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, IL4, 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.

We claim:  
     
         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 in vitro and/or in vivo;  
 (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;  
 (vi) is not an endotoxin; and  
   (b) 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.    
     
     
         2 . The combination according to  claim 1 , wherein said anticancer agent(s) is selected from the group consisting of a chemotherapeutic drug, radiation, a gene therapy and an antisense oligonucleotide.  
     
     
         3 . The combination according to  claim 2 , wherein said anticancer agent(s) is a chemotherapeutic drug, interleukin or interferon.  
     
     
         4 . The combination according to any one of claims  1 ,  2  or  3 , wherein at least one of said one or more anticancer agent(s) is a chemotherapeutic drug.  
     
     
         5 . The combination of  claim 4 , wherein the chemotherapeutic drug is gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin or mitoxantrone.  
     
     
         6 . Use of the combination according to any one of claims  1 ,  2 ,  3 ,  4  or  5  in the manufacture of a medicament.  
     
     
         7 . Use of the combination according to any one of claims  1 ,  2 ,  3 ,  4  or  5  in the manufacture of a pharmaceutical kit.  
     
     
         8 . 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 in vitro and/or in vivo;    (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;    (vi) is not an endotoxin; and    (b) a dosage unit of one or more chemotherapeutic drug(s) 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 chemotherapeutic drug(s) alone.    
     
     
         9 . The kit according to  claim 8 , wherein said one or more chemotherapeutic drug(s) is gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin or mitoxantrone.  
     
     
         10 . 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 in vitro and/or in vivo;  
 (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;  
 (vi) is not an endotoxin;  
   (b) one or more chemotherapeutic drug(s); 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 chemotherapeutic drug(s) alone.    
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein at least one of said one or more chemotherapeutic drug(s) is gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin or mitoxantrone.  
     
     
         12 . The pharmaceutical composition according to  claim 10  or  11 , formulated into a sterile solution, a lyophilate, a pill, a tablet, a cream, a capsule, a suppository, a gelatin capsule, a soft gelatin capsule, a gel, a membrane or a tubelet.  
     
     
         13 . The combination according to any one of claims  1 ,  2 ,  3 ,  4  or  5  for use in the treatment of cancer.  
     
     
         14 . The combination according to  claim 13 , wherein said composition and said one or more anticancer agent(s) are suitable for separate, concurrent or simultaneous administration.  
     
     
         15 . The combination according to  claim 13  or  14 , wherein said cancer is 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, head or neck cancer.  
     
     
         16 . The combination according to  claim 13 , wherein said cancer is melanoma, said anticancer agent is dacarbazine and said anticancer agent is suitable for concurrent administration with the composition.  
     
     
         17 . The combination according to  claim 13 , wherein said cancer is breast cancer, said anticancer agent is taxol and said anticancer agent is suitable for concurrent administration with the composition.  
     
     
         18 . The combination according to any one of claims  13 ,  14 ,  15 ,  16  or  17 , wherein said composition and/or said anticancer agent(s) are suitable for administration via oral, topical, rectal, parenteral, local, inhalant or intracerebral delivery.  
     
     
         19 . The combination according to  claim 18 , wherein said parenteral delivery is achieved via intramuscular injection.  
     
     
         20 . The pharmaceutical composition according to any one of claims  10 ,  11  or  12  for use in the treatment of cancer.  
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein said cancer is 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, head or neck cancer.  
     
     
         22 . The pharmaceutical composition according to  claim 20 , wherein said cancer is melanoma and said anticancer agent is dacarbazine.  
     
     
         23 . The pharmaceutical composition according to  claim 20 , wherein said cancer is breast cancer and said anticancer agent is taxol.  
     
     
         24 . The pharmaceutical composition according to any one of claims  20 ,  21 ,  22  or  23 , wherein said pharmaceutical composition is suitable for administration via oral, topical, rectal, parenteral, local, inhalant or intracerebral delivery.  
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein said parenteral delivery is achieved via intramuscular injection.  
     
