Studies concerning the mechanism of electrophilic substitution reactions of mitomycin C

Kohn, Harold; Zein, Nada

doi:10.1021/ja00350a067

Cited by 31 publications

(16 citation statements)

References 3 publications

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“…Thus, FK973 may be converted into the activated form in the cytoplasm of cells (6). Both the carbamoyl moiety and aziridine ring of MMC were re ported to bind to DNA after reduction of the quinone ring of MMC, the activated form, in cells (12,13). FK973 also has a carbamoyl moiety and an aziridine ring in its molecular structure, but it has no quinone ring.…”

Section: Discussionmentioning

confidence: 99%

Effect of FK973, a new antitumor antibiotic, on the cell cycle of L1210 cells in vitro.

et al. 1989

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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.

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Section: Discussionmentioning

confidence: 99%

Effect of FK973, a new antitumor antibiotic, on the cell cycle of L1210 cells in vitro.

et al. 1989

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“…Fig. 2 shows that the retention of 14 C-labeled DNA on the filter increased dose-dependently in the cells treated with FK317 and MMC, suggesting that both of these drugs form DNA-DNA interstrand cross-links, and that the effect of FK317 is stronger than that of MMC. Furthermore, FK317 formed DNA-protein cross-links dose-dependently and more potently than MMC (data not shown).…”

Section: Resultsmentioning

confidence: 97%

“…Since an aziridine ring and a carbamoyl moiety are both important in the reaction of MMC with DNA, 5,14) we studied the effects of FK317 on DNA using the alkaline elution method. After cells were exposed to a drug for 1 h, we detected concentration-dependent DNA-DNA interstrand and DNA-protein cross-links formed by both FK317 and MMC.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

Naoe

Inami

Kawamura

et al. 1998

Japanese Journal of Cancer Research

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FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.Key words: FK317 -Antitumor effect -Bioreductive agent -DT-diaphorase -Deacetyl metabolite FK317 is a new analog of FK973, which we previously showed to exhibit strong antitumor activities in a wide variety of animal tumor models and human xenografts, and has strong cytotoxic effects against in vitro-cultured tumor cell lines.1) FK973 has also been shown to have high therapeutic efficacy in clinical studies. However we were unable to develop this compound because it induces vascular leak syndrome (VLS) as a major side effect. 2, 3)In attempts to synthesize new FK973 derivatives which retain the antitumor activity, without the VLS side effect, FK317, 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0 2, 7 .0 10, 12 ]tetradeca-2,4,6,-trien-9-yl acetate, was identified. This agent has a unique bicyclic hydroxylamine hemiketal ring system, and its antitumor activity is more potent than, or equivalent to, that of mitomycin C (MMC), adriamycin (ADR), cisplatin (CDDP), taxol or irinotecan hydrochloride against murine tumors and human xenografts in mice. Moreover, its hematotoxic and myelosuppressive effects were weaker than those of MMC in mice. These preclinical data suggested that FK317 might represent a major advance in the treatment of cancer.The mechanisms by which FK317 induces these potent antitumor effects have not yet been defined, but if more clearly understood, would offer valuable in...

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“…It is known that the carbamoyl moiety and aziridine ring of MMC bind DNA after MMC is easily activated by the reduc tion of its quinone ring in the cytoplasm (15,16,18). Thus, the carbamoyl moiety and aziridine ring of FK973 may be related to its binding sites with DNA in the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, FK973 may be gradually ac tivated in the cytoplasm after the drug is in corporated, and the activated FK973 forms both types of cross-links. Mitomycin C (MMC) was reported to form interstrand DNA-DNA and DNA-protein cross-links after being easily reduced by NADPH-de pendent cytochrome P-450 reductase and xanthine oxidase in the cytoplasm (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). On the other hand, cisplatin (CDDP) forms these cross-links in the cells directly (19,20).…”

Section: Abstract-fk973mentioning

confidence: 99%

Specific Metabolic Activation of FK973, a New Antitumor Antibiotic, in L1210 Leukemia Cells

Masuda

Nakamura

Shimomura

1990

Japanese Journal of Pharmacology

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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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Studies concerning the mechanism of electrophilic substitution reactions of mitomycin C

Cited by 31 publications

References 3 publications

Effect of FK973, a new antitumor antibiotic, on the cell cycle of L1210 cells in vitro.

Effect of FK973, a new antitumor antibiotic, on the cell cycle of L1210 cells in vitro.

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

Specific Metabolic Activation of FK973, a New Antitumor Antibiotic, in L1210 Leukemia Cells

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