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Biomedical subjects

H Fujiki

Publications and source records attributed to H Fujiki.

At least 55 records · Page 3Linked to original sources
PubMed1999

Clinical application of adoptive immunotherapy and IL-2 for the treatment of advanced digestive tract cancer.

BACKGROUND/AIMS: We investigated the clinical efficacy of systemic and locoregional adoptive immunotherapy (AIT) with or without interleukin-2 (IL-2) against solid metastatic lesions from digestive tract cancer, which are refractory to conventional chemotherapy or radiotherapy. METHODOLOGY: Seven of 18 patients received hepatic arterial infusion (HAI) of lymphokine-activated killer (LAK) cells with or without IL-2 against metastatic liver tumors (local therapy group). The remaining 11 patients received systemic transfer of LAK cells with IL-2 against metastatic lesions located in organs other than the liver (systemic therapy group). RESULTS: Three of the 7 local therapy group patients showed clinically significant tumor regressions and this was evaluated as being equivalent to partial response (PR) (response rate: 43%). Two of the 11 systemic therapy group patients showed tumor regression which was evaluated as being equivalent to either complete response (CR) or PR (response rate: 18%). These 2 effective cases in the systemic therapy group were esophageal cancer patients. CONCLUSIONS: Locoregional AIT with or without IL-2 against liver metastases of digestive tract cancer could be an effective therapeutic modality in some patients who are refractory to conventional therapies. However, clinical efficacy of systemic AIT with IL-2 against metastases of digestive tract cancer would not be an effective modality except for the metastases of esophageal cancer.

Adult↗
PubMed1999

Mechanisms of action of OPC-28326, a selective hindlimb vasodilator.

The unique cardiovascular profile of OPC-28326 [4-(N-methyl-2-phenylethylamino)-1-(3, 5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monohydrate] provides insight into basic mechanisms of this new drug as determined by experiments in dogs and rats. In anesthetized open-chest dogs, an i.v. administration of a low dose (0.3 and 1.0 microg/kg) of OPC-28326 selectively increased femoral artery blood flow with only minimal action on systemic blood pressure, heart rate and coronary, carotid, vertebral, renal, and mesenteric blood flows. Biochemical study suggests that OPC-28326 had no effect on phosphodiesterase-3 and -5. OPC-28326 dose-dependently inhibited phenylephrine-induced increases in blood pressure in spinally anesthetized dogs. The potency of OPC-28326 was, however, about 180 times lower than that of prazosin. Although binding studies have revealed an affinity of OPC-28326 to serotonin 5-HT(2) receptors, the drug is without effect, except at very high concentrations, on serotonin-induced contraction in an isolated canine femoral artery preparation. The potency of OPC-28326 on the increase in femoral artery blood flow was about 14 times higher than that of prazosin but was at about the same level as that obtained with yohimbine in canine autoperfused femoral artery preparations. In perfused rat hindlimb preparations, OPC-28326 inhibited the decrease in perfusion flow induced by brimonidine, a selective alpha(2)-adrenoceptor agonist. The potency of OPC-28326 was at least 10 times less than that of yohimbine. Taken together, the results show that at low doses, OPC-28326 selectively exerts a potent vasodilating effect on the femoral arterial bed, in part due to an alpha(2)-adrenoceptor-blocking activity.

Adrenergic Antagonists↗
PubMed1998

Anticancer activity of morphine and its synthetic derivative, KT-90, mediated through apoptosis and inhibition of NF-kappaB activation.

We recently reported that morphine inhibits growth of various human cancer cell lines (IC50/2.7-8.8 mM). We then extended the study using newly synthesized morphine derivatives, such as KT-90 and KT-87, which are analgesics 5 times more potent than morphine. KT-90 was found to inhibit growth of human cancer cell lines (IC50/42-70 microM) up to 80 times more potently than morphine. As for mechanisms of action, KT-90 and morphine induced apoptosis, and inhibited tumor necrosis factor alpha (TNF-alpha) gene expression induced by tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13-acetate, associated with reduction of NF-kappaB DNA binding activity. This paper provides evidence that KT compounds confirmed the presence of anticancer activity of morphine in addition to its analgesic action.

Analgesics↗
PubMed1998

Cancer inhibition by green tea.

