Specific metabolic activation of FK973, a new antitumor antibiotic, in L1210 leukemia cells.

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Author(s)

    • MASUDA Kikuo
    • Department of Pharmacology, Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd.
    • NAKAMURA Takaaki
    • Department of Pharmacology, Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd.
    • SHIMOMURA Kyoichi
    • Department of Pharmacology, Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd.

Abstract

FK973 (11-acetyl-8-carbamoyloxymethyl-4-formyl-l4-oxa-1, 11 -diazatetracyclo[7.4.1.O<SUP>2, 7</SUP>O<SUP>10, 12</SUP>]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 crosslinks with FK973 in the cells, but did not suppress cross-links with mitomycin C or cisplatin. The incorporation of <SUP>14</SUP>C-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.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 53(4), 463-472, 1990

    The Japanese Pharmacological Society

Codes

  • NII Article ID (NAID)
    130000832877
  • Text Lang
    ENG
  • ISSN
    0021-5198
  • Data Source
    J-STAGE 
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