Method and composition for preventing and treating solid tumors

Abstract

Compositions and methods of preventing or treating a breast cancer are disclosed. The composition and method can utilize an endothelin B agonist and a chemotherapeutic agent as active ingredients to treat a solid tumor in mammals, including humans. Alternatively, the composition and method can utilize an endothelin B antagonist and an optional angiogenesis inhibitor to treat a solid tumor in mammals, including humans.

What is claimed is:  
     
         1 . A method of treating a solid tumor comprising administering to a mammal in need thereof a therapeutically effective amount of an endothelin B agonist and a therapeutically effective amount of a chemotherapeutic agent.  
     
     
         2 . The method of  claim 1  wherein the solid tumor is selected from the group consisting of an ovarian tumor, a colon tumor, Kaposi's sarcoma, a breast tumor, a melanoma, a prostate tumor, a meningioma, a liver tumor, and a breast phyllode tumor.  
     
     
         3 . The method of  claim 2  wherein the solid tumor is a breast tumor.  
     
     
         4 . The method of  claim 1  wherein the endothelin agonist is selected from the group consisting of ET-1, ET-2, ET-3, BQ3020, IRL1620, sarafotoxin 56c, [Ala 1, 3, 11, 15 ]ET-1, and mixtures thereof.  
     
     
         5 . The method of  claim 4  wherein the endothelin B agonist comprises IRL1620.  
     
     
         6 . The method of  claim 1  wherein the chemotherapeutic agent is selected from the group consisting of adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, doxorubicin, alpha, beta, or gamma interferon, interleukin 2, irinotecan, docetaxel, paclitaxel, topotecan, and mixtures thereof.  
     
     
         7 . The method of  claim 1  wherein the endothelin B agonist and the chemotherapeutic agent are administered simultaneously.  
     
     
         8 . The method of  claim 7  wherein the endothelin B agonist and the chemotherapeutic agent are administered from a single composition.  
     
     
         9 . The method of  claim 7  wherein the endothelin B agonist and the chemotherapeutic agent are administered from separate compositions.  
     
     
         10 . The method of  claim 1  wherein the endothelin B agonist and the chemotherapeutic agent are administered sequentially.  
     
     
         11 . The method of  claim 10  wherein the chemotherapeutic agent is administered prior to the endothelin B agonist.  
     
     
         12 . The method of  claim 10  wherein the endothelin B agonist is administered prior to the chemotherapeutic agent.  
     
     
         13 . The method of  claim 1  wherein the mammal is a human.  
     
     
         14 . A composition comprising a chemotherapeutic agent, an endothelin B agonist, and an optional excipient.  
     
     
         15 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin B agonist, and;    (b) an insert providing instructions for administration of (a) to treat a solid tumor in a mammal; and    (c) a container for (a) and (b).    
     
     
         16 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin B agonist;    (b) a packaged composition comprising a chemotherapeutic agent;    (c) an insert providing instructions for a simultaneous or sequential administration of (a) and (b) to treat a solid tumor in a mammal; and    (d) a container for (a), (b), and (c)    
     
     
         17 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin B agonist and a chemotherapeutic agent;    (b) an insert providing instructions for administration of (a) to treat a solid tumor in a mammal; and    (c) a container for (a) and (b).    
     
     
         18 . A method of treating a solid tumor comprising administering to a mammal in need thereof a therapeutically effective amount of an endothelin B antagonist.  
     
     
         19 . The method of  claim 18  wherein the solid tumor is selected from the group consisting of an ovarian tumor, a colon tumor, Kaposi's sarcoma, a breast tumor, a melanoma, a prostate tumor, a meningioma; a liver tumor, and a breast phyllode tumor.  
     
     
         20 . The method of  claim 19  wherein the solid tumor is a breast tumor.  
     
     
         21 . The method of  claim 18  wherein the endothelin B antagonist comprises a specific endothelin B antagonist.  
     
     
         22 . The method of  claim 18  wherein the endothelin B antagonist comprises a balanced endothelin B antagonist.  
     
     
         23 . The method of  claim 18  wherein the endothelin B antagonist is selected from the group consisting of compounds 1 through 74 of Appendices A, B, and C.  
     
