Specific metabolic activation of FK973, a new antitumor antibiotic, in L1210 leukemia cells.
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.
Masuda
K
K
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Nakamura
T
T
Shimomura
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D007490:Iproniazid / Q000494:pharmacology; D007939:Leukemia L1210 / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity; D010078:Oxazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000903:Antibiotics, Antineoplastic; D001596:Benzylamines; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D010078:Oxazines; C054974:FK 973; C055423:didimethylsulfoxide dichloroplatinum(II); D014191:Tranylcypromine; C030796:benzylamine; D007490:Iproniazid; D008995:Monoamine Oxidase