ANTITUMOR EFFECT OF KETO-DIEPOXIDES ISOLATED FROM THE FUNGUS NATTRASSIA-MANGIFERAE

A novel keto-diepoxide Sch 49909 and its derivative Sch 50672, produce d by the fungus Nattrassia mangiferae, inhibited tumor cell invasion t hrough an artificial basement membrane. These compounds, at nontoxic c oncentrations, inhibited invasion of HT-1080 cells in a dose-dependent manner. The IC50 values for Sch 49209 and Sch 50672 were 0.75 and 8 m u M, respectively when cells were incubated with drugs for 5 h. Sch 49 209 inhibited both tumor cell invasion and cell motility to the same e xtent under conditions that did not cause any apparent cytotoxicity. S ch 40209 and Sch 50672, however, inhibited the growth of ras-transform ed cells in a semisolid medium in a 5-day culture with IC50 values of 0.6 and 2.4 mu M, respectively, They also inhibited the anchorage-depe ndent growth of pT24 cells in vitro with IC50 values of 0.5 and 0.9 mu M for Sch 40209 and Sch 50672, respectively. Using the murine lung ep idermoid carcinoma M27 cells implanted SC in mice as a model, we found both Sch 49209 and Sch 50672 inhibited the growth of this tumor at do ses ranging from 2 to 10 mg/kg. These compounds also decreased the for mation of spontaneous lung metastasis in this model. Sch 50672 inhibit ed the growth of human tumor xenografts, SW620 and A431, in athymic nu de mice. Our data suggest that keto-diepoxides inhibit tumor growth an d metastasis and that this activity may be due, in part, to anti-invas ive activity.