Antitumor effect of keto-diepoxides isolated from the fungus Nattrassia mangiferae.
A novel keto-diepoxide Sch 49209 and its derivative Sch 50672, produced by the fungus Nattrassia mangiferae, inhibited tumor cell invasion through an artificial basement membrane. These compounds, at nontoxic concentrations, 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 microM, respectively, when cells were incubated with drugs for 5 h. Sch 49209 inhibited both tumor cell invasion and cell motility to the same extent under conditions that did not cause any apparent cytotoxicity. Sch 4209 and Sch 50672, however, inhibited the growth of ras-transformed cells in a semisolid medium in a 5-day culture with IC50 values of 0.6 and 2.4 microM, respectively. They also inhibited the anchorage-dependent growth of pT24 cells in vitro with IC50 values of 0.5 and 0.9 microM for Sch 40209 and Sch 50672, respectively. Using the murine lung epidermoid 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 doses ranging from 2 to 10 mg/kg. These compounds also decreased the formation of spontaneous lung metastasis in this model. Sch 50672 inhibited the growth of human tumor xenografts, SW620 and A431, in athymic mode mice. Our data suggest that keto-diepoxides inhibit tumor growth and metastasis and that this activity may be due, in part, to anti-invasive activity.
King
I
I
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Blood
C
C
Chu
M
M
Patel
M
M
Liu
M
M
Li
Z
Z
Robertson
N
N
Maxwell
E
E
Catino
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D013141:Spiro Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D013141:Spiro Compounds; C089783:diepoxin sigma; C096157:Sch 50672; D010741:Phospholipases A