Method of Treating Cancer Using Dithiocarbamate Derivatives

Abstract

Dithiocarbamate, particularly tetraethylthiuram disulfide, and thiocarbamate anions thereof, strongly inhibit the growth of cancer cells of a variety of cell types. Such inhibitory effect is enhanced by heavy metal ions such as copper ions, cytokines and ceruloplasmin. A method is presented for using tetraethylthiuram disulfide to reduce tumor growth, and to potentiate the effect of other anticancer agents.

1 . A method of treating cancer in a patient comprising administering a therapeutically effective amount of a dithiocarbamate disulfide, or a dithiocarbamate thiolate anion thereof, to the patient.  
   
   
       2 . The method of  claim 1 , wherein said administering step comprises administering a dithiocarbamate disulfide having the formula:  
       R 1 R 2 N(S)CS—SC(S)NR 3 R 4    wherein R 1 , R 2 , R 3 , and R 4  are the same or different, and each is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted alkoxy, and unsubstituted or substituted heteroaryl, or either R 1  and R 2  or R 3  and R 4  and the adjacent N atom together form an N-heterocyclic ring.    
   
   
       3 . The method of  claim 2 , wherein the dithiocarbamate disulfide is a disulfide form of a dithiocarbamate selected from the group consisting of diethyldithiocarbamate, pyrrolodinedithiocarbamate, N-methyl, N-ethyl dithiocarbamates, hexamethylenedithiocarbamate, imidazolinedithiocarbamates, dibenzyldithiocarbamate, dimethylenedithiocarbamate, dipolyldithiocarbamate, dibutyldithiocarbamate, diamyldithiocarbamate, N-methyl, N-cyclopropylmethyldithiocarbamate, cyclohexylamyldithiocarbamate, pentamethylenedithiocarbamate, dihydrxyethyldithiocarbamate, and N-methylglucosamine dithiocarbamate.  
   
   
       4 . The method of  claim 1 , wherein said administering step comprises administering a tetraalkyl thiuram disulfide.  
   
   
       5 . The method of  claim 4 , wherein the tetraalkyl thiuram disulfide is disulfuram.  
   
   
       6 . The method of  claim 1 , wherein said administering step comprises administering a thiolate anion of a dithiocarbamate disulfide.  
   
   
       7 . The method of  claim 6 , wherein the thiolate anion is administered in the form of a pharmaceutically acceptable salt.  
   
   
       8 . The method of  claim 7 , wherein the pharmaceutically acceptable salt is an alkali metal salt.  
   
   
       9 . The method of  claim 8 , wherein the thiolate anion in alkali metal salt form has the formula:  
     
       
         
         
             
             
         
       
       wherein R 2  and R 3  are the same or different, and each is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted alkoxy, and unsubstituted or substituted heteroaryl; M is an alkali metal; and n is the valence of the alkali metal.  
     
   
   
       10 . The method of  claim 6 , wherein the thiolate anion is diethyldithiocarbamate anion, optionally in the form of an alkali metal salt.  
   
   
       11 . The method of  claim 1 , further comprising administering a source of heavy metal ions to the patient in an amount effective to form a complex with the dithiocarbamate disulfide or dithiocarbamate thiolate anion thereof.  
   
   
       12 . The method of  claim 11 , wherein the heavy metal is selected from the group consisting of arsenic, bismuth, cobalt, copper, chromium, gallium, gold, iron, manganese, nickel, silver, titanium, vanadium, selenium, and zinc.  
   
   
       13 . The method of  claim 11 , wherein the source of heavy metal ions is administered in a separate formulation from the dithiocarbamate disulfide or dithiocarbamate thiolate anion thereof.  
   
   
       14 . The method of  claim 11 , wherein the source of heavy metal ions is in the form of an aqueous solution of a pharmaceutically suitable salt.  
   
   
       15 . The method of  claim 14 , wherein the salt form is selected from the group consisting of a chelate with an organic anion, a sulfate salt, and a chloride salt.  
   
   
       16 . The method of  claim 15 , wherein the organic anion is selected from the group consisting of acetate, lactate, glycinate, citrate, propionate, and gluconate.  
   
   
       17 . The method of  claim 1 , wherein the route of administration is selected from the group consisting of parenteral, intravenous, oral, intradermal, subcutaneous, and topical.  
   
   
       18 . The method of  claim 1 , further comprising administering a therapeutically effective amount of an anticancer agent to the patient.  
   
   
       19 . The method of  claim 18 , wherein the anticancer agent is a chemotherapeutic drug.  
   
