Biomedical subjects
Publications and source records attributed to T Takeuchi.
In the biosynthesis of valanimycin, valine is mostly incorporated into the isobutyl moiety of the antibiotic. The alpha-substituted acrylic moiety of valanimycin is derived from alanine. However, a part of alanine is metabolized into valine, thus incorporated also into the isobutyl moiety. Anaerobic conditions and some reducing agents strongly inhibit the biosynthesis.
Spergualin (SGL), a novel antitumor antibiotic, exhibited strong antitumor activity against transplantable leukemias in mice: L1210, L1210(IMC), P388, P815, C1498, EL-4 and RL male 1. It also exhibited antitumor activity against M5076 fibrosarcoma, AH66 and AH66F rat hepatomas, but not against Meth-A fibrosarcoma, B16 melanoma, Lewis lung carcinoma (LL) and C26 colon adenocarcinoma. The antitumor activity of SGL was administration-schedule dependent. The strongest activity against L1210 was obtained by ip continuous infusion for 7 days or daily ip administration for 9 days. Single ip injection of SGL at 100 mg/kg to mice caused convulsion and death within 15 minutes after injection. Such acute toxicity was not observed by continuous infusion. SGL showed its strongest activity at subtoxic dose against sensitive tumors except for L1210(IMC). Mice implanted ip with L1210(IMC) were cured by treatment with SGL at 3.13 mg/kg/day for 9 days, but died from the tumor at 50 mg/kg/day X 9. The cured mice rejected a second inoculation of up to 10(6) tumor cells. The tumor cells isolated from mice after treatment with the high dose showed resistance to SGL in vivo. Mice implanted sc with L1210(IMC) were also cured by 9 daily ip administrations of SGL at 12.5 mg/kg/day, but solid tumor was observed at the implantation site until 3 days after the final injection of SGL in some cured mice. These results suggest that the therapeutic effect of SGL has a relatively high specificity for leukemias and that the immunological effect is involved in the antitumor activity.
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Spergualin and its analog, 15-deoxyspergualin showed a marked antitumor effect against L1210 by intraperitoneal and oral administrations. After treatment with these substances 40- or 60-day survivors (cured mice of L1210) were resistant to reinoculation of L1210 cells. They were resistant only to L1210. The antitumor effector cells in these mice were determined to be T cells. NK activity of spleen cells was also enhanced by spergualins. The antitumor activity of 15-deoxyspergualin was markedly reduced in immuno-deficient mice. IL (interleukin)-2 production, but not IL-1, was enhanced in supernatant of mixed lymphocyte cultures by treatment with 15-deoxyspergualin. The mechanism of action of 15-deoxyspergualin on the immune system was discussed.
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Novel antibacterial antibiotics napyradiomycins A, B1, B2, B3, C1 and C2 have been isolated from the culture broth of Chainia rubra MG802-AF1. In this paper, taxonomy of the producer, and production, isolation, physico-chemical properties and biological activities of napyradiomycins are reported. They contain the naphtopyran chromophore and halogens, and inhibit the growth of Gram-positive bacteria including drug-resistant strains.
Structures of novel antibiotics, napyradiomycins A, B1, B2, B3, C1 and C2 were determined. By X-ray crystallography, napyradiomycin B2 was determined to be (3R,10aR)-3-chloro-10a-[[(1R,3S)-3-chloro-2, 2-dimethyl-6-methylenecyclohexyl]methyl]-3,10a-dihydro-6,8-dihydro xy-2, 2-dimethyl-2H-naphtho[2,3-b]pyran-5,10-dione. The structures of other napyradiomycins were elucidated by NMR studies. Napyradiomycins C1 and C2 have unique structures which contain 14-membered ring cyclized by carbon-carbon bond.
Forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine, prolonged the survival period of mice implanted with Meth A fibrosarcoma or Lewis lung carcinoma. The effect was observed in the mice when the primary tumor was removed by amputation. At autopsy, metastasized tumors were found in all dead mice but no tumor foci were detected in any of the mice still alive at the time of sacrifice. Moreover, forphenicinol suppressed the growth of subcutaneously implanted adenocarcinoma 755. When combined with surgical resection of primary tumors, forphenicinol administration both before and after resection suppressed the growth of recurrent tumors and prolonged the survival period of the mice.
Forphenicinol stimulated the production of BCG-induced gamma-interferon in BCG-sensitized mice as much as 11-fold whereas it did not induce interferon production in unsensitized mice. This stimulatory effect was also observed in mice immuno-suppressed by cyclophosphamide. Furthermore, BCG-induced gamma-interferon production was reduced in mice by treatment with an anti-macrophage agent (silica gel), and forphenicinol administration into such mice could augment their interferon production. Transplantation of macrophages from forphenicinol-treated mice into mice injected with silica gel remarkably enhanced the BCG-induced interferon production in the recipients. These results suggest that the stimulatory effect of forphenicinol on BCG-induced gamma-interferon production in mice was due to the activation of macrophages.
Oral administration of forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine, increased the production of Ia-positive peritoneal macrophages in healthy mice. Moreover, forphenicinol increased Ia-positive macrophages in L1210-bearing mice. Though forphenicinol was ineffective against mouse leukemia L1210 when administered alone, in combination with L1210 vaccine it prolonged the survival time of L1210-bearing mice and the increase in the number of Ia-positive macrophages in peritoneal cavity coincided with the prolongation of the survival time. These results suggest that the initial action of forphenicinol is the preferential induction of Ia-positive macrophages, which play a role in the subsequent activation of various immune responses including macrophage activation.
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Plipastatins have been isolated as part of a program designed to find inhibitors of porcine pancreatic phospholipase A2. They were purified from fermentation broth of Bacillus cereus BMG302-fF67 and finally separated into four fractions by reverse phase HPLC. The respective fractions were designated as plipastatins A1, A2, B1 and B2. Plipastatins also inhibited phospholipases C and D.