Combination Preparation of a Biological Response Modifier and an Anticancer Agent and Uses Thereof

Abstract

The present invention provides anticancer biological response modifier combinations. In accordance with an aspect of the present invention, there is provided a combination comprising: (i) a composition comprising small molecular weight components of less than 3000 daltons, and having the following properties: is extracted from bile of animals; is capable of stimulating monocytes and/or macrophages in vitro and/or in vivo; is capable of modulating tumor necrosis factor production and/or release; contains no measurable level of IL-1α, IL-1β, TNF, IL-6, IL-8, IL-4, GM-CSF or IFN-gamma; is not cytotoxic to human peripheral blood mononuclear cells; is not an endotoxin; and (ii) one or more anticancer agent(s), wherein said combination has therapeutic synergy or improves the therapeutic index in the treatment of cancer over the composition or the anticancer agent(s) alone. Another aspect of the present invention provides the use of this combination in the manufacture of a medicament or a pharmaceutical kit and in the treatment of cancer.

1 . A combination comprising:
 (a) a composition comprising small molecular weight components of less than 3000 daltons, and having the following properties:
 (i) is extracted from bile of animals; 
 (ii) is capable of stimulating monocytes and/or macrophages; 
 (iii) is capable of modulating tumor necrosis factor production and/or release; 
 (iv) contains no measurable level of IL-1α, IL-1β, TNF, IL-6, IL-8, IL-4, GM-CSF or IFN-gamma; 
 (v) is not cytotoxic to human peripheral blood mononuclear cells; and 
 (vi) is not an endotoxin; and 
   (b) one or more anticancer agents,   wherein said combination has therapeutic synergy or improves the therapeutic index in the treatment of cancer over the composition or the one or more anticancer agents alone.   
     
     
         2 . The combination according to  claim 1 , wherein said one or more anticancer agents are selected from the group consisting of a chemotherapeutic drug, radiation, a gene therapy and an antisense oligonucleotide. 
     
     
         3 . The combination according to  claim 1 , wherein said one or more anticancer agents are selected from the group consisting of a chemotherapeutic drug, an interleukin and an interferon. 
     
     
         4 . The combination according to  claim 1 , wherein at least one of said one or more anticancer agents is a chemotherapeutic drug. 
     
     
         5 . The combination according to  claim 4 , wherein the chemotherapeutic drug is selected from the group consisting of gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin and mitoxantrone. 
     
     
         6 . The combination according to  claim 1 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, lung cancer, Kaposi's sarcoma, leukemia, lymphoma, gastric cancer, colon cancer, colorectal cancer, esophageal cancer, renal cancer, and head and neck cancer. 
     
     
         7 . The combination according to  claim 1 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, ovarian cancer and lung cancer. 
     
     
         8 . The combination according to  claim 1 , wherein said composition and said one or more anticancer agents are formulated for separate, concurrent or simultaneous administration. 
     
     
         9 . The combination according to  claim 1 , wherein said composition and said one or more anticancer agents are formulated for administration via of oral, topical, rectal, parenteral, local, inhalant or intracerebral delivery, or a combination thereof. 
     
     
         10 . The combination according to  claim 1 , wherein said composition is formulated for intramuscular injection. 
     
     
         11 . A pharmaceutical kit comprising:
 (a) a dosage unit of a composition and a pharmaceutically acceptable carrier wherein the composition comprises small molecular weight components of less than 3000 daltons, and has the following properties:
 (i) is extracted from bile of animals; 
 (ii) is capable of stimulating monocytes and/or macrophages; 
 (iii) is capable of modulating tumor necrosis factor production and/or release; 
 (iv) contains no measurable level of IL-1α, IL-1β, TNF, IL-6, IL-8, IL-4, GM-CSF or IFN-gamma; 
 (v) is not cytotoxic to human peripheral blood mononuclear cells; and 
 (vi) is not an endotoxin; and 
   (b) a dosage unit of one or more anticancer compounds and a pharmaceutically acceptable carrier,   said (a) and (b) being provided in amounts that have therapeutic synergy or that improve the therapeutic index in the treatment of cancer over the composition or the one or more anticancer compounds alone.   
     
