Cancer treatment including glycolytic inhibitors

Abstract

Glycolytic inhibitors are useful in the treatment of solid tumors by attacking anaerobic cells at the center on the tumor. 2-deoxyglucose, oxamate and various analogs thereof are identified as having a natural selective toxicity toward anaerobic cells, and will significantly increase the efficacy of standard cancer chemotherapeutic and radiation regiments as well as new protocols emerging with anti-angiogenic agents.

1 . A pharmaceutical composition comprising at least one of the compounds 1 to 37:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The composition of  claim 1 , including, in combination with at least one of the compounds 1 to 37, at least one of cyclophosphamide, doxorubicin, 5-fluorouracil, docetaxel, cisplatin, ifosphamide, DTIC, vinorelbine, carboplatin, gemcitabine, VP-16, leukovorin, an anti-angiogenic factor, and irinotecan, so that the combination is useful for treating a human with both aerobically and anaerobically metabolizing cells.  
     
     
         3 . The composition of  claim 2 , wherein said at least one of the compounds 1 to 37 is 2-Deoxy-D-glucose.  
     
     
         4 . The composition of  claim 2 , wherein said at least one of the compounds 1 to 37 is 5-Thio-D-glucose.  
     
     
         5 . A method of killing anaerobic cells in a human, said method comprising administering an effective amount of a composition of  claim 1 .  
     
     
         6 . A method of killing cells in a human, wherein said cells are capable of using steps of the glycolytic pathway to create ATP for energy, said method comprising inhibiting at least one step of the glycolytic pathway by administering at least one glycolytic inhibitor.  
     
     
         7 . The method according to  claim 6 , wherein said cells are cancer cells, and which method additionally comprises the step of killing cancer cells that aerobically generate ATP, by administering at least one compound of a cancer chemotherapy protocol other than an inhibitor of oxidative phosphorylation.  
     
     
         8 . The method according to  claim 6 , which method additionally comprises a step of first treating aerobically growing tumor cells with an effective amount of a composition which inhibits oxidative phosphorylation to convert the aerobically growing tumor cells into anaerobically growing tumor cells which are thus made hypersensitized to at least one glycolytic inhibitor, and thereafter administering the effective amount of the at least one glycolytic inhibitor.  
     
     
         9 . A method for treating a human with a carcinoma or sarcoma that contains both aerobically and anaerobically metabolizing cells, said method comprising the steps of: 
 (a) administering a chemotherapy protocol for killing at least some of the aerobically metabolizing cells; and    (b) administering a pharmaceutically acceptable glycolytic inhibiting compound having the general formula                          for killing at least some of the anaerobically metabolizing cells.    
     
     
         10 . The method according to  claim 9 , wherein the glycolytic inhibiting compound is 5-Thio-D-glucose.  
     
     
         11 . The method according to  claim 9 , wherein the glycolytic inhibiting compound is 2-Deoxy-D-glucose.  
     
     
         12 . The method according to  claim 9 , wherein the chemotherapy protocol includes administering at least one of cyclophosphamide, doxorubicin, 5-fluorouracil, docetaxel, cisplatin, ifosphamide, DTIC, vinorelbine, carboplatin, gemcitabine, VP-16, leukovorin, an anti-angiogenic agent, and irinotecan.  
     
     
         13 . The method according to  claim 12 , wherein the glycolytic inhibiting compound is 5-Thio-D-glucose.  
     
     
         14 . The method according to  claim 12 , wherein the glycolytic inhibiting compound is 2-Deoxy-D-glucose.  
     
     
         15 . The method according to  claim 7 , wherein the at least one compound of a cancer chemotherapy protocol is selected from the group consisting of cyclophosphamide, doxorubicin, 5-fluorouracil, docetaxel, cisplatin, ifosphamide, DTIC, vinorelbine, carboplatin, gemcitabine, VP-16, leukovorin, an anti-angiogenic agent, and irinotecan.  
     
     
         16 . The method according to  claim 7 , wherein the glycolytic inhibitor is 2-Deoxy-D-glucose.  
     
     
         17 . The method according to  claim 7 , wherein the glycolytic inhibitor is 5-Thio-D-glucose.  
     
     
         18 . The method according to  claim 14 , wherein the chemotherapy protocol includes administering an anti-angiogenic agent.  
     
     
         19 . The method of  claim 16 , wherein the chemotherapy protocol includes administering an anti-angiogenic agent.  
     
     
         20 . A method for treating a human with a carcinoma or sarcoma that contains both aerobically and anaerobically metabolizing cells, said method comprising the steps of: 
 administering a chemotherapy protocol for killing at least some of the aerobically metabolizing cells; and    administering a pharmaceutically acceptable glycolytic inhibiting compound selected from the monosaccharide group consisting of 6-Fluoro-D-glucose, 2-Bromo-D-glucose, 2-Fluoro-D-glucose, 2-Iodo-D-glucose, Glucosyl fluoride, 3-Fluoro-D-glucose, 4-Fluoro-D-glucose, 1-Deoxy-D-glucose, 2-Deoxy-D-glucose, 6-Deoxy-D-glucose, 6-Thio-D-glucose, 5-Thio-D-glucose, 6-O-methyl-D-glucose, and valerate, myristate, and palmitate derivatives of 2-dg at 6-O, 4-O, 3-O, and 1-O; or    administering a pharmaceutically acceptable glycolytic inhibiting compound selected from the propionic acid derivative group consisting of 1,1-difluoro-3-phosphate-glycerol, 1,1-difluoro glycerate, 2-fluoro-glyceraldehyde, 2-iodo-glyceraldehyde, 2-thio-glyceraldehyde, 2-methoxy-glyceraldehyde, 2-fluoro-glycerate 2-iodo-glycerate, 2-thio-glycerate, 2-methoxy-glycerate, 3-fluoro-glycerate, 3,3-difluoro-glycerate, enolase 3-iodo-glycerate, 3-carboxylo-glycerate, 3-thio-glycerate; or    administering a pharmaceutically acceptable glycolytic inhibiting compound selected from the pyruvate analog group consisting of oxamate, 3-halo pyruvate, 2-halo-propionic acid or its salts, 2,2-difluoro-propionic acid, 3-halo-propionic acid, and 2-thiomethyl-acetic acid;    wherein one of said groups of glycolytic inhibiting compounds is administered for killing at least some of the anaerobically metabolizing cells.