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Isao Nishimori

Publications and source records attributed to Isao Nishimori.

At least 37 records · Page 2Linked to original sources
PubMed2005

Carbonic anhydrase inhibitors: inhibition of the human transmembrane isozyme XIV with a library of aromatic/heterocyclic sulfonamides.

The first inhibition study of the transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA XIV with a library of aromatic and heteroaromatic sulfonamides synthesized earlier is reported. Most of the inhibitors were sulfanilamide, homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives, to which tails that would induce diverse physicochemical properties have been attached at the amino moiety. Several of these compounds were metanilamide, benzene-1,3-disulfonamide or the 1,3,4-thiadiazole/thiadiazoline-2-sulfonamide derivatives. The tails incorporated in these molecules were of the alkyl/aryl-carboxamido/ sulfonamido-, ureido- or thioureido-types. The sulfanilamides acylated at the 4-amino group with short aliphatic/aromatic moieties incorporating 2-6 carbon atoms showed modest hCA XIV inhibitory activity (K(I)-s in the range of 1.25-4.2 microM) which were anyhow better than that of sulfanilamide (K(I) of 5.4 microM). Better activity showed the homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives bearing arylsulfonamido/ureido and thioureido moieties, with K(I)'s in the range of 203-935 nM. The best activity was observed for the heteroaromatic compounds incorporating 1,3,4-thiadiazole/thiadiazoline-2-sulfonamide and 5-arylcarboxamido/sulfonamido moieties, with K(I)'s in the range of 10-85 nM. All these compounds were generally also much better inhibitors of the other two transmembrane CA isozyme, hCA IX and XII. Thus, highly potent hCA XIV inhibitors were detected, but isozyme-specific inhibitors were not discovered for the moment.

Carbonic Anhydrase Inhibitors↗
PubMed2005

Overexpression of carbonic anhydrase-related protein XI promotes proliferation and invasion of gastrointestinal stromal tumors.

Three isoforms of carbonic anhydrase-related protein (CA-RP) are evolutionally well conserved among the CA gene family but lack classical CA activity. Although the biological function of CA-RPs is unknown, overexpression of CA-RP VIII has been reported in certain tumor types. Based on the finding that CA-RPs are commonly expressed in the neuronal cells, we investigated expression of all three CA-RPs in gastrointestinal stromal tumor (GIST). In contrast to no detectable signal of any of the three CA-RPs in intestinal cells of Cajal, immunohistochemical analysis showed distinct cytoplasmic expressions of CA-RPs VIII and XI in 13 (59%) and 20 (91%) of 22 GIST tissue specimens, respectively. The positive signals for both CA-RPs VIII and XI were more intense in the periphery than in the central part of GISTs, whereas no significant signal for CA-RP X expression was observed in any of the GISTs. These expression patterns of CA-RPs were consistently observed by reverse transcription-polymerase chain reaction-Southern blot and immunocytochemistry in the cultured GIST cell line GIST-T1. Ectopic expression of CA-RP XI in GIST-T1 cells induced cell proliferation and invasion in vitro. These findings indicate that CA-RP XI plays a role in the development of GIST.

Biomarkers, Tumor↗
PubMed2005

Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides-a new target for the design of antitumor and antiglaucoma drugs?

The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme XII (hCA XII), has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic drug topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with several medium potency inhibitors (K(I)s in the range of 34-220 nM), whereas ethoxzolamide and several halogenated sulfanilamides showed stronger potency, with K(I)s in the range of 11-22 nM. The antiglaucoma sulfonamides used clinically, except dichlorophenamide, which is a moderate inhibitor (K(I) of 50 nM), as well as topiramate, indisulam, and sulpiride behave as very potent hCA XII inhibitors, with K(I)s in the range of 3.0-5.7 nM. Several subnanomolar inhibitors (K(I)s in the range of 0.30-0.85 nM) have also been detected. Compounds with excellent selectivity against hCA XII over hCA II have been found, showing selectivity ratios in the range of 177.7-566.7. Apparently, hCA XII is a target of the antiglaucoma sulfonamides, and potent hCA XII inhibitors may be developed/used for the management of hypoxic tumors, together with inhibitors of the other tumor-associated isozyme, CA IX.

