Methods for protecting and regenerating bone marrow using cxcr3 agonists and antagonists

Abstract

CXCR3 agonists, including natural CXCR3 ligands, promote bone marrow regeneration, increase peripheral white blood cells, and increase survival if administered prior to treatment of a subject with chemotherapy or radiotherapy. Similar effects are obtained by administering an CXCR3 antagonists following chemotherapy radiotherapy. Compositions and methods are presented for the treatment of cancer and bone marrow diseases.

1 . A method for myeloprotection comprising: administering an effective amount of a CXCR3 agonist to a subject prior to administering chemotherapy or radiotherapy to the subject, wherein following chemotherapy or radiotherapy the bone marrow cell density or the level of peripheral white blood cells of the subject is increased compared to a control subject not receiving the CXCR3 agonist. 
     
     
         2 . The method of  claim 1 , wherein the chemotherapy is cell cycle specific. 
     
     
         3 . The method of  claim 2 , wherein the chemotherapy comprises administering an agent selected from the group consisting 5-fluorouracil, Ara-C, vinblastine, and methotrexate. 
     
     
         4 . The method of  claim 1 , wherein the chemotherapy is cell cycle non-specific. 
     
     
         5 . The method of  claim 4 , wherein the chemotherapy comprises administering an agent selected from the group consisting of cyclophosphamide, doxorubicin, cisplatin, and busulfan. 
     
     
         6 . The method of  claim 1 , wherein the radiotherapy comprises administering external beam radiation or a radiopharmaceutical agent. 
     
     
         7 . The method of  claim 1 , wherein CXCR3 agonist is administered in daily doses for two or more days prior to administering the chemotherapy or the radiotherapy. 
     
     
         8 . The method of  claim 7 , wherein the CXCR3 agonist is administered for 5 days or more. 
     
     
         9 . The method of  claim 1 , wherein the CXCR3 agonist is selected from the group consisting of CXCL9, CXCL10, CXCL11, and combinations thereof. 
     
     
         10 . The method of  claim 9 , wherein the CXCR3 agonist is recombinant human CXCL9 or biologically active fragments or variants thereof. 
     
     
         11 . The method of  claim 9 , wherein the CXCR3 agonist is a conjugated form of CXCL9 or an albumin-CXCL9 fusion protein. 
     
     
         12 . The method of  claim 1  further comprising administering an additional myelosuppressive agent to the subject prior to the chemotherapy or the radiotherapy. 
     
     
         13 . The method of  claim 12 , wherein the myelosuppressive agent is CCL3 or IL-1Ra. 
     
     
         14 . The method of  claim 1  further comprising administering a hematopoietic growth factor to the subject following the chemotherapy or the radiotherapy. 
     
     
         15 . The method of  claim 14 , wherein the growth factor is one or more of GM-CSF, G-CSF, TPO, or IL-11.