FK973 (11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11- diazatetracyclo[7.4.1.O2,7O10,12]tetradeca-2,4,6-
trien -6,9-diyl diacetate), a new substituted dihydrobenzoxazine, has potent cytotoxic and antitumor effects on murine and human
tumors in vivo and in vitro, and forms interstrand
DNA-
DNA and
DNA-
protein cross-links after being activated in the cytoplasm. In this study, the mechanism(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,
tranylcypromine,
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.