Therapeutics for cancer using 3-bromopyruvate and other selective inhibitors of atp production

Abstract

The present invention relates to methods of treating a cancerous tumor using selective inhibitors of ATP production. The present invention also relates to pharmaceutical preparations comprising such inhibitors and methods for administering them intraarterially directly to a tumor, as well as methods for identifying compositions that selectively inhibitor ATP production for use in the invention.

1 . A method of treating cancer in a subject comprising administering to the subject an effective amount of a 3-halopyruvate. 
   
   
       2 . The method of  claim 1 , wherein the 3-halopyruvate is selected from the group consisting of: 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate and 3-iodopyruvate. 
   
   
       3 . The method of  claim 1 , wherein the 3-halopyruvate is 3-bromopyruvate. 
   
   
       4 . The method of  claim 1 , further comprising administering a second chemotherapeutic agent. 
   
   
       5 . The method of  claim 4 , wherein the second chemotherapeutic agent is selected from the group consisting of: altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmusine, chlorambucil, cisplatin, claladribine, 2-chlorodeoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-dunomycin, dexamethosone, doxurubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin HCL, ifosfamide, interferon alfa, interferon alfa 2a, interferon alfa 2b, interfereon alfa n3, irinotecan, leucovorin calcium, leuprolide, levamisole, lomustine, inegestrol, melphalan, L-sarcosylin, melphalan hydrochloride, MESNA, mechlorethamine, methotrexate, mitomycin, mitoxantrone, mercaptopurine, paclitaxel, plicamycin, prednisone, procarbazine, streptozocin, tamoxifen, 6-thioguanine, thiotepa, vinblastine, vincristine and vinorelbine tartrate. 
   
   
       6 . The method of  claim 1 , wherein the effective amount of the 3-halopyruvate is delivered by direct intraarterial injection to a tumor. 
   
   
       7 . The method of  claim 6 , wherein the tumor is a liver tumor and the 3-halopyruvate is delivered to a hepatic artery. 
   
   
       8 . The method of  claim 7 , wherein the 3-halopyruvate is delivered by transcatheter hepatic artery injection. 
   
   
       9 . The method of any of  claims 1 - 8 , further comprising administering a 3-halopyruvate scavenger compound. 
   
   
       10 . The method of  claim 9 , wherein the scavenger compound is selected from the group consisting of: lipoleic acid, glutathione and cysteine. 
   
   
       11 . A method of treating cancer in a subject comprising administering to the subject an effective amount of a composition represented in general formula:
   X—CH 2 —CO—COOH,   wherein X represents a halide, a sulfonate, a carboxylate, an alkoxide, or an amine oxide.   
   
   
       12 . The method of  claim 11 , wherein the halide is selected from the group consisting of: fluoride, bromide, chloride, and iodide. 
   
   
       13 . The method of  claim 11 , wherein the sulfonate is selected from the group consisting of: triflate, mesylate and tosylate. 
   
   
       14 . The method of  claim 11 , wherein the carboxylate is selected from the group consisting of: methoxylate and ethyloxylate. 
   
   
       15 . The method of  claim 11 , wherein the alkoxide is selected from the group consisting of: methoxide and ethoxide. 
   
   
       16 . The method of  claim 11 , wherein the amine oxide is dimethylamine oxide. 
   
   
       17 . A method of treating a cancerous tumor comprising administering an effective amount of an inhibitor of ATP production directly to the arterial blood supply of the tumor. 
   
   
       18 . The method of  claim 17 , wherein the cancerous tumor is a liver cancer and the inhibitor of ATP production is injected directly into an hepatic artery. 
   
   
       19 . The method of  claim 17  or  18 , wherein the inhibitor of ATP production is a hexokinase inhibitor. 
   
   
       20 . The method of  claim 19 , wherein the hexokinase inhibitor is 3-halopyruvate. 
   
   
       21 . The method of  claim 20 , wherein 3-halopyruvate is selected from the group consisting of: 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate and 3-iodopyruvate. 
   
   
       22 . The method of  claim 21 , wherein the 3-halopyruvate is 3-bromopyruvate. 
   
   
       23 . The method of  claim 19 , wherein the hexokinase inhibitor is 2-deoxyglucose. 
   
   
       24 . The method of  claim 17 , further comprising systemic administration of a scavenger compound. 
   
   
       25 . The method of  claim 24 , wherein the scavenger compound is selected from the group consisting of: lipoleic acid, glutathione and cysteine. 
   
   
       26 . The method of  claim 19 , further comprising administering a second chemotherapeutic agent. 
   
   
       27 . The method of  claim 26 , wherein the second chemotherapeutic agent is selected from the group consisting of: altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmusine, chlorambucil, cisplatin, claladribine, 2-chlorodeoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-dunomycin, dexamethosone, doxurubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin HCL, ifosfamide, interferon alfa, interferon alfa 2a, interferon alfa 2b, interfereon alfa n3, irinotecan, leucovorin calcium, leuprolide, levamisole, lomustine, megestrol, melphalan, L-sarcosylin, melphalan hydrochloride, MESNA, mechlorethamine, methotrexate, mitomycin, mitoxantrone, mercaptopurine, paclitaxel, plicamycin, prednisone, procarbazine, streptozocin, tamoxifen, 6-thioguanine, thiotepa, vinblastine, vincristine and vinorelbine tartrate. 
   
