Compositions and methods for treating cancer

Abstract

Methods and compositions are provided for the treatment of cancer that take advantage of the increased uptake of glucose-anti-neoplastic agent conjugates in cancer cells relative to normal cells.

1 . A method for treating cancer in a subject, said method comprising administering to said subject an effective amount of a glucose-anti-neoplastic agent conjugate, wherein said glucose-anti-neoplastic agent conjugate has the formula: Glc-L-Z, wherein Glc is 2-deoxy-D-glucose or a 2-deoxy-D-glucose derivative; L is a non-releasable linkage; and Z is an anti-neoplastic agent  
     
     
         2 . A method in accordance with  claim 1 , wherein said 2-deoxy-D-glucose or 2-deoxyglucose derivative is selected from the group consisting of 2-deoxy-D-glucose, 2-deoxy-D-gulose, 2-deoxy-D-galactose, 2-deoxy-2-amino-D-glucose, 2-deoxy-2-amino-D-glucose, 2-deoxy-2-amino-D-galactose, and 2-deoxy-2-amino-D-mannose.  
     
     
         3 . A method in accordance with  claim 1 , wherein Z is an anti-neoplastic agent selected from the group consisting of a radionuclide selected from the group consisting of Yttrium-90, Iodine-125, Iodine-131, and Phosphate-32; an iodoaryl group bearing an Iodine-131; hydroxyurea; a ribonucleotide reductase inhibitor that chelates iron; 3-aminopyridine-2-carboxaldehyde thiosemicarabazone; 5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone; camptothecin and its analogs; carboplat and its analogs; DOTA and other radiometal ion chelators; methotrexate and its analogs; mitoxantrone and related anthraquinones; a protein kinase inhibitor; dacarbazine and procarbazine; and mitomycin.  
     
     
         4 . (canceled)  
     
     
         5 . A method in accordance with  claim 1 , wherein L is a non-releasable linkage having from 2 to 30 atoms selected from the group consisting of C, N, O, P, S and Si.  
     
     
         6 . A method in accordance with  claim 1 , wherein said glucose-anti-neoplastic agent conjugate has the formula:  
       
         
           
           
               
               
           
         
       
       wherein L is a non-releasable linkage; Z is an anti-neoplastic agent; each X is independently selected from the group consisting of O and N; and R 1 , R 3  and R 4  are each members independently selected from the group consisting of H, (C 1 -C 12 )alkyl, (C 1 -C 12 )acyl.  
     
     
         7 . (canceled)  
     
     
         8 . A method in accordance with  claim 1 , further comprising administering at least one additional anti-neoplastic agent.  
     
     
         9 . A method of  claim 8 , wherein said at least one additional anti-neoplastic agent is a member selected from the group consisting of cyclophosphamide, doxorubicin, prednisone and cisplatin.  
     
     
         10 . A method in accordance with  claim 1 , wherein said cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colon cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, brain cancer, head and neck cancer, skin cancer and melanoma.  
     
     
         11 . A method in accordance with  claim 1 , wherein said cancer is selected from the group consisting of low grade non-Hodgkin's Lymphoma, intermediate grade non-Hodgkin's Lymphoma, follicular lymphoma, large cell lymphoma, B-cell lymphoma, T-cell lymphoma, Mantle cell lymphoma, Burkitt's lymphoma, NK cell lymphoma and acute lymphoblastic lymphoma.  
     
     
         12 . A method in accordance with  claim 1 , wherein said cancer is selected from the group consisting of relapsed cancer and refractory cancer.  
     
     
         13 . A method in accordance with  claim 1 , further comprising a preliminary step of reducing glucose ingestion in said subject.  
     
     
         14 . A glucose-anti-neoplastic agent conjugate having the formula: Glc-L-Z, wherein Glc is 2-deoxyglucose or a 2-deoxyglucose derivative; L a non-releasable linking group; and Z is an anti-neoplastic agent.  
     
     
         15 . A glucose-anti-neoplastic agent conjugate of  claim 14 , having the formula:  
       
         
           
           
               
               
           
         
       
       wherein L is non-releasable linking group; Z is an anti-neoplastic agent; each X is independently selected from the group consisting of O and NH; and R 1 , R 3  and R 4  are each members independently selected from the group consisting of H, (C 1 -C 12 )alkyl, (C 1 -C 12 )acyl and a solubility or partitioning effector component.  
     
     
         16 . A glucose-anti-neoplastic agent conjugate of  claim 15 , having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         17 . A glucose-anti-neoplastic agent conjugate of  claim 15 , wherein Z is an anti-neoplastic agent selected from the group consisting of a radionuclide selected from the group consisting of Yttrium-90, Iodine-125, Iodine-131, and Phosphate-32; an iodoaryl group bearing an Iodine-131; hydroxyurea; a ribonucleotide reductase inhibitor that chelates iron; 3-aminopyridine-2-carboxaldehyde thiosemicarabazone; 5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone; camptothecin and its analogs; carboplat and its analogs; DOTA and other radiometal ion chelators; methotrexate and its analogs; mitoxantrone and related anthraquinones; a protein kinase inhibitor; dacarbazine and procarbazine; and mitomycin.  
     
     
         18 . A compound of structure:  
       
         
           
           
               
               
           
         
       
       wherein R is SnMe 3 .  
     
     
         19 . A composition comprising a pharmaceutically acceptable carrier and a glucose-anti-neoplastic agent conjugate of  claim 15 .  
     
     
         20 . The composition of  claim 19  that comprises 4-iodo-N-benzoyl-glucosamine and 4- 131 iodo-N-benzoylglucosamine.