Compositions and methods for restoring sensitivity of tumor cells to antitumor therapy and inducing apoptosis

Abstract

Methods and compositions for restoring sensitivity to the antitumorigenic effects of antiestrogen therapy and/or cytotoxic therapy and inducing cell apoptosis are provided. Contacting tumor cells to GP88 antagonists (e.g., anti-GP88 antibodies, anti-GP88 antisense nucleic acids, GP88 siRNA, and small molecules) induces apoptosis and restores sensitivity to the antitumorigenic effects of antiestrogen therapy and cytotoxic therapy.

1 . A method for restoring sensitivity to antitumorigenic effects of antiestrogen therapy, comprising contacting a tumor cell that is nonsensitive to the antitumorigenic effects of antiestrogen therapy with a PCDGF antagonist in an amount effective to restore sensitivity to antitumorigenic effects of antiestrogen therapy.  
     
     
         2 . The method of  claim 1 , wherein the antiestrogen therapy is selected from the group consisting of tamoxifen, raloxifene, aromatase inhibitors, and estrogen receptor down-regulators.  
     
     
         3 - 4 . (canceled)  
     
     
         5 . The method of  claim 1 , wherein the PCDGF antagonist is an anti-PCDGF receptor antibody.  
     
     
         6 . The method of  claim 5 , wherein the antibody is produced from a hybridoma cell line selected from the group consisting of 6G8 hybridoma cell line (ATCC Accession Number PTA-5263) and 5A8 hybridoma cell line (ATCC Accession Number PTA-5594).  
     
     
         7 . The method of  claim 1 , wherein the PCDGF antagonist is a PCDGF antisense nucleic acid.  
     
     
         8 . The method of  claim 7 , wherein the PCDGF antagonist is siRNA.  
     
     
         9 . The method of  claim 7 , wherein the PCDGF antisense nucleic acid is complementarity to PCDGF mRNA so as to cause hybridization between the antisense nucleic acid and said PCDGF mRNA to inhibit expression of PCDGF.  
     
     
         10 . The method of  claim 1  wherein the tumor is selected from the group consisting of prostate, head and neck, nasopharynx, thyroid, pancreas, bladder, cervix, colorectal, blood, liver, kidney, breast, bone, bone marrow, testes, ovaries, brain, neural, colon, and lung tumors.  
     
     
         11 . A method of inducing apoptosis in a tumor cell, comprising contacting a PCDGF antagonist to a tumor cell in an amount effective to induce apoptosis of the tumor cell.  
     
     
         12 . The method of  claim 11 , wherein the tumor cell is selected from the group consisting of prostate, head and neck, neural, nasopharynx, thyroid, bladder, cervix, colorectal, blood, liver, kidney, breast, bone, pancreas, bone marrow, testes, ovaries, brain, neural, colon, and lung tumors.  
     
     
         13 - 14 . (canceled)  
     
     
         15 . The method of  claim 11 , wherein the PCDGF antagonist is an anti-PCDGF receptor antibody.  
     
     
         16 . The method of  claim 15 , wherein the antibody is produced from a hybridoma cell line selected from the group consisting of 6G8 hybridoma cell line (ATCC Accession Number PTA-5263) and 5A8 hybridoma cell line (ATCC Accession Number PTA-5594).  
     
     
         17 . The method of  claim 11 , wherein the PCDGF antagonist is a PCDGF antisense nucleic acid.  
     
     
         18 . The method of  claim 11 , wherein the GP88 antagonist is siRNA.  
     
     
         19 - 23 . (canceled)  
     
     
         24 . A pharmaceutical composition for restoring sensitivity to antitumorigenic effects of antiestrogen therapy, comprising a GP88 PCDGF antagonist, a second antitumorigenic agent, and a pharmaceutically acceptable carrier.  
     
     
         25 . The composition of  claim 24 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of tablets, pills, injections, infusions, inhalations, transdermal patches, and suppositories.  
     
     
         26 . The composition of  claim 24 , wherein the antitumorigenic agent comprises an antiestrogen.  
     
     
         27 . The composition of  claim 26 , wherein the antiestrogen is selected from the group consisting of tamoxifen, raloxifene, aromatase inhibitors, and estrogen receptor down-regulators.  
     
     
         28 . The composition of  claim 24 , wherein the second antitumorigenic compound comprises a cytotoxic compound.  
     
     
         29 . The composition of  claim 26 , wherein the cytotoxic compound is selected from the group consisting of Altretamine, Bleomycin, Busulphan, Calcium Folinate, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Liposomal doxorubicin, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pentostatin, Procarbazine, Raltitrexed, Streptozocin, Tegafur-uracil, Temozolomide, Thiotepa, Tioguanine/Thioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, and Vinorelbine.