Antineoplastic Agents↗
PubMed2005

Adenosquamous carcinoma of the extrahepatic biliary tract: clinicopathological analysis of Japanese cases of this uncommon disease.

BACKGROUND: We analyzed the clinicopathologic variables and postoperative outcomes in patients with extrahepatic adenosquamous carcinoma to identify important factors for predicting postresection prognosis. METHODS: Thirty-six patients in Japan who underwent surgical resection for adenosquamous carcinoma of the extrahepatic biliary tract, with curative intent by the end of 2003, were studied. A retrospective review, with univariate and multivariate analyses, was performed on the clinical records of patients who underwent surgical exploration for adenosquamous carcinoma of the common bile duct. The clinical and pathologic factors that influenced patient survival were analyzed. RESULTS: The operative mortality rate in the patient cohort was 3%. The overall 1-, 3-, and 5-year survival rates were 57%, 26%, and 16%, respectively, and the median survival was 13 months. Univariate and multivariate analyses revealed that independent negative prognostic factors in resected specimens were: (1) the presence of pancreatic invasion, (2) the presence of n2 and n3 lymph node metastasis, and (3) curability C status. The presence of an abnormal arrangement of the pancreatobiliary ductal system and pathological serosal invasion of the tumor tended to be associated with poor survival. CONCLUSIONS: Curative surgical resection for adenosquamous carcinoma remains the only effective treatment, because it offers the chance of long-term survival. New adjuvant strategies are required for improvements in patient outcomes.

Adult↗
PubMed2005

Carbonic anhydrase inhibitors: Inhibition of the tumor-associated isozymes IX and XII with polyfluorinated aromatic/heterocyclic sulfonamides.

The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX (CA IX) and XII (CA XII) are involved in acidification of hypoxic tumors, a process correlated with poor prognosis and clinical outcome of patients harboring such tumors. This process may be reversed by inhibiting these enzymes with potent sulfonamide/sulfamate inhibitors. A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluorophenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII. Some of these compounds showed excellent inhibitory properties against both isozymes IX and XII, with several subnanomolar inhibitors detected for the first time. These sulfonamides may constitute valuable candidates for the development of novel antitumor therapies based on the inhibition of such tumor-associated CA isozymes.

Antigens, Neoplasm↗
PubMed2004

Serum antibody to carbonic anhydrase II in patients with chronic viral hepatitis: a review of its prevalence in liver diseases.

Serum antibody to carbonic anhydrase II (CA II) has been reported in patients with autoimmune pancreatitis and its related autoimmune liver diseases. To evaluate its diagnostic significance, we studied serum antibodies to CA II and also CA I in patients with chronic viral hepatitis by enzyme-linked immunosorbent assay and reviewed its prevalence previously reported in patients with liver diseases. Anti-CA II antibody was detected in 5 of 20 patients with chronic hepatitis type C (25%, p<0.05 versus normal controls), 2 of 10 patients with chronic hepatitis type B (20%, not significant versus normal controls), and 1 of 30 normal controls (3%). Anti-CA I antibody was detected in 3 of 20 patients with chronic hepatitis type C (15%, not significant versus normal controls). Anti-CA II antibody has previously been reported as being associated with a variety of liver diseases, including primary biliary cirrhosis with or without anti-mitochondrial antibody, autoimmune hepatitis and chronic hepatitis type C. These findings suggest less significance of anti-CA II antibody for the diagnosis of autoimmune pancreatitis and its hepatic involvements than as having been reported. However, the pathogenetic role of the antibody remains uncertain.

Journal Article↗
PubMed2004

Effect of carbonic anhydrase-related protein VIII expression on lung adenocarcinoma cell growth.

