Reversal of resistance by N-acetyltyramine or N-acetyl-2-phenylethylamine in doxorubicin-resistant leukemia P388 cells.
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Biomedical subjects
Publications and source records attributed to T Takeuchi.
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Alteromonas haloplanktis strain SB-1123 isolated from deep-sea mud produced a new siderophore, bisucaberin. Bisucaberin rendered tumor cells susceptible to cytolysis mediated by murine peritoneal macrophages which were elicited by Proteose peptone and not yet activated by lymphokine. Bisucaberin exerted its sensitizing activity by both the preincubation with tumor cells and the addition to co-culture of macrophages and tumor cells. The activity of bisucaberin was specifically inhibited by ferric ion. Bisucaberin showed direct cytostasis for tumor cells but did not cause cytolysis in the absence of macrophages. Cytostasis by bisucaberin was attributable to the specific inhibition of DNA synthesis in tumor cells.
The structure of bisucaberin, a new siderophore, was determined to be 1,12-dihydroxy-1,6,12,17-tetraazacyclodocosane-2,5,13,16-tetron e by spectroscopic analysis and X-ray crystallographic analysis. The molecule of bisucaberin consists of a cyclic dimer of 1-hydroxy-1,6-diazaundecane-2,5-dione moiety and is closely related to nocardamine, the trimer of the same moiety.
Biosynthetic studies on napyradiomycins were carried out based on the incorporation of [2-13C]acetate and [1,2-13C]acetate. The alignment of acetate units suggested that the B and C rings of napyradiomycins are derived from a pentaketide, while ring A and the side chain may be synthesized from mevalonate.
The effect of ubenimex on the release of interleukin 1 (IL-1) and interleukin 2 (IL-2) from immuno-competent cells was studied. Ubenimex enhanced release of IL-1 from mouse peritoneal macrophages at 1.0 and 100 micrograms/ml in vitro and the release at 1.0 microgram/ml was larger. When ubenimex was administered to mice IL-1-releasing activity of the peritoneal macrophages was enhanced 3 and 5 days after the administration but not enhanced 1 day after the administration. Ubenimex also enhanced IL-2 release from rat spleen cells at 0.1 and 10 micrograms/ml, when concanavalin A (Con A) was added in the IL-2-releasing system. The enhancement was still observed with mouse spleen cells, when serum was further added. Moreover, thymocyte-proliferating activity was attained in the broths which rat spleen cells were incubated with ubenimex from 0.1 to 10 micrograms/ml in the absence and presence of Con A.
The oral administration of forphenicinol increased the survival rate of both normal and immunodepressed mice intraperitoneally or intratracheally infected with clinically isolated strains of Pseudomonas aeruginosa. The therapeutic effect of amikacin on intraperitoneal infection with P. aeruginosa was enhanced by combined use with forphenicinol. Forphenicinol did not enhance the bactericidal activity of polymorphonuclear cells (PMN) towards P. aeruginosa in vitro, but enhanced it in vivo. In vitro study indicated that the macrophages taken from mice treated with forphenicinol or the cultured supernatant of these macrophages enhanced the bactericidal activity of PMN. The protective effect of forphenicinol against P. aeruginosa infection was thus suggested to be due to macrophage activation followed by the enhancement of the bactericidal activity of PMN.
Antitumor effector cells in spleens of tumor-bearing mice given ubenimex were investigated. The administration of ubenimex, starting 7 days after the tumor inoculation, was effective in inhibiting growth of IMC carcinoma. Spleen cells taken from these mice showed a marked suppression of the tumor growth by the WINN assay. The antitumor activity of spleen cells was reduced by treatment to remove T cells or NK cells, whereas spleen cell preparations enriched for T cells showed the strongest antitumor activity. Moreover, NK activity against YAC-1 cells was found in the spleen. These results indicate that the administration of ubenimex to IMC carcinoma-bearing mice generates cytotoxic T cells and NK cells in the spleen. The antitumor effect of ubenimex was not observed in X-ray-irradiated and in anti-asialo GM1 serum-treated mice.
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Three fluorochromes were applied to stain various parasitic protozoans. By double staining with 4',6-diamidino-2-phenylindole and propidium iodide, differentiation of the nuclei from the cytoplasm can easily be achieved within several seconds. The chromatoid bodies in Entamoeba cysts were stained bright red. Plasmodium yoelii at all stages except late trophozoites and young gametocytes was easily identified. In the oocysts of Cryptosporidium sp., the nuclei and cytoplasm of the sporozoites fluoresced bluish white and red, respectively, whereas the residual body appeared blue or green. The third fluorochrome, Calcofluor white M2R, was suitable for detecting the cysts of Entamoeba spp. and Chilomastix mesnili.
Oral administration of forphenicinol stimulated the production of lipopolysaccharide (LPS)-induced interferon (IFN) in mice up to 21-fold over control when given more than 10 days before the elicitation. The IFN production in mice sensitized with bacillus Calmette-Guerin (BCG) 14 days before LPS injection was further augmented by forphenicinol given after BCG. In addition to the IFN production, forphenicinol increased production of LPS-induced tumor necrosis factor (TNF) in mice sensitized with BCG, and the dose of LPS required to induce TNF was reduced by the drug. Furthermore, forphenicinol augmented the antitumor effect of BCG and LPS on Meth A fibrosarcoma.
