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Biomedical subjects

T Utsugi

Publications and source records attributed to T Utsugi.

At least 37 records · Page 2Linked to original sources
PubMed1999

In vitro antitumor activity of TAS-103, a novel quinoline derivative that targets topoisomerases I and II.

TAS-103 is a novel anticancer agent targeting both topoisomerase (Topo) I and Topo II, that stabilizes cleavable complexes of Topo-DNA at the cellular level. In this study, the in vitro antitumor effects of TAS-103 were compared with those of other known Topo I and Topo II inhibitors. TAS-103 inhibited DNA synthesis more strongly than RNA and protein synthesis, and induced an increase of cell population in the S-G2/M phase. The cytotoxicity of TAS-103 was strongest against S-phase cells, but its cell cycle phase specificity was not clear, and depended on drug concentration and exposure time. The cytotoxicity of TAS-103 (IC50: 0.0030-0.23 microM) against various tumor cell lines was much stronger than that of VP-16 and comparable to that of SN-38. The cytotoxicity of TAS-103 seemed to be more related to the amount of protein-DNA complexes than to the accumulation of TAS-103 in the cells. P-Glycoprotein (P-gp)-mediated MDR, CDDP-resistant and 5-FU-resistant cell lines did not show cross-resistance to TAS-103. Although PC-7/CPT cells bearing a Topo I gene mutation showed cross-resistance to TAS-103, the sensitivity of P388/CPT, HT-29/CPT and St-4/CPT cells, showing decreased Topo I expression, was not changed. KB/VM4 and HT-29/Etp cells, showing decreased Topo II expression, were slightly cross-resistant to TAS-103. These results suggest that TAS-103 may act as an inhibitor of both Topo I and Topo II at the cellular level. This property may be responsible for its strong antitumor effect and broad-spectrum, growth-inhibitory effect on drug-resistant cell lines.

Aminoquinolines↗
PubMed1999

A dual topoisomerase inhibitor, TAS-103, induces apoptosis in human cancer cells.

TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one dihydrochloride), a dual topoisomerase (topo) inhibitor, was developed as an anticancer agent by targeting topo I and topo II and has previously been shown to be effective against lung tumors. In this study, we investigated the cytotoxic activity of TAS-103 in various human cancer cell lines (including gastric, colon, squamous, lung, and breast cancer cells) and the induction of apoptosis by TAS-103. We next established stable transfectants of Bcl-2 in the gastric cancer cell line AZ521 and found that Bcl-2 blocked TAS-103-induced apoptosis. In addition, we demonstrated that the activities of ICE-like and CPP32-like proteases are involved in the signal transduction pathway of TAS-103-induced apoptosis. In summary, TAS-103 is a novel type of anticancer agent with a unique mechanism and could be useful as a lead compound for development of new drugs.

Aminoquinolines↗
PubMed1999

Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice.

Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic beta cells by T lymphocytes. It is believed that CD8(+) cytotoxic T lymphocytes (CTLs) effect the initial beta-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of beta cell-reactive CD8(+) T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8(+) CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2Kd complex on beta cells, to effect beta-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-beta-cell targets via both perforin and Fas, but they killed NOD beta cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8(+) CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill beta cells in a Fas-dependent and perforin-independent manner.

Animals↗
PubMed1999

Biopsy-proven cardiomyopathy in heterozygous Fabry's disease.

A 23-year-old woman with heterozygous Fabry's disease who had acroparesthesia was admitted to hospital for precise examination of the disease before childbearing. She had no cardiac-related symptoms and no abnormality on physical examination. The alpha-galactosidase A activity in her leukocytes was present, but lower than normal. However, the endomyocardial biopsy showed specific changes for Fabry's disease. As Fabry's disease is a rare X-linked recessive inborn error of glycosphingolipid metabolism, heterozygous females are usually asymptomatic, but rarely can be affected as severely as hemizygous males. This is an isolated case of heterozygous Fabry's disease in a female in whom cardiac involvement was detected by endomyocardial biopsy, although she had no cardiac abnormality on physiological examinations. In conclusion, endomyocardial biopsy is useful for evaluation of the cardiac involvement of Fabry's disease even in an asymptomatic case.

Adult↗
PubMed1999

Therapeutic efficacy of a new topoisomerase I and II inhibitor TAS-103, against both P-glycoprotein-expressing and -nonexpressing drug-resistant human small-cell lung cancer.