Carbonic anhydrase-related protein VIII (CA-RP VIII) is expressed in most non-small cell lung cancer, and especially strongly at the front of tumor progression. Screening analysis of CA-RP VIII expression in a panel of cultured lung cancer cell lines showed that a well differentiated adenocarcinoma cell line, PC-9, appeared to lack CA-RP VIII. Subsequently, CA8 cDNA was transfected with an expression vector into PC-9. Ectopic overexpression of CA-RP VIII reduced the growth of PC-9 cells on uncoated culture dishes, especially when the cultures were started at low cell density, but increased cell growth on laminin-coated dishes. Interestingly, ectopic CA-RP VIII expression markedly reduced caspase-3 activity induced by serum starvation and anti-cancer agents in PC-9 cells. The present findings suggest that CA-RP VIII expression promotes progression of lung cancer by multifarious mechanisms.

Adenocarcinoma↗
PubMed2004

Hereditary pancreatitis: clinical characteristics and diagnostic criteria in Japan.

BACKGROUND/AIM: Hereditary pancreatitis (HP) is the strongest known risk factor for pancreatic cancer. The aim of the present study is to establish diagnostic criteria for HP to predict and identify high-risk groups for pancreatic cancer. METHOD: We collected clinical data for 210 patients with recurrent acute or chronic pancreatitis, and examined mutations of the cationic trypsinogen (CT) gene in 57 patients with a family history of pancreatitis or with early-onset idiopathic recurrent acute or chronic pancreatitis (40 years of age or younger). DNA was extracted from peripheral blood leukocytes, and exons 2 and 3 of the CT gene were individually amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: Of these 57 patients in whom mutations of the CT gene were examined, the R122H (20 patients) and N29I (5 patients) mutations in the CT gene were observed in 25 patients (43.9%). From the analysis of clinical records and the CT gene of these patients, we proposed the following adaptations to the diagnostic criteria for HP: (1) at least one of the affected members in a family has no known etiological factors, (2) we deleted the definition of "different generation", but included the upper limit of the age of onset of pancreatitis in the case of siblings (at least 1 of the patients in a family <40 years of age). According to these criteria, all patients with the CT gene mutations in the present study could be classified as having HP, with the exception of 2 sporadic cases with the R122H and N29I mutations, respectively. Based on these findings, we revised the criteria for the diagnosis of HP; (1) recurrent acute or chronic pancreatitis with R122H or N29I mutation of the CT gene, or (2) recurrent acute or chronic pancreatitis with a family history of 2 or more affected patients, irrespective of generation, with at least 1 of the patients having no known etiological factors, and in case of siblings only, the onset of the disease in at least 1 of the patients is under age 40 years. CONCLUSION: The revised criteria in the present study are appropriate and of clinical usefulness to diagnose patients with HP even in cases without the genetic testing. However, if and when more genes are detected, it will be important to reexamine the mutation-negative patients now classified as HP based on our proposed criteria.

Adolescent↗
PubMed2004

Diminished cellular immune response to carbonic anhydrase II in patients with Sjögren's syndrome and idiopathic chronic pancreatitis.

CONTEXT: A serum antibody to carbonic anhydrase II has been reported in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. OBJECTIVE: To evaluate cellular immune response to carbonic anhydrase II in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. PATIENTS: Idiopathic chronic pancreatitis (n=23), Sjögren's syndrome (n=12), alcoholic chronic pancreatitis (n=3) and normal controls (n=13). MAIN OUTCOME MEASURES: Proliferation assay of peripheral blood mononuclear cells. RESULTS: Notable increased proliferation of the mononuclear cells upon stimulation with carbonic anhydrase II was observed in 2 patients with idiopathic chronic pancreatitis (9%) and 2 patients with Sjögren's syndrome (17%) but not in patients with alcoholic chronic pancreatitis nor in normal controls. Among the four study groups, there was no significant difference in the prevalence rate of the positive proliferative responses (P=0.444). CONCLUSION: Carbonic anhydrase II may not be a major target antigen for the immunological process in the pathogenesis of Sjögren's syndrome and idiopathic chronic pancreatitis. Serum antibody to carbonic anhydrase II may be detected in these patients as a consequence of the immune reaction against other antigens which mimic carbonic anhydrase II.