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Aclacinomycin is a member of naturally occurring anthracyclines having three sugar moieties in the molecule. It showed antitumour activity on various mouse and rat tumours. Combination therapy with AraC etc. gave remarkable clinical results on acute myeloid leukaemia. Aclacinomycin strongly inhibits RNA synthesis of the tumour cells. It has lower cardiac toxicity than adriamycin and no mutagenicity. THP-Adriamycin is a derivative of adriamycin designed from the structure of baumycins. It showed stronger effects than adriamycin in inhibiting many mouse tumours such as L1210 and P388 leukaemia, B16 melanoma and colon 38 adenocarcinoma. THP-Adriamycin is rapidly taken up by both adriamycin-sensitive and resistant leukaemic cells. Its level of cardiac toxicity is as low as that of aclacinomycin. Ditrisarubicins are new naturally occurring anthracyclines isolated from Streptomyces having six sugar moieties in the molecule. Ditrisarubicin has a potent cytostatic and antitumour activities on adriamycin resistant mouse leukaemia. Its binding constant to DNA is extremely high compared with other anthracyclines.
A rare case of prostatic rhabdomyosarcoma in a 3-year-old child is presented. He received a multimodal treatment of chemotherapy including vincristine, cyclophosphamide, actinomycin-D plus adriamycin, and linac irradiation followed by total prostatectomy with segmental resection of bladder. Despite no viable sarcoma cells in the surgical specimen, he showed relapse 4 months later. By the combination of cisplatin, vinblastine and peplomycin (PVP therapy), the bulky mass in the pelvis rapidly reduced by 95%. Furthermore, cisplatin, etoposide and peplomycin (PEP therapy), instead of PVP therapy, were administered to the refractory disease. Although the residual tumor was salvaged after 7 courses of PEP therapy, abdominal dissemination and liver metastasis occurred 2 months postoperatively. The combined modality of vincristine, peplomycin, ifosfamide, methotrexate, adriamycin, melphalan plus nimustine, and irradiation of microtron were effective for the abdominal dissemination, but he died of cerebral hemorrhage 31 months after the start of treatment. We emphasize that more aggressive chemotherapy including cisplatin, etoposide and so on is required to manage the advanced, relapsed, or resistant cases compared to the usual modality of rhabdomyosarcoma.
Vasodilating action of a new calmodulin antagonist, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-[( 4-(2- methoxyphenyl)-1-piperazinyl] methyl) isoquinoline (Ro 22-4849) was examined in various isolated canine vessels. Ro 22-4839 was found to dilate basilar and middle cerebral arteries and to non-selectively antagonize submaximal contraction of these arteries under the treatment of various constrictors (K+, Ca2+, PGF2 alpha (dinoprost), serotonin and incubated blood) with IC50 values ranging from 0.043 to 1.69 mumol/l. Vasospasmolytic action of the compound in these cerebral arteries was 9 and 20 times greater than those in coronary and femoral arteries, respectively. The arterial relaxation by Ro 22-4839 was hardly overcome by addition of extra calcium and Ro 22-4839 did not alter calcium channels in the guinea-pig papillary muscle, although the compound inhibited the tension development, confirming its calmodulin antagonistic properties. Ro 22-4839 inhibited norepinephrine (NE)-induced contraction of femoral arterial strips concentration-dependently, and prevented NE-induced lethal extravasation in mice with an ED50 value of 1.96 mg/kg p.o. In in vitro [3H]-dihydroergocryptine binding assay and ex vivo [3H]-WB-4101 (2-[(2',6'-dimethoxy)phenoxyethylamino] methylbenzodioxan) binding assay, the compound showed a potent inhibitory action on alpha 1-adrenoceptor. These findings indicate that Ro 22-4839 exerts the spasmolytic effects on cerebral vessels through calmodulin antagonistic properties combined with alpha 1-adrenoceptor blocking action.
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A tyrosine protein kinase inhibitor, erbstatin, showed no antineoplastic effect on L-1210 mouse leukemia when it was injected alone. Erbstatin was found to be inactivated by incubation in serum, but not in dialyzed serum. It was also inactivated in reconstituted serum containing dialyzed serum components and ferric or ferrous ion. Because erbstatin was considered to be inactivated by the ferric or ferrous ion in serum, foroxymithine, which is a potent chelator for the ferric ion, was given to the mice together with erbstatin. Administration of both erbstatin and foroxymithine showed antineoplastic activity against L-1210 leukemia.
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Ten puerperal women were put on a 1,200 kcal diet per day for 3 days followed by an ordinary 1,800 kcal diet per day for 3 days [Low-Caloric (LC) group]. Fifteen puerperal women were put on an ordinary 1,800 kcal diet per day for 6 days[Ordinary-Caloric (OC) group]. All of the women took breakfast at 7:30 am, blood was drawn at 9:30 am and then the breasts were milked for 2 minutes with an electric breast pump starting on the day of delivery (Day 0) and continuing to Day 5. Four women in the LC and OC groups underwent a thyrotropin-releasing hormone (TRH) stimulation test on Days 1 and 3. Serum prolactin (PRL) and TSH levels in the LC group tended to be much lower than those of the OC group during the test period. Serum PRL and TSH release response to TRH in the OC group were much higher than in the LC group on Days 1 and 3. No significant difference was noted between the OC and LC groups in serum estradiol (E2) and cortisol levels from Day 0 to Day 5. The milk volume in the LC group was significantly less than in the OC group on Day 1. Analysis of milk specimen components revealed little difference between the OC and LC groups. These results suggested that a low-caloric diet may suppress PRL, TSH and milk secretion and may not be useful for breast-feeding.