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

1. A method of treating neoplasms comprising administering parenterally to a mammalian subject with lung cancer, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

and

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms;

and optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day, and for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

2. A method of treating neoplasms comprising administering parenterally to a mammalian subject with lymphoma, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

3. A method of treating neoplasms comprising administering parenterally to a mammalian subject with breast cancer, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent; wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

4. A method of treating neoplasms comprising administering parenterally to a mammalian subject with liver cancer, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

5. A method of treating neoplasms comprising administering parenterally to a mammalian subject with pancreatic cancer, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

6. A method of treating neoplasms comprising administering parenterally to a mammalian subject with cervical cancer, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

7. A method of treating neoplasms comprising administering parenterally to a mammalian subject with multiple myeloma, 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 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein a lower alkenyl group contains between 1 to 7 carbon atoms,

R 3 is selected from hydrogen and

wherein the lower alkyl group contains 1-7 carbon atoms; and

optionally at least one secondary or adjunctive therapeutic agent;

wherein said effective amount is between about 10 μg to about 1500 μg of said phorbol ester of Formula I, administered every other day and wherein said phorbol ester of Formula I is administered for at least a total of 5 times; and

wherein one or more symptoms or conditions suffered by the mammalian subject is alleviated or treated, the one or more symptoms being selected from the group consisting of chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, and weakness.

8. The method of any one of claims 1 to 7 , wherein R 1 or R 2 is

the remaining R 1 or R 2 is

and R 3 is hydrogen.

9. The method of any one of claims 1 to 7 , 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-phenyl acetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.

10. The method of any one of claims 1 to 7 , further comprising administering at least one secondary or adjunctive therapeutic agent to said subject.

11. The method of claim 10 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.

12. The method of claim 10 , 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.

13. The method of any one of claims 1 to 7 , further comprising administering two secondary or adjunctive therapeutic agents to said subject.

14. The method of claim 13 , wherein the two secondary or adjunctive therapeutic agents are dexamethasone and choline magnesium trisalicylate.

15. The method of any one of claims 1 to 7 , wherein the phorbol ester is 12—O—tetradecanoylphorbol—13—acetate.