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Shiro Akinaga Tadashi Ashizawa Katsushige Gomi Hiroe Ohno Makoto Morimoto Chikara Murakata Masami Okabe 《Cancer chemotherapy and pharmacology》1992,29(4):266-272
Summary Novel derivatives of K-252a, (8R*,9S*,11S*)-(–)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i. p.-i. p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca2+-and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparantly exhibited DNA scission both dose-and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases. 相似文献
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K Takeuchi O Furukawa H Tanaka H Nishiwaki S Okabe 《Japanese journal of pharmacology》1987,44(2):163-170
The effects of hemorrhagic shock (HE) on duodenal pH, acid-neutralizing capacity and mucosal tolerance to acid were investigated in anesthetized rats, and they were compared with those of indomethacin. HE was performed by bleeding from the carotid artery to reduce arterial blood pressure to about 55 mmHg (3 ml of bleeding per 200 g of body weight), and indomethacin was given s.c. in a dose of 5 mg/kg. Duodenal pH was determined in the outflow from the proximal duodenum (1.7 cm) which was perfused with 10(-4) M HCl, and acid-neutralizing capacity was measured by back-titration of the perfusate to pH 4.0 with 10 mM HCl. Under these conditions, duodenal pH was kept at around 6.0 as the result of neutralization in the loop (approximately 8 microEq/hr). Both HE and indomethacin significantly decreased the pH and acid-neutralizing capacity. Administration of 16,16-dimethyl prostaglandin E2 (16-dmPGE2: 30 micrograms/kg, s.c.) significantly increased both pH and acid-neutralizing capacity in normal and indomethacin-treated rats, but failed to affect these parameters in rats under HE conditions. When the duodenal loop was perfused with 50 mM HCl for 1.5 hr, both HE and indomethacin induced extensive damage in the mucosa. Pretreatment with 16-dmPGE2 significantly reduced the formation of duodenal lesions induced by indomethacin but not by HE. These results suggest that HE as well as indomethacin impaired duodenal acid-neutralizing capacity to reduce the tolerance to acid of the mucosa. The deleterious effects of HE on the mucosa may be mainly due to a decreased mucosal blood flow, but not due to a deficiency of endogenous prostaglandins. 相似文献
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Tadashi Teshirogi M.D. Hiroeki Hosoi M.D. Yukashi Ohki M.D. Toshio Kagoshima M.D. 《Pediatrics international》1987,29(3):335-339
Residual pancreatic B-cell function was investigated in children with diabetes mellitus in whom classification of the type of disease was difficult at the first visit. Intravenous glucagon tests were performed at the first visit and subsequently, the C-peptide responses compared. Based on our data on a limited number of patients, we propose C-peptide concentrations of 3.0 to 3.5 ng/ml at the peak or at 6 min after injection of glucagon, as the critical level which distinguishes non-insulin dependent from insulin-dependent diabetes mellitus. However, the degree of obesity, clinical stage and other factors also need to be considered in the classification of diabetes mellitus. 相似文献
8.
Tadashi Kato 《Seishin shinkeigaku zasshi》2002,104(6):509-512
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Yutaka Okishio Tadayoshi Takeuchi Akikazu Fujita Kiyotaka Suenaga Kaori Fujinami Satoru Munakata Tadashi Takewaki Fumiaki Hata 《Journal of Smooth Muscle Research》2005,41(3):163-174
Recently an essential role of interstitial cells of Cajal (ICC) within myenteric plexus (ICC-MY) was suggested in ascending contraction and descending relaxation in the mouse ileum. The role of ICC in these neural reflexes was examined in the distal colonic segments prepared from the wild type and c-kit mutant, W/W(V) mice, in the present study. Localized distension of the segments from the wild type mice by using a small balloon resulted in ascending contraction and descending relaxation. In the segments from the mutant mice, localized distension also induced these neural reflexes similar to those observed in the wild type mice. Immunohistochemical examination demonstrated that ICC-MY and ICC present in muscle layers (ICC-IM) were severely disrupted in the mutant mouse, but only ICC, present within submucosal plexus (ICC-SMP), remained unchanged. In the small strips with ICC-SMP absent prepared from the mutant mouse, electrical field stimulation induced contraction or relaxation in the absence or presence of atropine, respectively. It was suggested that ICC have no important role in the ascending and descending neural reflexes in the mouse distal colon, this is in direct contrast to the role of ICC-MY in the ileum. 相似文献
10.
Tatsurou Tanaka Yasuhiro Morimoto Hiroshi Takano Kazuhiro Tominaga Shinji Kito Sachiko Okabe Tetsu Takahashi Jin-ichi Fukuda Takeshi Ohba 《Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics》2005,100(5):609-613
OBJECTIVE: To evaluate a proposed technique for the 3-dimensional (3D) detection of hemangiomas, including vascular malformation and their feeding arteries, in the head and neck. The new technique combines phase-contrast magnetic resonance angiography (PCMRA) without contrast medium and 3D fast asymmetric spin-echo (FASE) sequences. METHODS: The technique was applied to 3 patients having hemangiomas in the head and neck region. In 1 patient the image obtained with the proposed technique was compared to that obtained by standard contrast angiography. RESULTS: In all 3 patients, the 3D presence of the hemangiomas and the feeding arteries were well defined in images created by the proposed technique. Additionally, the characterization of the hemangioma's 3D structure and distribution of the feeding arteries coincided with those observed using contrast angiography in the case for which contrast angiography was also performed. CONCLUSIONS: Preliminary experience shows that the proposed technique combining 3D-FASE and 3D-PCMRA is useful to visualize both the 3D structure of hemangiomas and to identify the 3D distribution of the feeding arteries without using contrast medium. 相似文献