   
       20 . The method of  claim 18 , wherein the anticancer agent is selected from the group consisting of busulphan, chlorambucil, hydroxyurea, ifosfamide, mitomycin, mitotane, chlorambucil, mechlorethamine, carmustine, lomustine, cisplatin, carmustine, herceptin, carboplatin, cyclophosphamide, nitrosoureas, fotemustine, vindescine, etoposide, daunorubicin, adriamycin, paclitaxel, docetaxel, streptozocin, dactinomycin, doxorubicin, idarubicin, plicamycin, pentostatin, mitotoxantrone, valrubicin, cytarabine, fludarabine, floxuridine, clardribine, methotrexate, mercaptopurine, thioguanine, capecitabine, irinotecan, dacarbazine, asparaginase, gemcitabine, altretamine, topotecan, procarbazine, vinorelbine, pegaspargase, vincristine, rituxan, vinblastine, tretinoin, teniposide, fluorouracil, melphalan, bleomycin, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nambuetone, oxaprozin, doxirubicin, nonselective cycclooxygenase inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors.  
   
   
       21 . A method of treating cancer in a patient comprising: 
 administering a therapeutically effective amount of a dithiocarbamate disulfide, or a dithiocarbamate thiolate anion thereof, to the patient; and    administering a source of heavy metal ions in a separate formulation to the patient in an amount effective to form a complex with the dithiocarbamate disulfide or dithiocarbamate thiolate anion thereof, wherein the heavy metal is selected from the group consisting of arsenic, bismuth, cobalt, copper, chromium, gallium, gold, iron, manganese, nickel, silver, titanium, vanadium, selenium, and zinc.    
   
   
       22 . The method of  claim 21 , comprising administering disulfuram and a source of copper, zinc, gold, or silver.  
   
   
       23 . A method of treating cancer in a patient comprising: 
 administering a therapeutically effective amount of a dithiocarbamate disulfide, or a dithiocarbamate thiolate anion thereof, to the patient;    administering a source of heavy metal ions in a separate formulation to the patient in an amount effective to form a complex with the dithiocarbamate disulfide or dithiocarbamate thiolate anion thereof; and    administering a therapeutically effective amount of a chemotherapeutic drug to the patient.    
   
   
       24 . The method of  claim 23 , comprising administering disulfuram, a source of copper, zinc, gold, or silver, and a chemotherapeutic drug selected from the group consisting of cisplatin, cyclophosphamide, etoposide, duanorubicin, adriamycin, paclitaxel, docetaxel, gemcitabine, fluorouracil, vincristine, vinblastine, teniposide, and carboplatin.  
   
   
       25 . A pharmaceutical composition comprising: 
 a first pharmaceutical composition comprising a dithiocarbamate disulfide, or a dithiocarbamate thiolate anion thereof, in a pharmaceutically acceptable carrier; and    a second separate pharmaceutical composition comprising a source of heavy metal ions in a pharmaceutically acceptable carrier.    
   
   
       26 . The pharmaceutical composition of  claim 25 , wherein the first pharmaceutical composition comprises a dithiocarbamate disulfide having the formula:  
       R 1 R 2 N(S)CS—SC(S)NR 3 R 4    wherein R 1 , R 2 , R 3 , and R 4  are the same or different, and each is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted alkoxy, and unsubstituted or substituted heteroaryl, or either R 1  and R 2  or R 3  and R 4  and the adjacent N atom together form an N-heterocyclic ring.    
   
   
       27 . The pharmaceutical composition of  claim 25 , wherein the first pharmaceutical composition comprises a tetraalkyl thiuram disulfide.  
   
   
       28 . The pharmaceutical composition of  claim 27 , wherein the tetraalkyl thiuram disulfide is disulfuram.  
   
   
       29 . The pharmaceutical composition of  claim 25 , wherein the first pharmaceutical composition comprises a thiolate anion of a dithiocarbamate disulfide.  
   
   
       30 . The pharmaceutical composition of  claim 29 , wherein the thiolate anion is in the form of a pharmaceutically acceptable salt.  
   
   
       31 . The pharmaceutical composition of  claim 30 , wherein the thiolate anion is in the form of an alkali metal salt.  
   
   
       32 . The pharmaceutical composition of  claim 31 , wherein the thiolate anion in alkali metal salt form has the formula:  
     
       
         
         
             
             
         
       
       wherein R 2  and R 3  are the same or different, and each is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted alkoxy, and unsubstituted or substituted heteroaryl; M is an alkali metal; and n is the valence of the alkali metal.  
     
   
   
       33 . The pharmaceutical composition of  claim 29 , wherein the thiolate anion is diethyldithiocarbamate anion, optionally in the form of an alkali metal salt.  
   
   
       34 . The pharmaceutical composition of  claim 25 , wherein the heavy metal is selected from the group consisting of arsenic, bismuth, cobalt, copper, chromium, gallium, gold, iron, manganese, nickel, silver, titanium, vanadium, selenium, and zinc.  
   
   
       35 . The pharmaceutical composition of  claim 25 , wherein the source of heavy metal ions is in the form of an aqueous solution of a pharmaceutically suitable salt.  
   
   
       36 . The pharmaceutical composition of  claim 35 , wherein the salt form is selected from the group consisting of a chelate with an organic anion, a sulfate salt, and a chloride salt.  
   
   
       37 . The pharmaceutical composition of  claim 36 , wherein the organic anion is selected from the group consisting of acetate, lactate, glycinate, citrate, propionate, and gluconate.