Antifugetactic agents for the treatment of cancers

Abstract

This invention provides methods and compositions for modulating movement of eukaryotic cells with migratory capacity. More specifically, the invention provides anti-fugetactic agents and methods for the use thereof in enhancing an immune response.

What is claimed is: 
     
         1 . A method for mitigating immune cell-specific fugetactic activity of a cancer or tumor having fugetactic activity in a mammal, which method comprises administering a pharmaceutical composition comprising an anti-fugetactic agent which targets CXCR4 receptors, wherein said composition is administered in an amount effective to mitigate the fugetactic activity of said cancer or tumor, wherein the administration is sustained so as to initiate and maintain mitigation of said fugetactic activity, wherein said anti-fugetactic agent is 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane]. 
     
     
         2 . The method of  claim 1 , wherein after said administration migration of immune cells to the cancer or tumor is increased. 
     
     
         3 . The method of  claim 2 , wherein the immune cells comprise T cells and wherein the T cells infiltrate the cancer or tumor. 
     
     
         4 . The method of  claim 1 , wherein said cancer or tumor is selected from the group consisting of biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer, gastric cancer; hematological neoplasms; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms; liver cancer; lung cancer; lymphomas; neuroblastomas; oral cancers; ovarian cancers; pancreas cancer; prostate cancer; rectal cancer; sarcomas; skin cancers; testicular cancers, stromal tumors; germ cell tumors; thyroid cancers; and renal cancers. 
     
     
         5 . The method of  claim 1 , further comprising administering an anti-cancer agent to the mammal. 
     
     
         7 . The method of  claim 5  wherein said anti-cancer agent is co-administered with said anti-fugetactic agent. 
     
     
         8 . The method of  claim 5  wherein said anti-cancer agent is administered during mitigation of the fugetactic activity. 
     
     
         9 . The method of  claim 5 , wherein said anti-cancer agent is selected from the group consisting of Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophospha-mide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflorithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Fluorocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydro-chloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-Ia; Interferon Gamma-Ib; Iproplatini; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Podofilox; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Taxotere; Tecogalan Sodium; Tegafur, Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporlin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate Virlrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride. 
     
     
         10 . The method of  claim 9 , wherein the anti-cancer agent is cisplatin. 
     
     
         11 . The method of  claim 9 , wherein the anti-cancer agent is paclitaxel. 
     
     
         12 . The method of  claim 1 , wherein the anti-fugetactic agent is in a sustained release formulation. 
     
     
         13 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         14 . The method of  claim 1 , wherein cancer or tumor size is reduced. 
     
     
         15 . The method of  claim 1 , wherein mitigation of the fugetactic activity comprises down-regulation of said fugetactic activity. 
     
     
         16 . The method of  claim 1 , wherein the effective amount is at least about 0.01 mg/kg/day. 
     
     
         17 . The method of  claim 1 , wherein the effective amount is about 0.01 mg/kg/day to about 100 mg/kg/day. 
     
     
         18 . The method of  claim 1 , wherein the effective amount is about 0.01 mg/kg/day to about 10 mg/kg/day. 
     
     
         19 . The method of  claim 1 , wherein said effective amount is about 0.08 mg/mL to about 0.25 mg/mL. 
     
     
         20 . A method for treating a cancer or tumor in a mammal, said cancer or tumor having a fugetactic activity, which method comprises administering a pharmaceutical composition comprising an anti-fugetactic agent which targets CXCR4 receptors in an amount effective to mitigate the fugetactic activity of said cancer or tumor, wherein the administration is sustained so as to initiate and maintain mitigation of said fugetactic activity, wherein said anti-fugetactic agent is 1,1′[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane] and further comprising administering to said mammal an anti-cancer agent so as to treat the cancer or tumor. 
     
     
         21 . The method of  claim 20 , wherein said anti-cancer agent is selected from the group consisting of Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophospha-mide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflorithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Fluorocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydro-chloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-Ia; Interferon Gamma-Ib; Iproplatini; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Podofilox; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Taxotere; Tecogalan Sodium; Tegafur, Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporlin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate Virlrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride. 
     
     
         22 . The method of  claim 21 , wherein the anti-cancer agent is cisplatin. 
     
     
         23 . The method of  claim 21 , wherein the anti-cancer agent is paclitaxel. 
     
     
         24 . The method of  claim 20 , wherein said cancer or tumor is selected from the group consisting of biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer, gastric cancer; hematological neoplasms; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms; liver cancer; lung cancer; lymphomas; neuroblastomas; oral cancers; ovarian cancers; pancreas cancer; prostate cancer; rectal cancer; sarcomas; skin cancers; testicular cancers, stromal tumors; germ cell tumors; thyroid cancers; and renal cancers. 
     
     
         25 . The method of  claim 21  wherein said anti-cancer agent is co-administered with said anti-fugetactic agent. 
     
     
         26 . The method of  claim 21  wherein said anti-cancer agent is administered during mitigation of the fugetactic activity so as to treat the cancer or tumor. 
     
     
         27 . The method of  claim 20 , wherein after said administration migration of immune cells to the cancer or tumor is increased. 
     
     
         28 . The method of  claim 27 , wherein the immune cells comprise T cells and wherein the T cells infiltrate the cancer or tumor. 
     
     
         29 . The method of  claim 20 , wherein the anti-fugetactic agent is in a sustained release formulation. 
     
     
         30 . The method of  claim 20 , wherein the mammal is a human. 
     
     
         31 . The method of  claim 20 , wherein cancer or tumor size is reduced. 
     
     
         32 . The method of  claim 20 , wherein mitigation of the fugetactic activity comprises down-regulation of said fugetactic activity. 
     
     
         33 . The method of  claim 20 , wherein the effective amount is at least about 0.01 mg/kg/day. 
     
     
         34 . The method of  claim 20 , wherein the effective amount is about 0.01 mg/kg/day to about 100 mg/kg/day. 
     
     
         35 . The method of  claim 20 , wherein the effective amount is about 0.01 mg/kg/day to about 10 mg/kg/day. 
     
     
         36 . The method of  claim 20 , wherein said effective amount is about 0.08 mg/mL to about 0.25 mg/mL. 
     
     
         37 . A method for mitigating immune cell-specific fugetactic activity of a cancer or tumor in a mammal, which method comprises administering 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]. 
     
     
         38 . A method for mitigating immune cell-specific fugetactic activity of a cancer or tumor in a mammal, which method comprises administering 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane] and an anti-cancer agent.