We examined the effect of a novel topoisomerase I and II (topo I and II) inhibitor, TAS-103, on P-glycoprotein (P-gp)-expressing and -nonexpressing drug-resistant human small-cell lung cancer (SCLC) cells in vitro and in vivo. We observed that TAS-103 was effective in inhibiting in vitro proliferation of human SCLC (SBC-3 and H69) cells and their drug-resistant variants SBC-3/ADM or SBC-3/CDDP and H-69/VP, respectively. SBC-3/ADM and H-69/VP expressed high P-gp, whereas SBC-3/CDDP did not. TAS-103 also effectively reduced the tumor growth (more than 50% inhibition) of the parental as well as MDR SCLC cells grown SC in nude mice. Adriamycin (ADM) and cisplatin (CDDP), on the other hand, were effective only against the parental cells, while these drugs failed to inhibit the respective drug-resistant variants in vitro or in vivo. TAS-103 was observed to induce apoptosis dose dependently in the parental as well as drug-resistant SCLC cells as analyzed after 48 h of in vitro treatment, suggesting that the stabilization of cleavable topo I- or II-DNA complexes by topo I and II inhibitors like TAS-103 is followed by apoptosis of the cells. Overall, our study suggests that TAS-103 may have clinical application against drug-resistant human SCLC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Combination of OK432 and human interferon-alpha for treating viral-induced diabetes mellitus in mice.

We investigated the therapeutic effects of OK432 (picibanil; CAS39325-1-4), an immunomodulator that is derived from the Su strain of Streptococcus pyogenes. This agent was administered alone or combined with human interferon-alpha in a murine model of insulin-dependent diabetes mellitus. Interferon-alpha inhibits viral replication, reducing the incidence of virus-induced IDDM. Groups of DBA/2 mice (N = 25 per group) received an intraperitoneal injection of OK432 and interferon-alpha daily for 16 d beginning 1 d after inoculation with 500 plaque-forming units of encephalomyocarditis virus (EMCV). The dose of OK432 was one clinical unit (corresponding to 0.1 mg dried cells) per mouse, and that of interferon-alpha was 1 x 10(4) u/g. The animals were killed at random at 3 or 7 d after inoculation with EMCV. The survival rate of mice treated with the combination of OK432 and with interferon-alpha was significantly greater than that of the non-treated infected control animals (P < 0.01). Fasting levels of blood glucose were significantly lower in the mice administered the combination, than in the controls, both on day 3 (68 +/- 21 mg/dl vs. 270 +/- 135 mg/dl, P < 0.01) and on day 7 (101 +/- 29 mg/dl vs. 219 +/- 112 mg/dl, P < 0.01). Serum levels of insulin were significantly higher in the treated mice than in the controls (65 +/- 5 vs. 55 +/- 1 microU/ml, P < 0.05). However, in the mice treated with OK432 or interferon-alpha alone, the survival rate and the blood level of glucose and insulin did not differ from those of infected controls. Natural killer (NK) cell activity was significantly higher in the mice treated with the drug combination than in the controls on both days evaluated: day 3, 65 +/- 5 vs. 55 +/- 1%, n = 3, P < 0.05; day 7, 44 +/- 3 vs. 22 +/- 8%, n = 3, P < 0.05). Serum levels of murine interferon in the treated mice exceeded those in controls on both days evaluated (day 3, 671 U/ml vs. 442 U/ml; day 7, 57 U/ml vs. 43 U/ml). There were no significant differences in NK cell activity or in the interferon level in mice treated with either OK432 or interferon-alpha alone as compared with the infected, non-treated controls. Results suggest that the combination of OK432 and interferon-alpha protects against virally induced IDDM by increasing the activity of NK cells as well as the plasma level of interferon.

Animals↗
PubMed1998

Mutations in the hepatocyte nuclear factor-1 alpha gene (MODY3) are not a major cause of early-onset non-insulin-dependent (type 2) diabetes mellitus in Japanese.

Maturity-onset diabetes of the young (MODY3), a monogenic subtype of non-insulin-dependent diabetes mellitus (NIDDM) with an early age of onset, is characterized by a primary defect in insulin secretion. Recently, it has been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) cause MODY3. Since NIDDM in Japanese is characterized by insulin secretory defects due to primary beta-cell dysfunction, we screened 60 Japanese nonobese subjects with early-onset NIDDM for mutations in this gene, 45 of whom had a first-degree relative with NIDDM. Direct sequencing of the ten exons and flanking introns of the gene in these subjects identified eight nucleotide substitutions including two amino acid changes, Ile-27-Leu and Ser-487-Asn, the frequencies of which were not significantly different in subjects with early-onset NIDDM and nondiabetic subjects. These results suggest that mutations in the HNF-1 alpha gene are not a major cause of early-onset NIDDM in Japanese.

