugs, the method comprising administering an effective amount of at least one benzimidazole carbamate compound of formula (I). Also provide are compositions for carrying out methods of the invention.

1 . A method for the treatment of a tumor in a subject, the method comprising administering to the subject an effective amount of at least one taxoid and an effective amount of at least one benzimidazole carbamate compound of formula I: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 2  is selected from H, or substituted or unsubstituted alkyl; 
       R 3  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6-membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, —SR 14 , —OR 15 , —SOR 16 , —SO 2 R 17 , —SCN, —C(O)—R 18 , —OR 19 , NR 20 COOR 21 , where R 15  to R 21  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or arylalkyl; 
       or a metabolite, derivative or analog thereof and; 
       wherein the administration of the taxoid and benzimidazole carbamate has an additive and/or synergistic anti-tumor effect. 
     
   
   
       2 . The method of  claim 1  wherein the R 1  substitution occurs in the 5 or 6 position. 
   
   
       3 . The method of  claim 1  wherein the benzimidazole carbamate compound is a compound of Formula II: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11 , or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 21  is H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloakenylalkyl, aryl or arylalkyl. 
     
   
   
       4 . The method of  claim 1  wherein the benzimidazole carbamate compound is a compound of Formula III: 
     
       
         
         
             
             
         
       
       wherein R1 is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4. 
     
   
   
       5 . The method of  claim 1  wherein the benzimidazole carbamate compound is selected from the group consisting of albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole. 
   
   
       6 . The method of  claim 5  wherein the benzimidazole carbamate compound is albendazole, or a metabolite, derivative or analog thereof. 
   
   
       7 . The method of  claim 1  wherein the taxoid is paclitaxel, docataxel, or a metabolite, derivative or analog thereof. 
   
   
       8 . The method of  claim 1  wherein the tumor is a liver, ovarian, colorectal, lung, small cell lung, breast, prostate, pancreatic, renal, gastric, endometrial, esophageal, head or neck tumor, peritoneal carcinomatosis, leukemia, lymphoma, sarcoma, or secondary metastases thereof. 
   
   
       9 . The method of  claim 1  wherein the tumor is insensitive to treatment with one or more antimitotic drugs. 
   
   
       10 . The method of  claim 9  wherein the one or more antimitotic drugs are selected from a taxoid, a Vinca alkaloid and a colchicinoid. 
   
   
       11 . The method of  claim 9  wherein the tumor is a taxoid-insensitive the tumor. 
   
   
       12 . The method of  claim 1  wherein the taxoid and the benzimidazole carbamate compound are administered simultaneously. 
   
   
       13 . The method of  claim 1  wherein the taxoid and the benzimidazole carbamate compound are administered sequentially. 
   
   
       14 . The method of  claim 1  wherein the taxoid and the benzimidazole carbamate are administered systemically. 
   
   
       15 . A method for the treatment of a tumor in a subject, the method comprising administering to the subject an effective amount of paclitaxel and an effective amount of albendazole wherein the administration of paclitaxel and albendazole has an additive and/or synergistic anti-tumor effect. 
   
   
       16 . A method for the treatment of a taxoid-insensitive tumor in a subject, the method comprising systemically administering to the subject paclitaxel and an effective amount of albendazole wherein the administration of paclitaxel and albendazole has an additive and/or synergistic anti-tumor effect. 
   
   
       17 . The method of  claim 16  wherein the paclitaxel is administered in an amount ineffective to treat the tumor if administered alone. 
   
   
       18 . A pharmaceutical composition for the treatment and/or prevention of cancer comprising a synergistic combination of at least one taxoid and at least one benzimidazole carbamate compound of formula I: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 2  is selected from H, or substituted or unsubstituted alkyl; 
       R 3  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6-membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, —SR 14 , —OR 15 , —SOR 16 , —SO 2 R 17 , —SCN, —C(O)—R 18 , —OR 19 , NR 20 COOR 21 , where R 15  to R 21  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or arylalkyl; 
       or a metabolite, derivative or analog thereof. 
     
   
   
       19 . The composition of  claim 18  wherein the R 1  substitution occurs in the 5 or 6 position. 
   
   
       20 . The composition of  claim 18  wherein the benzimidazole carbamate compound is a compound of Formula II: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 21  is H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloakenylalkyl, aryl or arylalkyl. 
     
   
   
       21 . The composition of  claim 18  wherein the benzimidazole carbamate compound is a compound of Formula III: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4. 
     
   
   
       22 . The composition of  claim 18  wherein the benzimidazole carbamate compound is selected from the group consisting of albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole. 
   
