Methods for modulating chemotherapeutic cytotoxicity

Abstract

Disclosed herein are methods of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells by administering to a subject with cancer an effective amount of an agent that inhibits CD47 signaling and a chemotherapeutic agent. Example disclosed methods reduce cardiotoxicity of a chemotherapeutic agent. Also disclosed are methods of increasing cytotoxicity of a chemotherapeutic agent in cancer cells by administering to a subject with a tumor an effective amount of an agent that inhibits CD47 signaling and a chemotherapeutic agent. In some embodiments, the inhibitor of CD47 signaling is administered to the subject before, during, or after the administration of the chemotherapeutic agent.

We claim: 
     
         1 . A method of reducing cytotoxicity of an anthracycline, a topoisomerase inhibitor, or a nucleotide synthesis inhibitor to non-cancer cells in a subject in need thereof, comprising administering to the subject an effective amount of:
 an agent that inhibits TSP1-dependent CD47 signaling, wherein the agent that inhibits TSP1-dependent CD47 signaling is an anti-CD47 antibody; and   the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor, wherein the agent that inhibits TSP1-dependent CD47 signaling is administered to the subject before, during, or after administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or valrubicin. 
     
     
         3 . The method of  claim 1 , wherein the nucleotide synthesis inhibitor is cladribine, clofarabine, fludarabine, mercaptopurine, thioguanine, pentostatin, capecitabine, cytarabine, 5-fluorouracil, floxuridine, or gemcitabine. 
     
     
         4 . The method of  claim 1 , wherein the topoisomerase inhibitor is camptothecin, topotecan, irinotecan, or etoposide. 
     
     
         5 . The method of  claim 1 , wherein the anti-CD47 antibody is anti-human CD47 antibody B6H12. 
     
     
         6 . The method of  claim 1 , wherein the subject has breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, bladder cancer, stomach cancer, multiple myeloma, soft tissue sarcoma, leukemia, or lymphoma. 
     
     
         7 . The method of  claim 1 , wherein the cytotoxicity of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor to non-cancer cells is cardiotoxicity, nephrotoxicity, hepatotoxicity, myelosuppression, alopecia, gastrointestinal distress, or peripheral neuropathy. 
     
     
         8 . The method of  claim 1 , wherein the agent that inhibits TSP1-dependent CD47 signaling is administered to the subject prior to administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor. 
     
     
         9 . The method of  claim 8 , wherein the agent that inhibits TSP1-dependent CD47 signaling is administered to the subject at least about 24 hours prior to administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor or at least about 48 hours prior to the administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor. 
     
     
         10 . The method of  claim 1 , further comprising detecting cytotoxicity to non-cancer cells in the subject by detecting a reduction or inhibition of cardiotoxicity in the subject compared to a control. 
     
     
         11 . The method of  claim 1 , further comprising selecting a subject who is at risk for cytotoxicity of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor to non-cancer cells for administration of the agent that inhibits TSP1-dependent CD47 signaling and the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor, wherein the subject has pre-existing heart disease, hypertension, previous mediastinal irradiation, female gender, and/or age less than 4 years, or the subject has received a cumulative dose of greater than 400 mg/m 2  and/or administration of an anthracycline at more than 50 mg/m 2  dose per day. 
     
     
         12 . A method of reducing cytotoxicity of an anthracycline, a topoisomerase inhibitor, or a nucleotide synthesis inhibitor to non-cancer cells in a subject in need thereof, comprising:
 (a) administering to the subject an agent that inhibits TSP1-depedent CD47 signaling, wherein the agent that inhibits TSP1-dependent CD47 signaling is an anti-CD47 antibody;   (b) administering the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor to the subject, wherein (a) and (b) can be performed in either order or concurrently; and   (c) detecting a reduction of cytotoxicity to non-cancer cells in the subject by detecting a reduction or inhibition of cardiotoxicity, nephrotoxicity, hepatotoxicity, myelosuppression, alopecia, gastrointestinal distress, or peripheral neuropathy in the subject compared to a control.   
     
     
         13 . The method of  claim 12 , further comprising selecting a subject who is at risk for cytotoxicity of the DNA damaging agent to non-cancer cells for administration of the agent that inhibits TSP1-dependent CD47 signaling and the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor, wherein the subject has pre-existing heart disease, hypertension, previous mediastinal irradiation, female gender, and/or age less than 4 years, or the subject has received a cumulative dose of greater than 400 mg/m 2  and/or administration of an anthracycline at more than 50 mg/m 2  dose per day. 
     
     
         14 . A method of increasing cytotoxicity of an anthracycline, a topoisomerase inhibitor, or a nucleotide synthesis inhibitor to cancer cells in a subject in need thereof, comprising administering to a subject with cancer an effective amount of:
 an agent that inhibits TSP1-dependent CD47 signaling, wherein the agent that inhibits TSP1-dependent CD47 signaling is an anti-CD47 antibody; and   the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor,   wherein the agent that inhibits TSP1-dependent CD47 signaling is administered to the subject before, during, or after administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor.   
     
     
         15 . The method of  claim 14 , wherein the agent that inhibits TSP1-dependent CD47 signaling is administered to the subject prior to administration of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor. 
     
     
         16 . The method of  claim 14 , wherein increasing cytotoxicity of the anthracycline, the topoisomerase inhibitor, or the nucleotide synthesis inhibitor to cancer cells comprises decreasing tumor size, decreasing tumor number, decreasing tumor metastasis, decreasing tumor recurrence, increasing survival, or any combination of two or more thereof. 
     
     
         17 . The method of  claim 14 , wherein the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or valrubicin. 
     
     
         18 . The method of  claim 14 , wherein the nucleotide synthesis inhibitor is cladribine, clofarabine, fludarabine, mercaptopurine, thioguanine, pentostatin, capecitabine, cytarabine, 5-fluorouracil, floxuridine, or gemcitabine. 
     
     
         19 . The method of  claim 14 , wherein the topoisomerase inhibitor is camptothecin, topotecan, irinotecan, or etoposide. 
     
     
         20 . The method of  claim 14 , wherein the anti-CD47 antibody is anti-human CD47 antibody B6H12.