Adolescent↗
PubMed1998

Induction of virus-induced IDDM in virus resistant mice without lymphocyte maturation.

The role of lymphocytes in the pathogenesis of viral-induced insulin dependent diabetes mellitus (IDDM) is controversial. To better understand how a virus-induced IDDM depends on the infiltrating lymphocytes, encephalomyocarditis virus (EMCV) was inoculated intraperitoneally into three kinds of mice; virus-susceptible C57BL/6, virus-resistant 129/SV and recombination activity gene-2 (Rag2) knockout 129/SV mice. Pancreatic inflammation and beta cell necrosis were evaluated after EMCV, D variant (10(3) pfu/mouse) inoculation. On post-inoculation day 14, the lethal rates of C57BL/6, 129/SV and Rag2 knockout mice were 52, 10 and 100%, respectively. The blood glucose in Rag2KO mice on day 8 was significantly elevated as compared with 129SV mice (231 +/- 49 vs 169 +/- 32 mg/dl, P<0.05). In situ hybridization demonstrated the EMCV genome in the pancreas of Rag2 knockout and C57BL/6 mice, but not in 129/SV mice. Beta cell necrosis were more severe in Rag-2 knockout mice than in wild type 129/SV mice, but lymphocyte infiltration was less severe than C57BL/6. Pancreas in Rag2 knockout mice infected with virus were affected more severely than the virus-resistant strain of mice. Diabetogenic virus induced IDDM in virus-resistant mice without mature lymphocytes.

Animals↗
PubMed1998

Pre-clinical Cushing's syndrome with body weight loss and normal circadian rhythm of blood pressure.

A 68-year-old woman was referred for evaluation of an incidentally discovered left adrenal mass. Her chief complaint was body weight loss. She showed no symptoms or signs suggestive of Cushing's syndrome. The circadian rhythm of blood pressure was also normal. Hormonal assessment revealed an abnormal diurnal variation in serum cortisol levels, suppressed baseline plasma adrenocorticotrophic hormone, and nonsuppression of serum and urinary cortisol with the dexamethasone suppression test. Adrenal scintigraphy with (131)I-6-beta-iodomethyl-norcholesterol showed uptake on the left adrenal and inhibition of the contralateral adrenal gland. She was diagnosed as pre-clinical Cushing's syndrome. Due to the lack of clinical symptoms and the risks of surgery, we emphasize the importance of careful assessment of the cortisol metabolism and scintigraphic scanning under dexamethasone suppression to avoid post-surgical Addisonian crisis.

Adrenal Gland Neoplasms↗
PubMed1998

[Three patients with insulin-treated diabetes and senile dementia of Alzheimer's type].

Senile dementia of Alzheimer's type (SDAT) is reported to be less frequent in patients with Diabetes Mellitus. However the, the number of elderly people in still increasing in Japan, an is the incidence of diabetes mellitus, especially in middle-aged and elderly people. Thus, we can expect to encounter more elderly people with diabetes and SDAT. We encountered three patients with diabetes who were treated with insulin and in whom SDAT developed. In all three, control of blood glucose levels gradually worsened, despite increases in the dose of injected insulin. It was later found that they did not inject insulin properly because of SDAT. They lived alone and their dementia was not diagnosed before their admission to the hospital. In its early phase, SDAT can be difficult to diagnose, especially in patients who live alone. SDAT should be considered when the control of blood glucose levels for no apparent reason in elderly patients with diabetes.

Aged↗
PubMed1997

Mutation of the mouse klotho gene leads to a syndrome resembling ageing.

A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.

Aging↗
PubMed1997

Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice.

