Treatment of astrocytes-tumor cells inhibitors of endothelin receptors

Abstract

The disclosure relates to an endothelin receptor antagonist for use in the prevention or treatment of brain metastases in combination with a cytotoxic chemotherapy agent, radiotherapy or both. The endothelin receptor antagonist may for example be bosentan, macitentan or a mixture of bosentan and macitentan.

1 - 26 . (canceled) 
     
     
         27 . A method of treating an existing brain metastasis tumor in a subject comprising administering an endothelin receptor antagonist and at least one cytotoxic chemotherapeutic agent, wherein the endothelin receptor antagonist is macitentan and the at least one cytotoxic chemotherapeutic agent is a mitotic inhibitor. 
     
     
         28 . The method of  claim 27 , wherein the mitotic inhibitor is paclitaxel. 
     
     
         29 . A method for administering a cytotoxic chemotherapy to treat a brain metastasis in a patient comprising:
 a. administering an effective amount of endothelin receptor antagonist to desensitize astrocyte mediated protection of a brain metastasis cell from a cytotoxic chemotherapy induced cell death, wherein the endothelin receptor antagonist is macitentan; and   b. further administering a cytotoxic chemotherapy agent to induce cell death, wherein the cytotoxic chemotherapeutic agent is a mitotic inhibitor.   
     
     
         30 . The method of  claim 29 , wherein the mitotic inhibitor is paclitaxel. 
     
     
         31 . The method of  claim 29 , wherein the brain metastasis cell is located in an existing brain metastasis tumor in a subject and the existing brain metastasis tumor is a visible tumor. 
     
     
         32 . The method of  claim 30 , wherein the brain metastasis cell is located in an existing brain metastasis tumor in a subject and the existing brain metastasis tumor is a visible tumor. 
     
     
         33 . A method of inhibiting in a human an astrocyte mediated protection of a brain metastasis cell from a cytotoxic chemotherapy induced cell death, wherein the brain metastasis cell is located in an existing brain metastasis tumor in said human or is an isolated cell, and said existing brain metastasis tumor is a micrometastasis, said method comprising:
 a. administering an effective amount of an endothelin receptor antagonist to the brain metastasis cell and the astrocyte thereby inhibiting the astrocyte mediated protection, wherein the endothelin receptor antagonist is macitentan; and   b. administering at least one cytotoxic chemotherapeutic agent to the brain metastasis cell, wherein the cytotoxic chemotherapeutic agent is a mitotic inhibitor; and   c. further performing whole brain radiotherapy, stereotactic radiosurgery, or combinations thereof.   
     
     
         34 . The method of  claim 33 , wherein the mitotic inhibitor is paclitaxel. 
     
     
         35 . A method of inhibiting in a human an astrocyte mediated protection of a brain metastasis cell from a cytotoxic chemotherapy induced cell death, wherein the brain metastasis cell is located in an existing brain metastasis tumor in said human or is an isolated cell, and said existing brain metastasis tumor is a visible tumor, said method comprising:
 a. administering an effective amount of an endothelin receptor antagonist to the brain metastasis cell and the astrocyte thereby inhibiting the astrocyte mediated protection, wherein the endothelin receptor antagonist is macitentan; and   b. administering at least one cytotoxic chemotherapeutic agent to the brain metastasis cell, wherein the cytotoxic chemotherapeutic agent is a mitotic inhibitor; and   c. further performing whole brain radiotherapy, stereotactic radiosurgery, or combinations thereof.   
     
     
         36 . The method of  claim 35 , wherein the mitotic inhibitor is paclitaxel.