Method of activation of oxazaphosphorines

Abstract

The present invention provides a method of hydroxylating or oxidizing a compound of interest in a subject (e.g., a cytotoxic oxazaphosphorine prodrug), by administering the compound of interest to the subject; and concurrently administering the subject a metalloporphyrin in an amount effective to hydroxylate or oxidize the compound of interest in the subject.

What is claimed is: 
     
         1 . In a method of treating a subject in need thereof with a cytotoxic oxazaphosphorine prodrug, the improvement comprising:
 concurrently administering said subject a metalloporphyrin in an amount effective to enhance the efficacy of said oxazaphosphorine in said subject.   
     
     
         2 . The method of  claim 1 , wherein said oxazaphosphorine prodrug is selected from the group consisting of cyclophosphamide, ifosfamide, mafosfamide, trofosfamide, and pharmaceutically acceptable salts and prodrugs thereof. 
     
     
         3 . The method of  claim 1 , wherein said subject is afflicted with cancer. 
     
     
         4 . The method of  claim 3 , wherein said cancer is selected from the group consisting of lung, colon, colorectal, liver, breast, prostate, ovarian, brain, and skin cancers or tumors. 
     
     
         5 . The method of  claim 1 , wherein said subject is afflicted with autoimmune disease. 
     
     
         6 . The method of  claim 5 , wherein said autoimmune disease is selected from the group consisting of arthritis, type 1 insulin-dependent diabetes mellitus, adult respiratory distress syndrome, inflammatory bowel disease, dermatitis, thrombotic thrombocytopenic purpura, Sjogren's syndrome, encephalitis, uveitis, leukocyte adhesion deficiency, rheumatoid arthritis, rheumatic fever, Reiter's syndrome, psoriatic arthritis, progressive systemic sclerosis, primary biliary cirrhosis, pemphigus, pemphigoid, necrotizing vasculitis, myasthenia gravis, multiple sclerosis, lupus erythematosus, polymyositis, sarcoidosis, granulomatosis, vasculitis, pernicious anemia, CNS inflammatory disorder, antigen-antibody complex mediated diseases, autoimmune haemolytic anemia, Hashimoto's thyroiditis, Graves disease, habitual spontaneous abortions, Reynard's syndrome, glomerulonephritis, dermatomyositis, chronic active hepatitis, celiac disease, tissue specific autoimmunity, degenerative autoimmunity delayed hypersensitivities, autoimmune complications of AIDS, atrophic gastritis, ankylosing spondylitis and Addison's disease. 
     
     
         7 . The method of  claim 1 , wherein said metalloporphyrin contains a coordinated metal selected from the group consisting of iron, manganese, cobalt, nickel, ruthenium, and copper. 
     
     
         8 . The method of  claim 1 , wherein said metalloporphyrin is administered orally. 
     
     
         9 . The method of  claim 1 , wherein said metalloporphyrin is administered parenterally. 
     
     
         10 . The method of  claim 1 , wherein said patient is afflicted with a tumor and said metalloporphyrin is administered by injection directly into said tumor. 
     
     
         11 . A pharmaceutical composition comprising:
 a cytotoxic oxazaphosphorine prodrug;   a metalloporphyrin in an amount effective to enhance the efficacy of said oxazaphosphorine in a subject; and   a pharmaceutically acceptable carrier.   
     
     
         12 . The composition of  claim 11 , wherein said oxazaphosphorine prodrug is selected from the group consisting of cyclophosphamide, ifosfamide, mafosfamide, trofosfamide, and pharmaceutically acceptable salts and prodrugs thereof. 
     
     
         13 . The composition of  claim 11 , wherein said cytotoxic oxazaposhporine prodrug and said metalloporphyrina are carried by lipid particles. 
     
     
         14 . The composition of  claim 11  in the form of a tablet or capsule. 
     
     
         15 . A method of hydroxylating or oxidizing a compound of interest in a subject, comprising:
 administering said compound of interest to said subject; and   concurrently administering said subject a metalloporphyrin in an amount effective to hydroxylate or oxidize said compound of interest in said subject.   
     
     
         16 . The method of  claim 1 , wherein said compound of interest is a cytotoxic oxazaphosphorine prodrug.