Fourteen-membered ring macrolides as anti-angiogenic compounds

Macrolide antibiotics have been widely used for infectious diseases since the 1950s. For the last decade, 14-membered ring macrolides, of which erythromycin is the prototype, have attracted a great deal of attention because of their additional therapeutical activities far beyond antibiotics. First, erythromycin has prokinetic effects on the gastrointestinal tract as a motilin receptor agonist. Second, 14-membered ring macrolides, including erythromycin, roxithromycin and clarithromycin have immunomodulating or anti-inflammatory effects in a variety of settings, whereas 16-membered ring macrolides do not. Recently, we found roxithromycin and clarithromycin suppressed angiogenesis and tumor growth in vivo. Both these drugs are administered per os with insignificant side-effects. Their safety has been established through the experience of long-term treatment for chronic lower respiratory infectious diseases such as diffuse panbronchiolitis. Although the precise mechanisms have not yet been clarified, 14-membered ring macrolides and their derivatives are promising in therapeutic applications for solid tumors.