     
         24 . The method of  claim 18  wherein the endothelin B antagonist is selected from the group consisting of compounds 1 through 22 of Appendix A.  
     
     
         25 . The method of  claim 18  wherein the endothelin B antagonist is selected from the group consisting of compounds 23 through 32 of Appendix B.  
     
     
         26 . The method of  claim 18  wherein the endothelin B antagonist is selected from the group consisting of compounds 33 through 74 of Appendix C.  
     
     
         27 . The method of  claim 18  wherein the endothelin B antagonist is selected from the group consisting of atrasentan, tezosentan, bosentan, sitaxsentan, enrasentan, Ro468443, TBC10950, TBC10894, A192621, A308165, SB209670, SB17242, A182086, (s)-Lu302872, J-104132, TAK-044, Sarafotoxin 56c, IRL2500, RES7011, Aselacins A, B, and C, Ro470203, Ro462005, sulfamethoxazole, cochinmicin I, II, and III, L749329, L571281, L754142, J104132, CGS27830, PD142893, PD143296, PD145065, PD156252, PD159020, PD160672, PD160874, TM-ET-1, IRL3630, Ro485695, L75037, LU224332, PD142893, LU302872, PD145065, Ro610612, SB217242, BQ788, and mixtures thereof.  
     
     
         28 . The method of  claim 18  wherein the endothelin B antagonist comprises BQ788.  
     
     
         29 . The method of  claim 18  further comprising administering a therapeutically effective amount of an angiogenesis inhibitor.  
     
     
         30 . The method of  claim 29  wherein the angiogenesis inhibitor is selected from the group consisting of thalidomide, marimastat, COL-3, BMS275291, squalamine, 2-ME, SU6668, neovastat, Medi522, EMD121974, CAI, celecoxib, interleukin-12, IM862, TNP470, avastin, gleevac, herceptin, and mixtures thereof.  
     
     
         31 . The method of  claim 29  wherein the endothelin B antagonist and the angiogenesis inhibitor are administered simultaneously.  
     
     
         32 . The method of  claim 31  wherein the endothelin B antagonist and the angiogenesis inhibitor are administered from a single composition.  
     
     
         33 . The method of  claim 29  wherein the endothelin B antagonist and the angiogenesis inhibitor are administered from separate compositions.  
     
     
         34 . The method of  claim 29  wherein the and endothelin B antagonist and the angiogenesis inhibitor are administered sequentially.  
     
     
         35 . The method of  claim 34  wherein the angiogenesis inhibitor is administered prior to the endothelin B antagonist.  
     
     
         36 . The method of  claim 34  wherein the endothelin B antagonist is administered prior to the angiogenesis inhibitor.  
     
     
         37 . The method of  claim 18  further comprising treating the solid tumor with radiation and an optional radiosensitizer.  
     
     
         38 . The method of  claim 37  wherein the radiosensitizer is selected from the group consisting of metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine, 5-iododeoxyuridine, bromodeoxycytidine, fluorodeoxyuridine, hydroxyurea, cisplatin, therapeutically effective analogs and derivatives thereof, and mixtures thereof.  
     
     
         39 . The method of  claim 18  wherein the mammal is a human.  
     
     
         40 . A composition comprising (a) an endothelin B antagonist, (b) an angiogenesis inhibitor, and (c) an optional excipient.  
     
     
         41 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin B antagonist;    (b) a packaged composition comprising an angiogenesis inhibitor;    (c) an insert providing instructions for a simultaneous or sequential administration of (a) and (b) to treat a solid tumor in a mammal; and    (d) a container for (a), (b), and (c).    
     
     
         42 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin antagonist and an angiogenesis inhibitor;    (b) an insert providing instructions for administration of (a) to treat a solid tumor in a mammal; and    (c) a container for (a) and (b).    
     
     
         43 . An article of manufacture comprising: 
 (a) a packaged composition comprising an endothelin B antagonist;    (b) an insert providing instructions for administration of (a) to treat a solid tumor in a mammal; and    (c) a container for (a) and (b).