Use of non-peptidic nk1 receptor antagonists for the production of apoptosis in tumor cells

Abstract

Substance P antagonists and, in particular, non-peptidic NK1 receptor antagonists are useful for the treatment of cancer and, more specifically, human melanoma, neuroblastoma, glioma, human Hodgkin's lymphoma KM-H2, lymphoblastic leukemia, human rhabdomyosarcoma, human breast carcinoma, human Burkitt's lymphoma, human lung carcinoma, human Ewing's sarcoma, human glioma and human osteosarcoma.

What is claimed is:  
     
         1 . A pharmaceutical composition for the treatment of cancer in humans, comprising an effective amount of a non-peptide NK1 receptor antagonist, selected from the group consisting of aprepitant (MK 869 or L-754,030 (MSD)), L-758,298 (MSD), L-733,060 (MSD/Sigma-Aldrich), TAK-637 (Takeda/Abbot), GW597,599 (GSK), GW679,769 (GSK), and R673 (Roche), to achieve a concentration of between 5-50 μM at cancer cells to be treated. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the effective amount is sufficient to achieve a concentration of at least 20 μM. 
     
     
         3 . A pharmaceutical composition for treating a human having cancel by inducing apoptosis in human cancer cells expressing at least 400% greater NK1 receptors than corresponding non-tumor cells of the same cell type, comprising an effective amount of a non-peptide NK1 receptor antagonist to achieve a concentration of at least an IC 50  for proliferation of the human cancer cells. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein the effective amount is sufficient to achieve a concentration of at least 5 μM. 
     
     
         5 . The pharmaceutical composition according to  claim 3 , wherein the effective amount is sufficient to achieve a concentration of at least 20 μM. 
     
     
         6 . The pharmaceutical composition according to  claim 3 , comprising an effective amount of the non-peptide NK1 receptor antagonist to achieve a concentration of between about 5-50 μM. 
     
     
         7 . The pharmaceutical composition according to  claim 3 , wherein the non-peptide NK1 receptor antagonist is selected from the group consisting of:
 L-733,060 (2S,3S) 3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine (MSD/Sigma-Aldrich);   Vofopitant GR-205,171 (Pfizer);   eziopitant CJ-11974 (Pfizer);   CP-122,721 (Pfizer);   Aprepitant (MK 869) (L-754,030) (MSD) (5-[[(2R,3S)-2-[(1R)-I-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one);   L-758,298 (MSD);   TAK-637 (Takeda/Abbot);   GW597,599 (GSK);   GW679,769 (GSK); and   R673 (Roche).   
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the non-peptide NK1 receptor antagonist comprises aprepitant. 
     
     
         9 . The pharmaceutical composition according to  claim 7 , wherein the non-peptide NK1 receptor antagonist comprises L-733,060. 
     
     
         10 . The pharmaceutical composition according to  claim 7 , wherein the non-peptide NK1 receptor antagonist comprises a 3,5-bis(trifluoromethyl)phenyl alkoxy ligand. 
     
     
         11 . The pharmaceutical composition according to  claim 7 , wherein the non-peptide NK1 receptor antagonist comprises at least one trifluoromethyl ligand. 
     
     
         12 . A pharmaceutical formulation for treatment of a tumor in an animal, the tumor having tumor cells which have a number of NK1 receptors of at least 400% of normal cells of the same type, comprising a non-peptide NK1 receptor antagonist in an amount sufficient to achieve a concentration of between about 5-50 μM in the animal. 
     
     
         13 . The pharmaceutical formulation according to  claim 12 , comprising an effective amount of a non-peptide NK1 receptor antagonist to achieve a concentration of at least 20 μM. 
     
     
         14 . The pharmaceutical formulation according to  claim 12 , wherein the non-peptide NK1 receptor antagonist is selected from the group consisting of:
 (2S,3S) 3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine L-733,060 (MSD/Sigma-Aldrich);   Vofopitant GR-205171 (Pfizer);   eziopitant CJ-11974 (Pfizer);   CP-122721 (Pfizer);   Aprepitant (MK 869) (L-754030) (MSD) (5-[[(2R,3S)-2-[(1R)-I-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one);   L-758298 (MSD);   TAK-637 (Takeda/Abbot);   GW597599 (GSK);   GW679769 (GSK); and   R673 (Roche).   
     
     
         15 . The pharmaceutical formulation according to  claim 14 , wherein the non-peptide NK1 receptor antagonist comprises aprepitant. 
     
     
         16 . The pharmaceutical formulation according to  claim 14 , wherein the non-peptide NK1 receptor antagonist comprises L-733,060. 
     
     
         17 . The pharmaceutical formulation according to  claim 14 , wherein the non-peptide NK1 receptor antagonist comprises a 3,5-bis(trifluoromethyl)phenyl alkoxy ligand. 
     
     
         18 . The pharmaceutical formulation according to  claim 14 , wherein the non-peptide NK1 receptor antagonist comprises at least one trifluoromethyl ligand. 
     
     
         19 . The pharmaceutical formulation according to  claim 12 , wherein the amount sufficient to achieve a concentration of between about 5-50 μM in the animal is in excess of an IC 50  for proliferation of the tumor cells. 
     
     
         20 . The pharmaceutical formulation according to  claim 12 , wherein the tumor cells are selected from the group consisting of:
 invasive primary and invasive malignant melanomas;   metastatic melanoma cells;   cells localized in ganglion lymph nodes;   glioma cells—human breast cancer cells;   Acute lymphoblastic leukemia B cells;   Acute lymphoblastic leukemia T cells;   primary neuroblastoma cells;   astrocytoma cells;   Burkitt's lymphoma cells;   Hodgkin's lymphoma cells;   Rhabdomyosarcoma cells;   small lung cancer cells;   Ewing's sarcoma cells; and osteosarcoma cells.