Cancer treatment method

Abstract

Invented is a method of treating cancer or a pre-cancerous syndrome in a mammal, including a human, in need thereof which comprises the administration of an effective amount of a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell cycle activator and a chemotherapeutic agent to such mammal, suitably a human.

1 . A method of treating a cancer which is known to enter noncycling cell phases in a mammal in need thereof which comprises the in vivo administration of an effective amount of
 a) at least one TPO cell cycle activator, and   b) at least one chemotherapeutic agent.   
     
     
         2 . The method of  claim 1  wherein the mammal is a human. 
     
     
         3 . The method of  claim 2  wherein the cancer is selected from:
 Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia, multiple myeloma, acute myelogenous leukemia (AML), promyelocytic leukemia, acute megakaryocytic leukemia, and Erythroleukemia. 
 
     
     
         4 . The method of  claim 2  wherein the TPO cell cycle activator is AMG531. 
     
     
         5 . The method of  claim 3  wherein the TPO cell cycle activator is AMG531. 
     
     
         6 . The method of  claim 2  wherein the chemotherapeutic agent is selected from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         7 . The method of  claim 3  wherein the chemotherapeutic agent is selected from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         8 . The method of  claim 4  wherein the chemotherapeutic agent is selected from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         9 . The method of  claim 5  wherein the chemotherapeutic agent is selected from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         10 . A method of treating a pre-cancerous syndrome in a human in need thereof which comprises the in vivo administration of an effective amount of
 a) at least one TPO cell cycle activator, and   b) at least one chemotherapeutic agent.   
     
     
         11 . The method of  claim 10  wherein the pre-cancerous syndrome is selected from:
 cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis. 
 
     
     
         12 . The method of  claim 11  wherein the chemotherapeutic agent is selected from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         13 . A method of treating a cancer in a human in need thereof which comprises the in vivo administration of an effective amount of:
 a) a non-peptide thrombopoietin (TPO) receptor agonist, and   b) a chemotherapeutic agent.   
     
     
         14 . The method of  claim 13  wherein the cancer is selected from:
 brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, 
 Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, and Erythroleukemia, 
 malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, 
 neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. 
 
     
     
         15 . The method of  claim 14  wherein the non-peptide thrombopoietin (TPO) receptor agonist is selected from:
 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid; 
 3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl; 
 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid; 
 3′-{N′-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid; and 
 2′-hydroxy-3′-{N′-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-4-carboxylic acid; 
 or a pharmaceutically acceptable salt thereof, and 
 the chemotherapeutic agent is selected from: 
 gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
 
     
     
         16 . The method of  claim 15  wherein the non-peptide thrombopoietin (TPO) receptor agonist is 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16  wherein the non-peptide thrombopoietin (TPO) receptor agonist is 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine). 
     
     
         18 . A method of treating a pre-cancerous syndrome in a human in need thereof which comprises the in vivo administration of an effective amount of:
 a) a non-peptide thrombopoietin (TPO) receptor agonist, and   b) a chemotherapeutic agent.   
     
     
         19 . The method of  claim 18  wherein the cancer is selected from:
 cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis and cirrhosis. 
 
     
     
         20 . The method of  claim 19  wherein the non-peptide thrombopoietin (TPO) receptor agonist is selected from:
 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid; 
 3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl; 
 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid; 
 3′-{N′-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid; and 
 2′-hydroxy-3′-{N′[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-4-carboxylic acid; 
 
       or a pharmaceutically acceptable salt thereof, and 
       the chemotherapeutic agent is selected from: 
       gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide, Revlimid® and decitabine. 
     
     
         21 . The method of  claim 20  wherein the non-peptide thrombopoietin (TPO) receptor agonist is 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 21  wherein the non-peptide thrombopoietin (TPO) receptor agonist is 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine).