Angiogenesis inhibition by cephalotaxine alkaloids, derivatives, compositions and uses thereof

Abstract

The invention relates to compositions and methods useful in treating or preventing angiogenic disease. The invention provides for compositions comprising cephalotaxine alkaloids as antiangiogenic agents for treatment of a host with an angiogenic disease or for prophylactic treatment of a host to inhibit the onset or progression of an angiogenic disease.

1 . A method of inhibiting the onset or progression of an angiogenic disease in a host, consisting essentially of contacting said host with a cephalotaxine in an amount sufficient to inhibit the onset or progression of an angiogenic disease, wherein angiogenesis associated with said angiogenic disease is inhibited in said host. 
   
   
       2 . The method of  claim 1 , wherein the angiogenic disease is cancer. 
   
   
       3 . The method of  claim 2 , wherein the cancer is characterized by cancer cells that have not yet been vascularized to form a solid tumor. 
   
   
       4 . The method of  claim 1 , wherein the angiogenic disease is an angiogenic disease other than cancer. 
   
   
       5 . The method of  claim 1 , wherein the angiogenic disease is selected from the group consisting of an inflammatory disease, diabetic retinopathy, macular degeneration, angiofibroma, neovascular glaucoma, arteriovenous malformation, nonunion fracture, connective tissue disorder, Osler-Weber syndrome, atherosclerotic plaque, psoriasis, corneal graft neovascularization, Pyogenic granuloma, retrolental fibroplasia, scleroderma, granulations, hemangioma, trachoma, hemophilic joints and vascular adhesions. 
   
   
       6 . The method of  claim 5 , wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis. 
   
   
       7 . The method of  claim 1 , wherein the cephalotaxine comprises homoharringtonine (cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate ester). 
   
   
       8 . The method of  claim 1 , wherein the cephalotaxine comprises a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1  is an ester or an alkyl and wherein R 2  is an ester or an alkyl. 
   
   
       9 . The method of  claim 8 , wherein the cephalotaxine is selected from the group consisting of harringtonine, isoharringtonine, homoharringtonine, deoxyharringtonine, and acetylcephalotaxine. 
   
   
       10 . The method of  claim 5 , wherein the connective tissue disorder is lupus. 
   
   
       11 . The method of  claim 1 , wherein the contacting is by a route selected from the group consisting of oral, intravenous, topical, intravesicular, intraperitoneal, intramuscular, intradermal, subcutaneous and intraarterial. 
   
   
       12 . A method of treating a host with an angiogenic disease comprising contacting the host with a cephalotaxine in an amount sufficient to inhibit angiogenesis associated with the angiogenic disease,
 wherein the angiogenic disease is selected from the group consisting of diabetic retinopathy, inflammatory disease, macular degeneration, angiofibroma, neovascular glaucoma, arteriovenous malformation, nonunion fracture, lupus, Osler-Weber syndrome, atherosclerotic plaque, corneal graft neovascularization, Pyogenic granuloma, retrolental fibroplasia, scleroderma, granulations, hemangioma, trachoma, hemophilic joints and vascular adhesions; and   wherein the angiogenesis associated with the angiogenic disease is inhibited in the host.   
   
   
       13 . The method of  claim 12  wherein the inflammatory disease is selected from the group consisting osteoarthritis, asthma, and pulmonary fibrosis. 
   
   
       14 . The method of  claim 12  wherein the cephalotaxine comprises a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1  is an ester or an alkyl and wherein R 2  is an ester or an alkyl. 
   
   
       15 . The method of  claim 14  wherein the cephalotaxine is selected from the group consisting of harringtonine, isoharringtonine, homoharringtonine, deoxyharringtonine, and acetylcephalotaxine. 
   
   
       16 . The method of  claim 15  wherein the cephalotaxine is homoharringtonine (cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate ester). 
   
   
       17 . The method of  claim 12 , wherein the contacting is by a route selected from the group consisting of oral, intravenous, topical, intravesicular, intraperitoneal, intramuscular, intradermal, subcutaneous and intraarterial.