Aged↗
PubMed2004

[Treatment of acute pancreatitis with protease inhibitor, H2 receptor antagonist and somatostatin analogue].

Acute pancreatitis sometimes develops to severe condition with a variety of clinical manifestations and high mortality. Autodigestion of the pancreas, secondary to the activation of digestive enzymes, plays a major role in the pathogenetic mechanism of acute pancreatitis. To improve the mortality and complication rates, appropriate treatments based on the precise prediction of disease severity are required. To this end, the early administration of protease inhibitors has commonly been employed for the therapy of acute pancreatitis in Japan. However, a number of clinical trials have failed to show the clinical effects of protease inhibitors, H2 receptor antagonist and somatostatin analogue on the treatment of acute pancreatitis. To evidence the therapeutic value of these agents for acute pancreatitis, well-organized clinical studies will be required.

Acute Disease↗
PubMed2004

[Pancreatitis-associated gene mutations].

Since the discovery of the cationic trypsinogen gene mutations in patients with hereditary pancreatitis, a variety of pancreatitis-associated gene mutations have been reported, including pancreatic secretory trypsin inhibitor and cystic fibrosis transmembrane conductance regulator. Although the patients with these mutations are rarely seen, genetic disorders inducing pancreatitis have provided us major breakthroughs to understand the molecular basis of the disease. Furthermore, the major stream in pancreatology has been evidenced in patients with hereditary pancreatitis: acute pancreatitis --> chronic pancreatitis --> pancreatic cancer. This report will focus on the pancreatitis-associated genes and the molecular mechanism of pancreatitis associating with these gene mutations.

Animals↗
PubMed2003

Overexpression of carbonic anhydrase-related protein VIII in human colorectal cancer.

Carbonic anhydrase-related protein (CA-RP) VIII, which is a member of the CA gene family, has been shown to have no catalytic CA activity and its biological function is still unknown. Recently, overexpression of CAs IX and XII has been reported in certain types of malignancy. To investigate a potential role for CA-RP VIII in human colorectal epithelial carcinogenesis, colorectal tissue specimens from surgically resected adenocarcinomas (n = 60) and endoscopically polypectomized adenomas (n = 13) were analysed by immunohistochemistry using monoclonal antibodies to CA-RP VIII and Ki-67 antigen. Less than 5% of epithelial cells in normal colonic mucosae (n = 73) were CA-RP VIII-positive and these were localized to the deep part of the cryptal epithelium. Increased expression of CA-RP VIII was observed in 78% of colorectal carcinomas. An intense signal was frequently observed at the tumour invasion front and its distribution was completely different from that of Ki-67 antigen. Colorectal adenomas also showed significant immunopositivity for CA-RP VIII, but its expression level was much lower than in adenocarcinomas. These findings suggest that CA-RP VIII plays a role in the process of invasion in colorectal cancer.

Adenocarcinoma↗
PubMed2003

Mutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in Japan.

BACKGROUND: Mutations in the pancreatic secretory trypsin inhibitor ( PSTI) gene have been reported in patients suffering from chronic pancreatitis. The aim of the present study was to investigate whether similar gene mutations are present in familial and juvenile pancreatitis patients in Japan. METHODS: All four exons of the PSTI gene and their flanking intronic sequences were amplified by polymerase chain reaction and sequenced for 37 familial pancreatitis patients (24 families) and 15 juvenile pancreatitis patients, distributed throughout Japan. RESULTS: Three types of exonic mutation in the PSTI gene were observed. The N34S mutation was found in six familial pancreatitis patients (three families) and in one juvenile pancreatitis patient, and the R67C mutation was found in one familial pancreatitis patient and one juvenile pancreatitis patient. We also found a 272C>T mutation in the 3' untranslated region of exon 4 in one familial pancreatitis patient and four juvenile pancreatitis patients. It should be noted that the N34S mutation was cosegregated with two intronic mutations, specifically, IVS1-37T>C and IVS3-69insTTTT. CONCLUSIONS: The same set of N34S mutations (N34S + IVS1-37T>C + IVS3-69insTTTT) that exists in other countries was found in the PSTI gene in Japanese familial and juvenile pancreatitis patients. Another unique mutation (R67C) was also observed in two patients; 272C>T was suggested to be a normal polymorphism.

