title: A new antitumor antibiotic, FK973: its metabolism in the blood and the antitumor effects of its metabolites on experimental models.
abstract: Our previous studies showed that a new, substituted dihydrobenzoxazine, FK973 (11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo+ ++- [7.4.1.0(2,7).0(10,12)tetradeca-2,4,6-trien-6,9-diyl diacetate), which is a triacetylated derivative of the fermentation product FR900482 of Streptomyces sandaensis No. 6897, had potent antitumor effects on experimental tumors in vivo and in vitro. In the present study, we investigated the metabolism of FK973 in the blood of human and animals and the antitumor effects of its metabolites. After the incubation of FK973 in the blood (hemolysate) or serum of humans, dogs, rats and mice, it was rapidly metabolized to two diacetates and a monoacetate, and slowly to FR900482. FK973 and all its deacetylated metabolites showed strong cytotoxicity on in vitro cultured murine L1210 leukemia cells, and the cytotoxicity of FK973 was the most potent. In the vivo experiments, FK973 and its metabolites prolonged the life of mice bearing ascitic P388 leukemia, and it potently inhibited the growth of murine B16 melanoma and Colon 38 adenocarcinoma implanted subcutaneously in mice. FK973 was the most effective compound. Thus, these results suggest that the antitumor effects of FK973 are stronger than those of its deacetylated metabolites produced in the blood of humans and animals.
authors.affiliation: Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Masuda
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Takagaki
authors.forename: K
authors.initials: K
authors.lastname: Noda
authors.forename: K
authors.initials: K
authors.lastname: Shimomura
authors.forename: H
authors.initials: H
authors.lastname: Noguchi
authors.forename: F
authors.initials: F
authors.lastname: Shibayama
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D010078:Oxazines / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D010078:Oxazines; C054974:FK 973