     
         12 . The kit according to  claim 11 , wherein at least one of said one or more anticancer compounds is selected from the group consisting of gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin and mitoxantrone. 
     
     
         13 . The pharmaceutical kit according to  claim 11 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, lung cancer, Kaposi's sarcoma, leukemia, lymphoma, gastric cancer, colon cancer, colorectal cancer, esophageal cancer, renal cancer, and head and neck cancer. 
     
     
         14 . The pharmaceutical kit according to  claim 11 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, ovarian cancer and lung cancer. 
     
     
         15 . The pharmaceutical kit according to  claim 11 , wherein said composition is formulated for intramuscular injection. 
     
     
         16 . A pharmaceutical composition comprising:
 (a) a composition comprising small molecular weight components of less than 3000 daltons, and having the following properties:
 (i) is extracted from bile of animals; 
 (ii) is capable of stimulating monocytes and/or macrophages; 
 (iii) is capable of modulating tumor necrosis factor production and/or release; 
 (iv) contains no measurable level of IL-1α, IL-1β, TNF, IL-6, IL-8, IL-4, GM-CSF or IFN-gamma; 
 (v) is not cytotoxic to human peripheral blood mononuclear cells; and 
 (vi) is not an endotoxin; 
   (b) one or more anticancer compounds; and   (c) a pharmaceutically acceptable carrier;   wherein said pharmaceutical composition has therapeutic synergy or improves the therapeutic index in the treatment of cancer over the composition or the one or more anticancer compounds alone.   
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein at least one of said one or more anticancer compounds is selected from the group consisting of gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin and mitoxantrone. 
     
     
         18 . The pharmaceutical composition according to  claim 16 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, lung cancer, Kaposi's sarcoma, leukemia, lymphoma, gastric cancer, colon cancer, colorectal cancer, esophageal cancer, renal cancer, and head and neck cancer. 
     
     
         19 . The pharmaceutical composition according to  claim 16 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, ovarian cancer and lung cancer. 
     
     
         20 . A method for treating cancer comprising administering a therapeutically effective amount of the combination according to  claim 1  to a patient in need thereof. 
     
     
         21 . The method according to  claim 20 , wherein said one or more anticancer agents are selected from the group consisting of a chemotherapeutic drug, radiation, a gene therapy and an antisense oligonucleotide. 
     
     
         22 . The method according to  claim 20 , wherein said one or more anticancer agents are selected from the group consisting of a chemotherapeutic drug, an interleukin and an interferon. 
     
     
         23 . The method according to  claim 20 , wherein at least one of said one or more anticancer agents is a chemotherapeutic drug. 
     
     
         24 . The method according to  claim 23 , wherein the chemotherapeutic drug is selected from the group consisting of gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin and mitoxantrone. 
     
     
         25 . The method according to  claim 20 , wherein administration of said composition and said one or more anticancer agents is via oral, topical, rectal, parenteral, local, inhalant, or intracerebral delivery, or a combination thereof. 
     
     
         26 . The method according to  claim 20 , wherein administration of said composition is via intramuscular injection. 
     
     
         27 . The method according to  claim 20 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, lung cancer, Kaposi's sarcoma, leukemia, lymphoma, gastric cancer, colon cancer, colorectal cancer, esophageal cancer, renal cancer, and head and neck cancer. 
     
     
         28 . The method according to  claim 20 , wherein said cancer is selected from the group consisting of pancreatic cancer, melanoma, breast cancer, ovarian cancer and lung cancer. 
     
     
         29 . The method according to  claim 20 , wherein administration of said composition and said one or more anticancer agents is separate, concurrent, or simultaneous.