Green tea is now an acknowledged cancer preventive in Japan. This paper discusses several important features of (-)-epigallocatechin gallate (EGCG), the main constituent of green tea and tea polyphenols. EGCG and other tea polyphenols inhibited growth of human lung cancer cell line, PC-9 cells with G2/M arrest. 3H-EGCG administered by p.o. intubation into mouse stomach revealed that small amounts of 3H-activity were found in various organs where EGCG and green tea extract had previously demonstrated their anticarcinogenic effects, such as skin, stomach, duodenum, colon, liver, lung and pancreas. Cancer onset of patients who had consumed over 10 cups of green tea per day was 8.7 years later among females and 3.0 years later among males, compared with patients who had consumed under three cups per day. The mechanisms of action of EGCG were briefly discussed with regard to inhibition of tumor necrosis factor-alpha (TNF-alpha) release.

3T3 Cells↗
PubMed1998

Induction of growth inhibition of 293 cells by downregulation of the cyclin E and cyclin-dependent kinase 4 proteins due to overexpression of TIS21.

We earlier reported that TIS21 mRNA expression was markedly decreased in A549 and NCIH69 human lung cancer cells and in thymic carcinoma tissues obtained from transgenic mice containing simian virus 40 large T antigen (J Cancer Res Clin Oncol 121:279-284, 1995). To determine how TIS21 inhibits growth, we made 293 cells that constitutively expressed TIS21 protein. The constitutive TIS21 expresser lines C9 and C11 grew to a lower saturation density than did those in the vector-transfected clones (V7 and V10) and antisense-transfected clones (AS1 and AS4), and the size of the C9 and C11 cells increased significantly after transfection with TIS21 cDNA. The serum-stimulated cell cycle was analyzed by fluorescence-activated cell sorting after double thymidine treatment; V10 progressed normally through the cell division cycle, but C9 and C11 cells accumulated continuously in G1 phase until 36 h after treatment. On the other hand, the progression of cells that had already entered to S or G2/M phase was not inhibited. When cell-cycle regulatory proteins were measured, C9 and C11 cells showed significantly reduced synthesis of cyclin E and cyclin-dependent kinase (cdk) 4 as well as a decrease in cyclin E-associated cdk activity. These observations led us to conclude that TIS21 overexpression in G1 phase decreased the amounts of cyclin E and cdk4, thereby decreasing the activity of cdks at the G1-S transition.

Animals↗
PubMed1998

Molecular pathogenesis of interstitial pneumonitis with TNF-alpha transgenic mice.

Tumour necrosis factor alpha (TNF-alpha) transgenic mice, which overexpress TNF-alpha in the lungs, develop interstitial pneumonitis resembling idiopathic pulmonary fibrosis (IPF) in humans. Transgenic mice were used to study molecular pathogenesis of interstitial pneumonitis with regard to sequential histological changes and cytokine network induced by TNF-alpha. The authors divided the histological process of interstitial pneumonitis into three stages: early stage with lymphocytic infiltration in alveolar septa, middle stage with recruitment of macrophages, and late stage with hyperplasia of epithelial cells and mild fibrosis. As for cytokine network, prolonged overexpression of TNF-alpha along with increasing interleukin 6 (IL-6) were associated with the progression of interstitial pneumonitis. Increasing IL-1 was found only in the early stage, the beginning of lymphocyte proliferation. The mRNA level of an anti-inflammatory cytokine, IL-10, was constantly enhanced in the lungs of transgenic mice. However, transforming growth factor beta 1 (TGF-beta 1) protein decreased, which is closely associated with prolonged TNF-alpha synthesis, resulting in development of chronic inflammation and less severe fibrosis in the lungs of this animal model, analogous to inflammatory stage of human IPF. TNF-alpha transgenic mice enabled the analysis of the sequential process of interstitial pneumonitis as a model of IPF pathogenesis in humans, the results of which will give rise to new therapeutic measures for human IPF.

Animals↗
PubMed1998

Pranidipine, a new 1,4-dihydropyridine calcium channel blocker, enhances cyclic GMP-independent nitric oxide-induced relaxation of the rat aorta.

