EFFECTS OF CYTOGENIN, A NOVEL MICROBIAL PRODUCT, ON EMBRYONIC AND TUMOR CELL-INDUCED ANGIOGENIC RESPONSES IN-VIVO

Cytogenin (8-hydroxy-3-hydroxymethyl-6-methoxyisocoumarin) is a new mi crobial product with antitumor and anti-rheumatoid arthritis effects i n vivo when administered orally, although its mechanism(s) of action i s not known well. Both neoplasia and rheumatoid arthritis are referred to as angiogenesis-dependent diseases. The aim of the present study w as to investigate the effects of cytogenin on both physiological and p athological angiogenesis, using the growing chick embryo chorioallanto ic membrane and mouse dorsal air sac assay systems, respectively. The microbial product at doses up to 100 mu g/egg did not significantly af fect embryonic angiogenesis when topically placed on the surface of th e chorioallantoic membrane, suggesting that it has no effect on the ph ysiological (or normal) angiogenic response. By contrast, systemic adm inistration of cytogenin (100 mg/kg p.o., for 5 consecutive days) sign ificantly suppressed angiogenesis induced by malignant tumor cells (S- 180), one of pathological neovascularization, in a mice dorsal air sac assay system. Pharmacokinetic studies in mice revealed that the maxim al concentration of cytogenin in plasma after a single 100 mg/kg oral dose of the compound was 32 mu M. In vitro experiments involving cultu red vascular endothelial cells showed that cytogenin at concentrations determined by pharmacokinetic study, had little effect on plasminogen activator secretion, tube formation and the proliferation of endothel ial cells. These results suggest that cytogenin is a novel oral antian giogenic agent, that the mechanism of its antiangiogenic action contri butes to its suppressive effects on both tumor growth and rheumatoid a rthritis that we previously found and that it could be developed as a potential therapeutic agent for cancer, rheumatoid arthritis and other angiogenesis-dependent disorders such as diabetic retinopathy.