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.