Pranidipine, a new calcium channel blocker, prolonged endothelium-dependent relaxation induced by acetylcholine in an aortic ring preparation, contracted with prostaglandin F2alpha. This action was not shared by amlodipine. The effect was not modified by indomethacin, suggesting that the action of pranidipine does not involve prostanoid metabolism. N(G)-nitro-L-arginine completely prevented the action of Pranidipine. The drug affected neither nitric oxide (NO) synthase activity nor the level of cyclic GMP in the vessel. Pranidipine did not affect the sensitivity of the contractile proteins to calcium. Pranidipine also did not alter cyclic GMP-induced relaxation in alpha-toxin-skinned vascular preparations. Pranidipine also prolonged glyceryl trinitrate-induced relaxation in the endothelium denuded rat aorta. Furthermore, pranidipine enhanced relaxation of the aorta induced by glyceryl trinitrate even in the presence of methylene blue, a guanylyl cyclase inhibitor. This action was not modified by iberiotoxin or by charybdotoxin, two inhibitors of the calcium-activated potassium channel. The results strongly suggest that pranidipine enhances cyclic GMP-independent NO-induced relaxation of smooth muscle by a mechanism other than through NO-induced hyperpolarization. These effects were in direct contrast to amlodipine, another new 1,4-dihydropyridine calcium antagonist.

Amlodipine↗
PubMed1998

Tumourigenicity of MTG8, a leukaemia-related gene, in concert with v-Ha-ras gene in BALB/3T3 cells.

The MTG8 (ETO) gene has been identified as the translocation partner of AML1 (PEBP2alphaB or CBFalpha2) gene in the AML1/MTG8 (ETO) fused gene caused by t(8;21) translocation in human acute myeloid leukaemia, M2 type. Although AML1/MTG8 chimaeric protein is known to inhibit the functioning of AML1 protein, the precise function of MTG8 gene itself is not known yet. We studied the significance of MTG8 gene in the oncogenicity of AML1/MTG8 fused gene, by introducing full-length MTG8 cDNA into both BALB/3T3 cells containing v-Ha-ras gene (Bhas 42 cells) and BALB/3T3 cells without v-Ha-ras gene. Irrespective of the overexpression of MTG8 gene in both groups of cells, Bhas-MTG8 clones which contained v-Ha-ras gene and expressed the MTG8 gene at a level more than twice that of parental Bhas 42 cells induced cell transformation, whereas BALB-MTG8 clones without v-Ha-ras gene did not. Furthermore, injection of the transformed Bhas-MTG8 clones into the subcutaneous tissue of nude mice induced tumours, whereas that of BALB-MTG8 clones did not. These results suggest that MTG8 gene product, in cooperation with viral Ras protein, resulted in tumour formation. We provide the first evidence that MTG8 gene by itself has a carcinogenic property within the AML1/MTG8 (ETO) fused gene.

3T3 Cells↗
PubMed1998

Wide distribution of [3H](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue.

The increasing recognition of green tea and tea polyphenols as cancer preventives has created a need for a study of their bioavailability. For this purpose, we synthesized [3H] (-)-epigallocatechin gallate ([3H]EGCG) with a specific activity of 48.1 GBq/mmol and directly administered the solution into the stomachs of CD-1 female or male mice. Radioactivity in the digestive tract, various organs, blood, urine and feces was measured with an oxidizer at various times after administration and significant radioactivity was found in the previously reported target organs of EGCG and green tea extract (digestive tract, liver, lung, pancreas, mammary gland and skin), as well as other organs (brain, kidney, uterus and ovary and testes) in both sexes. Incorporation of radioactivity in the cells was confirmed by microautoradiography. Within 24 h, 6.6 (females) and 6.4% (males) of total administered radioactivity was excreted in the urine and 37.7 and 33.1% in feces. HPLC analysis of urine from both sexes revealed that 0.03-0.59% of administered [3H]EGCG, along with at least five metabolites, was excreted. In addition, we found that a second, equal administration to female mice after a 6 h interval enhanced tissue levels of radioactivity in blood, brain, liver, pancreas, bladder and bone 4-6 times above those after a single administration. These results suggest that frequent consumption of green tea enables the body to maintain a high level of tea polyphenols and this paper is the first pharmacological evidence of a wide distribution of [3H]EGCG in mouse organs, indicating a similar wide range of target organs for cancer prevention in humans.

Animals↗
PubMed1998

Twist form of teleocidin derivatives is active in in vivo tumor promotion by (-)-benzolactam-V8-310.

Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to tumor promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and teleocidin B-4, induced tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic tumor promoter designed from data obtained using the receptor cavity model of TPA-type tumor promoters.

