A new antitumor antibiotic, FR-900482. II. Production, isolation, characterization and biological activity.

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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“…6897 in the Fujisawa Research Labora tories (1)(2)(3). The substance was found to have a strong antitumor effect on experi mental tumors (4).…”

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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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“…A potent antineoplastic agent, FK973, 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo-[7.4.1.0 2,7 .0 10,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate, was obtained by chemical modification of the novel antibiotic FR900482, which was isolated from the fermentation products of Streptomyces sandaensis No. 6897.…”

mentioning

confidence: 99%

FK317, a Novel Substituted Dihydrobenzoxazine, Exhibits Potent Antitumor Activity against Human Tumor Xenografts in Nude Mice

Naoe

Inami

Matsumoto

et al. 1998

Japanese Journal of Cancer Research

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The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growthinhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14 C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials. Key words:FK317 -Antitumor effect -Human tumor xenograft -Selective toxicityMitomycin C A potent antineoplastic agent, FK973, 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo-[7.4.1.0 2,7 .0 10,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate, was obtained by chemical modification of the novel antibiotic FR900482, which was isolated from the fermentation products of Streptomyces sandaensis No. 6897.1-3) This compound has a unique chemical structure including a hydroxylamine function, whose hydroxyl group forms an intramolecular hemiketal moiety. The antitumor activity of FK973 is equivalent to, or more potent than, those of mitomycin C (MMC), adriamycin (ADR) and cisplatin (CDDP) against murine tumors and human xenografts in mice, and its hematotoxic and myelosuppressive effects are weaker than those of MMC in mice.4) FK973 showed good efficacy in clinical studies, but its development was terminated because of a vascular leak syndrome (VLS) side effect which was characterized by pericardial and pleural effusion, ascites and subcutaneous edema. 5,6) Various FK973 derivatives were synthesized in an attempt to isolate the antitumor activity of FK973 from the VLS side effect, and 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 selected for further examination. FK317 showed similar antitumor activity to FK973, but did not induce pleural effusion in rats.7) FK317 contains an aziridine ring and a carbamoyl moiety, which are also present in MMC. MMC is a "bioreductive alkylating agent," which causes damage to DNA after reductive activation of the prodrug to form a DNA-reactive species.8, 9) FK317 also forms DNA-DNA interstrand and DNA-protein...

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“…FK973 (11 -acetyl-8- (1)(2)(3)(4)(5). In our previous study, we showed that FK973 had strong in vitro and in vivo activities against a wide variety of tumors (6).…”

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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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A new antitumor antibiotic, FR-900482. II. Production, isolation, characterization and biological activity.

Abstract: FR-900482 is a new antitumor antibiotic produced by a new actinomyces named Streptomyces sandaensis No. 6897. It exhibits potent cytotoxic activity against various tumor cells in vitro. Furthermore, it has weak antimicrobial activity against some Gram-positive or

Cited by 77 publications

References 0 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.

FK317, a Novel Substituted Dihydrobenzoxazine, Exhibits Potent Antitumor Activity against Human Tumor Xenografts in Nude Mice

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

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