Abstract-Our previous study showed that FK973 (11-acetyl-8-carbamoyloxy methyl 4 formyl -14 oxa -1,11 diazatetracyclo [7.4.1.02'701 0,1 2]tetradeca 2,4,6 trien-6,9-diyl diacetate), a novel substituted dihydrobenzoxazine, which is a derivative of the fermentation product of Streptomyces sandaensis No. 6897, had strong antitumor effects on experimental tumors in vitro and in vivo. In this report, we investigated its effect on the cell cycle of murine leukemia L1210 cells in vitro by means of DNA/5-bromo-2'-deoxyuridine double staining and compared these effects with those of other antitumor drugs. Both FK973 and mitomycin C arrested the cells in the G2 phase. Vinblastine arrested the cells in the M phase and cytosine arabinoside, in the G1 phase. Although FK973 and mitomycin C were shown to act on the cell cycle in a similar way, FK973 was slower in producing its effect. From the results, FK973 arrests the cells in the G2 phase, and it appears that FK973 must be converted into the activated form in the cells for the development of its antitumor effects.
Abstract--Our previous studies showed that a new, substituted dihydrobenzoxazine, FK973(1 1 -acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo [7.4.1.02.7.01o.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 in 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.
Abstract-FK973(11-acetyl-8-carbamoyloxymethyl-4-formyl-l4-oxa-1,11 -diaza tetracyclo[7.4.1.O2,7O10,12]tetradeca-2,4,6-trien-6,9-diyl diacetate), a new sub stituted dihydrobenzoxazine, has potent cytotoxic and antitumor effects on murine and human tumors in vivo and in vitro, and forms interstrand DNA-DNA and DNAprotein cross-links after being activated in the cytoplasm.In this study, the mech anism(s) by which FK973 is activated in the cytoplasm of in vitro cultured murine L1210 leukemia cells were studied using compounds that affect monoamine oxidase. When the cells were incubated with an antitumor drug and the compounds, tranylcy promine, benzylamine, phenylethylamine and tyramine of the many compounds tested reduced the cytotoxicity of FK973, but not that of mitomycin C or cisplatin. These compounds also suppressed the formation of interstrand DNA-DNA cross links with FK973 in the cells, but did not suppress cross-links with mitomycin C or cisplatin.The incorporation of 14C-FK973 into the cells was not affected by these compounds.The results suggest that FK973 is activated by some drug-metabolic system(s) in the cytoplasm to form interstrand DNA-DNA cross-links, and induces cytotoxicity against the cells. This activation of FK973 in the cytoplasm is discussed in connection with the drug-metabolic system(s) in relation to the structures of the compounds.
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