     
         26 . Use of the pharmaceutical composition according to any one of claims  10 ,  11  or  12 , for administration to a patient in need thereof.  
     
     
         27 . Use of the combination according to any one of claims  1 ,  2 ,  3 ,  4  or  5 , for administration to a patient in the treatment of cancer.  
     
     
         28 . The use according to  claim 27 , wherein said composition and one or more anticancer agent(s) are administered separately, concurrently or simultaneously.  
     
     
         29 . A method for treating cancer, comprising the step of administering a therapeutically effective amount of the combination of any one of claims  1 ,  2 ,  3 ,  4  or  5  to a patient in need of such the  
     
     
         30 . A method for treating cancer comprising administering a therapeutically effective amount of a composition and one or more anticancer agent(s) to a patient in need thereof, wherein said composition comprises small molecular weight components of less than 3000 daltons, and has the following properties: 
 (a) is extracted from bile of animals;    (b) is capable of stimulating monocytes and/or macrophages in vitro and/or in vivo;    (c) is capable of modulating tumor necrosis factor production and/or release;    (d) contains no measurable level of IL-1α, IL-1β, TNF, IL-6, IL-8, IL-4, GM-CSF or IFN-gamma;    (e) is not cytotoxic to human peripheral blood mononuclear cells;    (f) is not an endotoxin;    and wherein said composition and said anticancer agent(s) are formulated for administration to a patient in need thereof.    
     
     
         31 . The method according to  claim 30 , wherein said anticancer agent(s) is selected from the group consisting of a chemotherapeutic drug, radiation, a gene therapy and an antisense olig  
     
     
         32 . The method according to  claim 31 , wherein said anticancer agent(s) is a chemotherapeutic drug, interleukin or interferon  
     
     
         33 . The method according to any one of claims  30 ,  31  or  32 , wherein at least one of said one or more anticancer agent(s) is a chemotherapeutic drug.  
     
     
         34 . The method according to  claim 33 , wherein the chemotherapeutic drug is gemcitabine, 5-fluorouracil, dacarbazine, taxol, taxotere, cisplatin or mitoxantrone.  
     
     
         35 . The method according to any one of claims  29 ,  30 ,  31 ,  32 ,  33  or  34 , wherein said cancer is 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, head or neck cancer.  
     
     
         36 . The method according to any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34  or  35 , wherein said combination is formulated into a sterile solution, a lyophilate, a pill, a tablet, a cream, a capsule, a suppository, a gelatin capsule, a soft gelatin capsule, a gel, a membrane or a tubelet.  
     
     
         37 . The method according to any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35  or  36 , wherein said administering is achieved by means of oral, topical, rectal, parenteral, local, inhalant, or intracerebral delivery.  
     
     
         38 . The method of  claim 37 , wherein said parenteral delivery is achieved via intramuscular injection.  
     
     
         39 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein said cancer is pancreatic cancer.  
     
     
         40 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein said cancer is melanoma.  
     
     
         41 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein said cancer is breast cancer.  
     
     
         42 . The method of  claim 39  wherein one of the one or more anticancer agent(s) is gemcitabine.  
     
     
         43 . The method of  claim 39  wherein one of the one or more anticancer agent(s) is 5-fluorouracil.  
     
     
         44 . The method of  claim 41  wherein one of the one or more anticancer agent(s) is dacarbazine.  
     
     
         45 . The method of  claim 41  wherein one of the one or more anticancer agent(s) is taxol.  
     
     
         46 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein peripheral blood monocytes and/or tumor associated macrophages are stimulated to express cytocidal activity in a manner that is insensitive to the inhibitory effects of prostaglandins.  
     
     
         47 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein suitable modulation of the immune system is elicited in a patient in need of such modulation by activating macrophages and/or monocytes to produce and/or release cytokines or promote activity to seek and remove or destroy cancerous cells.  
     
     
         48 . The method of any one of claims  29 ,  30 ,  31 ,  32 ,  33 ,  34 ,  35 ,  36 ,  37  or  38 , wherein the release of TNF, Il-1β and GM-CSF is stimulated.