The novel immunosuppressant AS1387392 has been isolated from Acremonium sp. No. 27082. This compound showed a strong inhibitory effect against mammalian histone deacetylase and T-cell proliferation. Further, AS1387392 showed a good oral absorption, and its plasma concentration was higher than that of FR235222, an analog of AS1387392 that inhibited histone deacetylase previously reported. Given these findings, AS1387392 may represent an important new lead in developing immunosuppressant.
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...
FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrugresistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB-V1 vinblastine (VLB)-resistant human epidermal carcinoma KB cells, as well as the parent cells (KB-3-1). However, KB-V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB-V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB-V1 and SBC-3/ADM, ADM-resistant human lung carcinoma, decreased. In addition, photolabeling of P-glycoprotein with [3 H]azidopine in KB-V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P-glycoprotein and are incorporated into MDR cells, causing cytotoxic effects. Key words: FK317 -Antitumor effect -Deacetyl metabolite -MDR -P-GlycoproteinIt is widely accepted that drug resistance is a major obstacle to cancer chemotherapy. Cross-resistance of cancer cells to many types of drugs which show little structural similarity is termed multidrug resistance (MDR). 1,2) Over the past several years, evidence has accumulated to show the association between the development of MDR and the appearance of a P-glycoprotein in resistant cells.3, 4) The human gene coding for the P-glycoprotein, which exhibits similarity to certain bacterial transport proteins and has ATPase activity, has been sequenced. [5][6][7][8][9] PGlycoprotein appears to act as an efflux pump for functionally and structurally unrelated drugs such as the vinca alkaloids and anthracyclins, which are very important in the treatment of many cancers, and is responsible for decreasing the drug levels and cytotoxicity in MDR tumor cells.10-12) Therefore, there is clearly a need for chemosensitizers which can overcome MDR, or new antitumor agents which are effective on MDR tumors. FK973, which is a triacetyl derivative of FR900482 isolated from the fermentation products of Streptomyces sandaensis No.6897 in the Fujisawa Research Laboratories (Osaka), forms DNA-DNA interstrand and DNA-protein cross-links after being metabolically activated, shows strong cytotoxicity against tumor cells, and has strong antitumor activities against a wide variety of animal tumor models and human xenografts. 13,14) FK973 showed high therapeutic efficacy in clinical studies. 15,16) However, it was not developed for clinical use because of its propensity to induce capillary leak syndrome. In attempts to discover new FK973 derivatives which retain the antitumor activity without the capillary leak syndrome side effect, the novel analog FK317 (11-ac...
Abstract--Our previous studies showed that a new, substituted dihydrobenzoxazine, FK973(1 1 -acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo [7.4.1.02.7.01o.12]tetradeca-2,4,6-trien-6,9-diyl diacetate), which is a triacetylated derivative of the fermentation product FR900482 of Streptomyces sandaensis No. 6897, had potent antitumor effects on experimental tumors in vivo and in vitro. In the present study, we investigated the metabolism of FK973 in the blood of human and animals and the antitumor effects of its metabolites.After the incubation of FK973 in the blood (hemolysate) or serum of humans, dogs, rats and mice, it was rapidly metabolized to two diacetates and a monoacetate, and slowly to FR900482. FK973 and all its deacetylated metabolites showed strong cytotoxicity on in vitro cultured murine L1210 leukemia cells, and the cytotoxicity of FK973 was the most potent.In the in vivo experiments, FK973 and its metabolites prolonged the life of mice bearing ascitic P388 leukemia, and it potently inhibited the growth of murine B16 melanoma and Colon 38 adenocarcinoma implanted subcutaneously in mice. FK973 was the most effective compound.Thus, these results suggest that the antitumor effects of FK973 are stronger than those of its deacetylated metabolites produced in the blood of humans and animals.
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