Novel use of ansamycin antibiotics and method of screening novel angiogenesis inhibitor

Abstract

The present invention provides novel angiogenesis inhibitors effective, safe and highly practical for inhibition of angiogenesis in various diseases, and a method for screening the same. The active ingredients of the angiogenesis inhibitors of the present invention comprise ansamycin antibiotics such as rifampicin, rifamycin SV and 3-formyl rifamycin, which have long been used extensively as antibacterial agents for treating tuberculosis or Gram-positive bacterial infections. The active ingredients of the present invention have excellent angiogenesis-inhibiting activity. The angiogenesis inhibitor of the present invention is effective for inhibition of angiogenesis in malignant tumors, diabetic retinopathy, retinal angiogenesis, inflammatory diseases, and angiogenesis accompanying cardiovascular remodeling, etc., and can be used as therapeutic agents against each disease, etc. Further, the screening method of the present invention makes it possible to perform an effective screening of angiogenesis-inhibiting substances by detecting angiogenesis-inhibiting signals based on gene expression levels.

1 . An angiogenesis inhibitor containing an ansamycin antibiotic or a pharmacologically acceptable derivative thereof as an active ingredient.  
   
   
       2 . The angiogenesis inhibitor according to  claim 1 , wherein the ansamycin antibiotic is rifampicin, rifamycin SV or 3-formyl rifamycin.  
   
   
       3 . The angiogenesis inhibitor according to  claim 1 , wherein the pharmacologically acceptable derivative is a pharmacologically acceptable salt or a hydrate thereof.  
   
   
       4 . The angiogenesis inhibitor according to  claim 1 , wherein angiogenesis in a malignant tumor is inhibited.  
   
   
       5 . The angiogenesis inhibitor according to  claim 1 , wherein angiogenesis in diabetic retinopathy is inhibited.  
   
   
       6 . The angiogenesis inhibitor according to  claim 1 , wherein angiogenesis in retinal angiogenesis is inhibited.  
   
   
       7 . The angiogenesis inhibitor according to  claim 1 , wherein angiogenesis in an inflammatory disease is inhibited.  
   
   
       8 . The angiogenesis inhibitor according to  claim 1 , wherein angiogenesis accompanying cardiovascular remodeling is inhibited.  
   
   
       9 . A method for screening an angiogenesis-inhibiting substance wherein a test substance is added to cultured vascular endothelial cells, and an angiogenesis-inhibiting signal based on gene expression level is detected.  
   
   
       10 . The method for screening an angiogenesis-inhibiting substance according to  claim 9 , wherein the angiogenesis-inhibiting signal based on reduced gene express ion level in a cultured cell line is similar to the change induced by endostatin at a concentration showing a tumor regression effect.  
   
   
       11 . The method for screening an angiogenesis-inhibiting substance according to  claim 9 , wherein the angiogenesis-inhibiting signal based on reduced gene expression level in a cultured cell line consists of one or more of an immediate early response gene or a related gene thereof, a growth/cell-cycle-related gene, a cell adhesion factor, a vasoactive factor, and a vasoactive factor receptor gene expressed in a vascular endothelial cell.  
   
   
       12 . An angiogenesis inhibitor containing an ansamycin antibiotic or a pharmacologically acceptable derivative thereof as an active ingredient; 
 wherein the ansamycin antibiotic is rifampicin, rifamycin SV or 3-formyl rifamycin and the pharmacologically acceptable derivative is a pharmacologically acceptable salt or a hydrate thereof.    
   
   
       13 . An angiogenesis inhibitor according to  claim 2 , wherein angiogenesis in a malignant tumor is inhibited.  
   
   
       14 . An angiogenesis inhibitor according to  claim 12 , wherein angiogenesis in a malignant tumor is inhibited.  
   
   
       15 . The angiogenesis inhibitor according to  claim 2 , wherein angiogenesis in diabetic retinopathy is inhibited.  
   
   
       16 . The angiogenesis inhibitor according to  claim 12 , wherein angiogenesis in diabetic retinopathy is inhibited.  
   
   
       17 . The angiogenesis inhibitor according to  claim 2 , wherein angiogenesis in retinal angiogenesis is inhibited.  
   
   
       18 . The angiogenesis inhibitor according to  claim 12 , wherein angiogenesis in retinal angiogenesis is inhibited.  
   
   
       19 . The angiogenesis inhibitor according to  claim 2 , wherein angiogenesis in an inflammatory disease is inhibited.  
   
   
       20 . The angiogenesis inhibitor according to  claim 12 , wherein angiogenesis in an inflammatory disease is inhibited.  
   
   
       21 . The angiogenesis inhibitor according to  claim 2 , wherein angiogenesis accompanying cardiovascular remodeling is inhibited.  
   
   
       22 . The angiogenesis inhibitor according to  claim 12 , wherein angiogenesis accompanying cardiovascular remodeling is inhibited.  
   
   
       23 . The method for screening an angiogenesis-inhibiting substance according to  claim 10 , wherein the angiogenesis-inhibiting signal based on reduced gene express ion level in a cultured cell line consists of one or more of an immediate early response gene or a related gene thereof, a growth/cell-cycle-related gene, a cell adhesion factor, a vasoactive factor, and a vasoactive factor receptor gene expressed in a vascular endothelial cell.