   
       28 . A method of treating cancer in a subject comprising administering to the subject an effective amount of a composition represented in general formula: 
     
       
         
         
             
             
         
       
       wherein, independently of each occurrence: 
       X represents a halide, a sulfonate, a carboxylate, an alkoxide, or an amine oxide; 
       R1 represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; 
       R″ represents H, C1-C6 alkyl, or C6-C12 aryl; 
       R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′; and 
       R′ represents H, C1-C20 alkyl or C6-C12 aryl; 
       wherein administration of the composition treats cancer in the subject. 
     
   
   
       29 . The method of  claim 28 , wherein the halide is selected from the group consisting of: fluoride, bromide, chloride, and iodide. 
   
   
       30 . The method of  claim 28 , wherein the sulfonate is selected from the group consisting of: triflate, mesylate and tosylate. 
   
   
       31 . The method of  claim 28 , wherein the carboxylate is selected from the group consisting of: methoxylate and ethyloxylate. 
   
   
       32 . The method of  claim 31 , wherein the alkoxide is selected from the group consisting of: methoxide and ethoxide. 
   
   
       33 . The method of  claim 28 , wherein the amine oxide is dimethylamine oxide. 
   
   
       34 . The method of  claim 28 , wherein the composition is administered directly to the arterial blood supply of the tumor. 
   
   
       35 . The method of  claim 34 , wherein the cancerous tumor is a liver cancer and the composition is injected directly into an hepatic artery. 
   
   
       36 . The method of  claim 34 , further comprising systemic administration of a scavenger compound. 
   
   
       37 . The method of  claim 36 , wherein the scavenger compound is selected from the group consisting of: lipoleic acid, glutathione and cysteine. 
   
   
       38 . The method of  claim 34 , further comprising administering a second chemotherapeutic agent. 
   
   
       39 . The method of  claim 38 , wherein the second chemotherapeutic agent is selected from the group consisting of: altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmusine, chlorambucil, cisplatin, claladribine, 2-chlorodeoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-dunomycin, dexamethosone, doxurubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin HCL, ifosfamide, interferon alfa, interferon alfa 2a, interferon alfa 2b, interfereon alfa n3, irinotecan, leucovorin calcium, leuprolide, levamisole, lomustine, megestrol, melphalan, L-sarcosylin, melphalan hydrochloride, MESNA, mechlorethamine, methotrexate, mitomycin, mitoxantrone, mercaptopurine, paclitaxel, plicamycin, prednisone, procarbazine, streptozocin, tamoxifen, 6-thioguanine, thiotepa, vinblastine, vincristine and vinorelbine tartrate. 
   
   
       40 . A method for identifying a selective ATP synthesis inhibitor, comprising: (a) contacting at least a portion of a VX2 tumor with a candidate inhibitor; and (b) assaying for ability of said candidate inhibitor to modulate the activity of a polypeptide comprising a pathway involved in ATP synthesis in said tumor, wherein the ability to modulate said activity indicates said candidate inhibitor may be a selective ATP synthesis inhibitor. 
   
   
       41 . The method of  claim 40 , wherein said tumor is implanted in a host. 
   
   
       42 . The method of  claim 40 , wherein said assaying step comprises assaying the ability of said candidate inhibitor to modulate the activity of an enzyme in the glycolytic pathway. 
   
   
       43 . The method of  claim 42 , wherein said enzyme is a hexokinase. 
   
   
       44 . The method of  claim 40 , wherein said assaying step comprises assaying the ability of said candidate inhibitor to modulate the activity of an enzyme in the mitochondrial respiration pathway. 
   
   
       45 . A method for identifying a selective inhibitor of ATP production, comprising: (a) contacting a cell derived from a VX2 tumor with a candidate inhibitor; and; (b) assaying for ability of said candidate inhibitor to modulate the activity of a polypeptide comprising a pathway involved in ATP production in said cell, wherein the ability to modulate said activity indicates said candidate inhibitor may be a selective inhibitor of ATP production. 
   
   
       46 . A composition for treating cancer in a subject comprising a therapeutically effective amount of a 3-halopyruvate and a pharmaceutically acceptable carrier. 
   
   
       47 . The composition of  claim 46 , wherein the 3-halopyruvate is 3-bromopyruvate. 
   
   
       48 . A composition for treating cancer in a subject comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a composition represented in general formula:
   X—CH 2 —CO—COOH,   wherein X represents a halide, a sulfonate, a carboxylate, an alkoxide, or an amine oxide.   
   
   
       49 . A composition for treating cancer in a subject comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a composition represented in general formula: 
     
       
         
         
             
             
         
       
       wherein, independently of each occurrence: X represents a halide, a sulfonate, a carboxylate, an alkoxide, or an amine oxide; R1 represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; R″ represents H, C1-C6 alkyl, or C6-C12 aryl; R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R; and R′ represents H, C1-C20 alkyl or C6-C12 aryl; wherein administration of the composition treats cancer in the subject.