Compositions and methods of use of phorbol esters in the treatment of neoplasms

Abstract

Methods and compositions containing a phorbol ester or a derivative of a phorbol ester are provided for the treatment of chronic and acute conditions. Such conditions may be caused by disease, be symptoms, treatments, or sequelae of disease. The phorbol esters described are particularly useful in the treatment of neoplastic diseases and/or managing the side effects of chemotherapeutic and radiotherapeutic treatments of neoplastic diseases.

1 - 20 . (canceled) 
     
     
         21 . A method of treating neoplasms in a mammalian subject suffering from neoplastic disease comprising administering an effective amount of a phorbol ester of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, or polymorph thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  may be hydrogen; hydroxyl; 
       
       
         
           
           
               
               
           
         
          wherein the alkyl group contains 1 to 15 carbon atoms; 
       
       
         
           
           
               
               
           
         
          wherein the lower alkenyl group contains 1 to 7 carbon atoms; 
       
       
         
           
           
               
               
           
         
          and R 3  may be hydrogen or 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 21 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
          the remaining R 1  or R 2  is 
       
       
         
           
           
               
               
           
         
          and R 3  is hydrogen. 
       
     
     
         23 . The method of  claim 21 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13 ,20-triacetate, 12-deoxyphorbol 13 -angelate, 12-deoxyphorbol 13 -angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenyl acetate, 12-deoxyphorbol 13 -phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         24 . The method of  claim 21 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         25 . The method of  claim 21 , wherein the phorbol ester of Formula I is administered parenterally. 
     
     
         26 . The method of  claim 21 , wherein said phorbol ester of Formula I is administered at least 30 times. 
     
     
         27 . The method of  claim 21 , wherein said effective amount is between about 100 μg to about 300 μg. 
     
     
         28 . The method of  claim 21 , further comprising administering at least one secondary or adjunctive therapeutic agent to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject. 
     
     
         29 . The method of  claim 28 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate. 
     
     
         30 . The method of  claim 28 , wherein two secondary or adjunctive therapeutic agents are administered to said subject. 
     
     
         31 . The method of  claim 30 , wherein the two secondary or adjunctive therapeutic agents are dexamethasone and choline magnesium trisalicylate. 
     
     
         32 . A method for inducing remission in a mammalian subject suffering from neoplastic disease comprising administering to said subject an effective amount of a phorbol ester of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, or polymorph thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  may be hydrogen; hydroxyl; 
       
       
         
           
           
               
               
           
         
          wherein the alkyl group contains 1 to 15 carbon atoms; 
       
       
         
           
           
               
               
           
         
          wherein the lower alkenyl group contains 1 to 7 carbon atoms; 
       
       
         
           
           
               
               
           
         
          and R 3  may be hydrogen or 
       
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 32 , wherein R 1  or R 2  is 
       
         
           
           
               
               
           
         
          the remaining R 1  or R 2  is 
       
       
         
           
           
               
               
           
         
          and R 3  is hydrogen. 
       
     
     
         34 . The method of  claim 32 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate. 
     
     
         35 . The method of  claim 32 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate. 
     
     
         36 . The method of  claim 32 , wherein the phorbol ester of Formula I is administered parenterally. 
     
     
         37 . The method of  claim 32 , wherein said phorbol ester of Formula I is administered at least 30 times. 
     
     
         38 . The method of  claim 32 , wherein said effective amount is between about 100 μg to about 300 μg. 
     
     
         39 . The method of  claim 32 , further comprising administering at least one secondary or adjunctive therapeutic agent to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject. 
     
     
         40 . The method of  claim 39 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate. 
     
     
         41 . The method of  claim 39 , wherein two secondary or adjunctive therapeutic agents are administered to said subject. 
     
     
         42 . The method of  claim 29 , wherein the two secondary or adjunctive therapeutic agents are dexamethasone and choline magnesium trisalicylate.