   
       23 . The composition of  claim 22  wherein the benzimidazole carbamate compound is albendazole, or a metabolite, derivative or analog thereof. 
   
   
       24 . The composition of  claim 18  wherein the taxoid is paclitaxel, docataxel, or a metabolite, derivative or analog thereof. 
   
   
       25 . A pharmaceutical composition comprising a synergistic combination of paclitaxel and albendazole. 
   
   
       26 . The composition of  claim 18  or  25  further comprising one or more pharmaceutically acceptable carriers, adjuvants or diluents. 
   
   
       27 . A composition for the treatment of a tumor in a subject, the composition comprising a synergistic combination of at least one taxoid and at least one benzimidazole carbamate compound of formula I. 
   
   
       28 . The composition of  claim 27  wherein the benzimidazole carbamate compound is albendazole, or a metabolite, derivative or analog thereof. 
   
   
       29 . The composition of  claim 27  wherein the taxoid is paclitaxel, docataxel, or a metabolite, derivative or analog thereof. 
   
   
       30 . The composition of  claim 27  wherein the tumor is a liver, ovarian, colorectal, lung, small cell lung, breast, prostate, pancreatic, renal, gastric, endometrial, esophageal, head or neck tumor, peritoneal carcinomatosis, leukemia, lymphoma, sarcoma or secondary metastases thereof. 
   
   
       31 . The composition of  claim 27  wherein the tumor is insensitive to treatment with one or more antimitotic drugs. 
   
   
       32 . The composition of  claim 31  wherein the one or more antimitotic drugs are selected from a taxoid, a Vinca alkaloid and a colchicine. 
   
   
       33 . The composition of  claim 31  wherein the tumor is a taxoid-insensitive tumor. 
   
   
       34 . A composition for the treatment of a taxoid-insensitive tumor in a subject, the composition comprising paclitaxel and albendazole. 
   
   
       35 . A method for the treatment of a tumor in a subject, the method comprising administering to the subject an effective amount of a composition according to any one of  claim 18 ,  25 ,  27  or  34 . 
   
   
       36 . (canceled) 
   
   
       37 . A method for the treatment of a tumor in a subject, wherein the tumor is insensitive to one or more anti-mitotic drugs, the method comprising administering to the subject an effective amount of at least one benzimidazole carbamate compound of formula I: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 2  is selected from H, or substituted or unsubstituted alkyl; 
       R 3  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6-membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, —SR 14 , —OR 15 , —SOR 16 , —SO 2 R 17 , —SCN, —C(O)—R 18 , —OR 19 , NR 20 COOR 21 , where R 15  to R 21  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or arylalkyl; 
       or a metabolite, derivative or analog thereof. 
     
   
   
       38 . The method of  claim 37  wherein the R 1  substitution occurs in the 5 or 6 position. 
   
   
       39 . The method of  claim 37  wherein the benzimidazole carbamate compound is a compound of Formula II: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4; 
       R 21  is H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloakenylalkyl, aryl or arylalkyl. 
     
   
   
       40 . The method of  claim 37  wherein the benzimidazole carbamate compound is a compound of Formula III: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, —SR 7 , —SOR 8 , —SO 2 R 9 , —SCN, B′(CH 2 ) n BR 10 , —C(O)—R 11  or —OR 12 , COOR 13 , —NO 2 , NR 13a COOR 13b , isothiocyanato, or —CN where R 7  to R 13b  are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B′ are independently selected from O, S, S(O) or SO 2  and n is 1 to 4. 
     
   
   
       41 . The method of  claim 37  wherein the benzimidazole carbamate compound is selected from the group consisting of albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole. 
   
   
       42 . The method of  claim 41  wherein the benzimidazole carbamate compound is albendazole, or a metabolite, derivative or analog thereof. 
   
   
       43 . The method of  claim 37  wherein the tumor is insensitive to one or more of a taxoid, a Vinca alkaloid and a colchicinoid. 
   
   
       44 . The method of  claim 43  wherein the tumor is insensitive to paclitaxel. 
   
   
       45 . The method of  claim 43  wherein the tumor is insensitive to vincristine. 
   
   
       46 . The method of  claim 43  wherein the tumor is insensitive to colchicine. 
   
   
       47 . The method of  claim 37  wherein the tumor is a liver, ovarian, colorectal, lung, small cell lung, breast, prostate, pancreatic, renal, gastric, endometrial, esophageal, head or neck tumor, peritoneal carcinomatosis, leukemia, lymphoma, sarcoma, or secondary metastases thereof. 
   
   
       48 . (canceled)