Animals↗
PubMed1997

Protection of 5alpha-dihydrotestosterone against TGF-beta-induced apoptosis in FaO cells and induction of mitosis in HepG2 cells.

Administration of TGF-beta1 to both FaO and HepG2 cells significantly induced apoptosis, particularly in FaO cells. Degradation of genomic DNA in FaO cells was rapidly induced by treatment with TGF-beta1 (5 ng/ml) for only 4 hr. 5alpha-dihydrotestosterone (DHT, 25 nM) alone did not affect any significant changes in cell viability and in nuclei of FaO cells; however, pre-treatment with DHT protected genomic DNA degradation induced by TGF-beta1 for 14 hr. Simultaneous treatment with DHT plus TGF-beta1 (D + T) inhibited TGF-beta-induced apoptosis by approximately 50% in FaO cells. On the other hand, D + T treatment increased mitosis in actively growing HepG2 cells. Thus, it is reasonable to conclude that DHT gives growth advantage to hepatocellular-carcinoma cells by inhibiting TGF-beta-induced DNA fragmentation in FaO cells and by inducting mitosis in HepG2 cells.

Animals↗
PubMed1997

Sealing effects of (-)-epigallocatechin gallate on protein kinase C and protein phosphatase 2A.

(-)-Epigallocatechin gallate (EGCG) was reported to inhibit protein kinase C (PKC) activation by 12-O-tetradecanoylphorbol-13-acetate (TPA), and inhibit interaction of tumor promoter with its receptors, named 'a sealing effect'. In order to clarify the sealing effect of EGCG, we prepared liposomes and examined inhibition of PKC activation by various concentrations of EGCG dispersed in the liposome. EGCG added to a liposome dispersion existed either in a buffer solution as aggregates or in phospholipid bilayer membranes, and EGCG disturbed membrane structure. The potency of inhibitory effect of EGCG on PKC activation was dependent on the nature of liposomes, indicating that interaction of EGCG with phospholipid bilayer membrane affects PKC activation. Moreover, EGCG prevented the binding of adenosine 5'-triphosphate and TPA to PKC, resulting in inhibition of PKC activation. On the other hand, the activity of protein phosphatase 2A (PP2A) was suppressed in the presence of liposomes, but was not influenced by EGCG. Moreover, EGCG recovered phosphatase activity of PP2A in a buffer solution, the activity of which was inhibited by okadaic acid. All the results indicated that EGCG possesses sealing effects in terms of PKC and PP2A, by inhibiting interaction of various ligands with proteins.

Catechin↗
PubMed1997

Venodilator effects of pranidipine, a 1,4-dihydropyridine Ca2+ channel antagonist, in rats: comparison with nifedipine and amlodipine.

The effects of pranidipine, a dihydropyridine Ca2+ channel antagonist, on mean circulatory filling pressure, an index of body venous tone, were compared with those of other dihydropyridines (nifedipine and amlodipine) and nitroglycerin in anaesthetized hexamethonium- and norepinephrine-treated rats. In this study, the compounds were used at doses having a equi-hypotensive effect. Intravenous bolus injection of pranidipine (10 and 30 microg/kg) significantly decreased mean circulatory filling pressure in a dose-dependent manner, as did nitroglycerin (30 and 100 microg/kg). Nifedipine (30 and 100 microg/kg), however, did not affect mean circulatory filling pressure. Amlodipine (1000 and 3000 microg/kg) decreased mean circulatory filling pressure only at the higher dose. These results suggest that pranidipine has a greater venodilator effect than nifedipine and amlodipine.

Amlodipine↗
PubMed1997

Expression of the tumor necrosis factor alpha gene and early response genes by nodularin, a liver tumor promoter, in primary cultured rat hepatocytes.