A new type of CD4+ T cell clone (NY4.2) isolated from pancreatic islet-infiltrated lymphocytes of acutely diabetic non-obese diabetic (NOD) mice prevents the development of insulin-dependent diabetes mellitus (IDDM) in NOD mice, as well as the recurrence of autoimmune diabetes in syngeneic islet-transplanted NOD mice. It has been demonstrated that the cytokine TGF-beta, secreted from the cells of this clone, is the substance which prevents autoimmune IDDM. This investigation was initiated to determine the molecular role TGF-beta plays in the prevention of autoimmune IDDM by determining its effect on IL-2-induced signal transduction in Con A-activated NOD mouse splenocytes and HT-2 cells. First, we determined whether TGF-beta, secreted from NY4.2 T cells, inhibits IL-2-dependent T cell proliferation in HT-2 cells (IL-2-dependent T cell line) and NOD splenocytes. We found that TGF-beta suppresses IL-2-dependent T cell proliferation. Second, we determined whether TGF-beta inhibits the activation of Janus kinases (JAKs), as well as signal transducers and activators of transcription (STAT) proteins, involved in an IL-2-induced signalling pathway that normally leads to the proliferation of T cells. We found that TGF-beta inhibited tyrosine phosphorylation of JAK1, JAK3, STAT3 and STAT5 in Con A blasts from NOD splenocytes and HT-2 cells. Third, we examined whether TGF-beta inhibits the cooperation between STAT proteins and mitogen-activated protein kinase (MAPK), especially extracellular signal-regulated kinase 2 (ERK2). We found that TGF-beta inhibited the association of STAT3 and STAT5 with ERK2 in Con A blasts from NOD splenocytes and HT-2 cells. On the basis of these observations, we conclude that TGF-beta may interfere with signal transduction via inhibition of the IL-2-induced JAK/STAT pathway and inhibition of the association of STAT proteins with ERK2 in T cells from NOD splenocytes, resulting in the inhibition of IL-2-dependent T cell proliferation. TGF-beta-mediated suppression of T cell activation may be responsible for the prevention of effector T cell-mediated autoimmune IDDM in NOD mice by TGF-beta-producing CD4+ suppressor T cells.

Acute-Phase Proteins↗
PubMed1997

Change of plasma 1,5-anhydro-D-glucitol levels after the onset of diabetes in spontaneous diabetes prone BB/Wor/(/)Tky rats.

Plasma 1,5-anhydro-D-glucitol (AG) is a marker of the diabetic state and also reflects the glycosuria induced by hyperglycemia but not by renal pathology. To investigate the benefits of the AG determination in order to diagnose diabetes in BB/Wor/(/)Tky rats, AG was measured in non-diabetic (n = 104) and diabetic (n = 113) BB/Wor/(/)Tky rats. AG was significantly higher in non-diabetic rats than in diabetic rats (25.2 +/- 9.3 vs 4.1 +/- 7.4 micrograms/ ml, mean +/- SD, p < 0.001). The best cut-off level for AG (8.5 micrograms/ml) was highly specific (100%) for ruling out diabetes and fairly sensitive (82.3%) to detect diabetes. Based on the AG cut-off levels, 90% of false-negative diabetic rats (18/20) were observed within 4 days after the onset of diabetes, which corresponded to 38.3% in diabetic rats (18/47) at that time. The false-negative diabetic rats and positive rats could be effectively distinguished based on the cumulative points given according to the urinary glucose after the onset of diabetes. 1 point for each cross [+] indicating glycosuria using the Testape, i.e. 2 or less points false negative and 4 or more points for diabetic rats in the first 4 days. In conclusion, there is a close inverse relation between the level of plasma AG and the amount of glycosuria detected just after the onset of overt diabetes in BB/Wor/(/)Tky rats.

Animals↗
PubMed1997

Antitumor activity of a novel quinoline derivative, TAS-103, with inhibitory effects on topoisomerases I and II.

A novel quinoline derivative, TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin -7-one dihydrochloride), was developed as an anticancer agent targeting topoisomerases (topo) I and II, with marked efficacy in solid tumors. TAS-103 inhibited topo I and II (IC50: 2 microM, 6.5 microM) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50: 0.0011 microM, 0.0096 microM). TAS-103 stabilized topo I and II-DNA cleavable complexes in KB cells, generating a similar amount of topo II-DNA complex to that induced by etoposide (VP-16) but a smaller amount of topo I-DNA complex than that produced by camptothecin (CPT). In the in vivo study, intermittent i.v. administration was markedly effective against s.c.-implanted murine tumors. Furthermore, TAS-103 had marked efficacy against various lung metastatic tumors, and a broad antitumor spectrum in human tumor xenografts (derived from lung, colon, stomach, breast, and pancreatic cancer). The efficacy of TAS-103 was generally greater than that of irinotecan (CPT-11), VP-16, or cis-diamminedichloroplatinum (CDDP).

Adenocarcinoma↗
PubMed1997

Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM.

One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deficient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 alpha cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1 alpha gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1 alpha gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291 fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1 alpha was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1 alpha gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1 alpha-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.

Adolescent↗
PubMed1996

Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains.

The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.

Amino Acid Sequence↗