Nodularin is a new liver carcinogen possessing a potent tumor-promoting activity in rat liver, mediated through inhibition of protein phosphatases 1 and 2A, and a weak initiating activity. Since we previously reported evidence that nodularin up-regulated expression of the tumor necrosis factor alpha gene (TNF alpha) and early-response genes in rat liver after its i.p. administration, and since TNF alpha had tumor-promoting activity in vitro, it is possible that TNF alpha itself is involved in liver tumor promotion. We investigated whether hepatocytes themselves induce expression of the TNF alpha gene and early-response genes in primary cultured rat hepatocytes treated with nodularin. Like nodularin, microcystin-LR, which is another liver tumor promoter belonging to the okadaic acid class, strongly induced TNF alpha gene expression in rat hepatocytes, as well as TNF alpha release from those cells into the medium. On the other hand, 12-O-tetradecanoylphorbol-13-acetate, which has been reported to induce no tumor promotion in rat liver, induced no apparent expression of the TNF alpha gene in primary cultured rat hepatocytes. As for the expression of early-response genes, 1 microM nodularin or microcystin-LR induced expression of the c-jun, jun B, jun D, c-fos, fos B and fra-1 genes in the hepatocytes, and the expression of these genes was prolonged up to 24 h, suggesting mRNA stabilization induced by inhibition of protein phosphatases 1 and 2A. This paper presents new evidence that the TNF alpha gene and early-response genes were expressed in hepatocytes treated with a liver tumor promoter.

Animals↗
PubMed1997

Comparative study of toborinone (OPC-18790) and milrinone on energy metabolism in microembolized guinea pig hearts.

The effects of toborinone (OPC-18790) and milrinone on cardiac function and energetics were compared in microembolized guinea pig hearts. Male guinea pig hearts were perfused according to the Langendorff method and microembolization was induced by injecting microspheres. The hearts were then treated with toborinone (10 microM), milrinone (4 microM), and vehicle. Energy metabolism in hearts was assessed by 31-phosphorus magnetic resonance spectroscopy (31P-MRS). Microembolization produced a decrease in coronary perfusion flow (CPF), left ventricular developed pressure (LVP), and peak LVdP/dt by about 50% concomitantly with a decrease in creatine phosphate (PCr) and ATP and an increase in inorganic phosphate (Pi) and Pi/PCr ratio. Toborinone and milrinone increased peak LVdP/dt, an index of contractility, by 15 +/- 2% and 18 +/- 3%, respectively. Milrinone increased heart rate (HR) by 22 +/- 4% but toborinone did not change HR. Toborinone did not change PCr, ATP, Pi, Pi/PCr, and intracellular pH (pHi) compared with the vehicle. On the other hand, milrinone decreased PCr and increased Pi and Pi/PCr compared with toborinone or vehicle. These results suggest that the different effects between toborinone and milrinone on energy metabolism in microembolized hearts may be due to the difference of chronotropic action between these drugs. Thus toborinone, a positive inotropic agent without chronotropic action, may be effective in acute treatment of ischemic heart failure.

Animals↗
PubMed1997

Mechanisms of growth inhibition of human lung cancer cell line, PC-9, by tea polyphenols.

(-)-Epigallocatechin gallate (EGCG), the main constituent of green tea, and green tea extract show growth inhibition of various cancer cell lines, such as lung, mammary, and stomach. We studied how tea polyphenols induce growth inhibition of cancer cells. Since green tea extract contains various tea polyphenols, such as EGCG, (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC), the inhibitory potential of each tea polyphenol on the growth of a human lung cancer cell line, PC-9 cells, was first examined. EGC and ECG inhibited the growth of PC-9 cells as potently as did EGCG, but EC did not show significant growth inhibition. The mechanism of growth inhibition by EGCG was studied in relation to cell cycle regulation. Flow cytometric analysis revealed that treatment with 50 microM and 100 microM EGCG increased the percentages of cells in the G2-M phase from 13.8% to 15.6% and 24.1%, respectively. The DNA histogram after treatment with 100 microM EGCG was similar to that after treatment with genistein, suggesting that EGCG induces G2-M arrest in PC-9 cells. Moreover, we found by microautoradiography that [3H]EGCG was incorporated into the cytosol, as well as the nuclei. These results provide new insights into the mechanisms of action of EGCG and green tea extract as cancer-preventive agents in humans.

Antineoplastic Agents↗
PubMed1997

Significance of MTG8 in leukemogenesis.

MTG8 is a counterpart gene of AML1 in acute myeloid leukemia with t(8:21) translocation. Most of the coding region of the MTG8 is fused with AML1 runt domain. In normal tissues, the MTG8 is highly expressed in brain, but not in hematopoietic tissues. MTG8 may be important in leukemogenesis as well as in AML1 truncation. The function of MTG8 is assumed to be as a transcription factor, because it possesses several features common to transcription factors; putative zinc finger motifs, serine/threonine/proline-rich sequences and a region similar to TAF110. In this paper, we report on the protein properties of the MTG8.

Acute Disease↗