Adolescent↗
PubMed2003

Inflammatory pseudotumor of the liver: report of a case diagnosed by needle biopsy.

We report a case of a 76-year-old man with inflammatory pseudotumor, xanthogranuloma type of the liver. The patient showed clinical manifestations of a liver abscess. Abdominal sonography and computed tomography revealed an additional tumor-like lesion adjoining the liver abscess. Following treatment with antibiotics for 20 days, the liver abscess disappeared, but there was no change in the size and shape of the tumor-like lesion. Histological analysis of a specimen obtained from the tumor-like lesion by needle biopsy revealed an infiltration of abundant foamy histiocytes with massive fibrosis. Without any treatment, the tumor-like lesion gradually diminished in 5 months. In previous literatures, most cases with xanthogranuloma of the liver underwent hepatectomy or diagnostic laparotomy. The findings presented herein suggest that in cases of an atypical solid mass in the liver accompanied by a clinical inflammatory process, inflammatory pseudotumor should be considered, and, if the disease is suspected, liver needle biopsy is recommended to prevent an unnecessary surgical operation.

Journal Article↗
PubMed2003

Biliopancreatic fistula caused by an intraductal papillary-mucinous tumor of the pancreas confirmed by biochemical analysis of mucin.

Intraductal papillary-mucinous tumor of the pancreas is occasionally accompanied by biliopancreatic fistula. However, it is difficult to show the inflow of mucin produced by the tumor into the common bile duct. To confirm the biliopancreatic fistula, the mucin-rich fraction was purified from the bile and stained with antimucin antibodies. Western blot analysis showed characteristic smear staining patterns for mucin molecules with three types of antimucin antibodies. Immunohistochemical analysis with the antibody showed significant signals of the cancer cells and the luminal content of the dilated pancreatic duct. These results showed that the bile contained an abundance of mucin, which was produced by the primary pancreatic tumor. In cases with intraductal papillary-mucinous tumor of the pancreas, biochemical analysis of mucin molecules in the bile can be of clinical use in consideration of pathological process of tumor progression.

Adenocarcinoma, Mucinous↗
PubMed2002

cDNA cloning and developmental expression of murine carbonic anhydrase-related proteins VIII, X, and XI.

To help understand the biological functions of carbonic anhydrase-related proteins (CA-RPs VIII, X, and XI), we obtained cDNA clones of murine CA-RPs X and XI and studied the tissue distribution of all three CA-RPs and their developmental expression in the murine embryonic brain. The amino acid sequences of murine CA-RPs are highly conserved with their human homologues, indicating a fundamental biological role of CA-RPs. Among a panel of vital organs, the strongest mRNA expression of all three CA-RPs was consistently observed in the brain. Immunohistochemical analysis revealed the expression of all three CA-RPs in the neural cell body and neurites. CA-RP X was also observed in the myelin sheath, as demonstrated using the shiverer demyelinated mouse. In murine embryos, CA-RP VIII and X messages first appeared in the middle of the gestation period, while the CA-RP XI message was seen at an early gestational stage and expressed to a lesser extent as gestation progressed. All CA-RPs were expressed in the neuroprogenitor cells in the subventricular area and subsequently detected in the neural cells migrating to the cortex. Although the exact function of CA-RPs is still undefined, these findings suggest an important role of CA-RPs in the CNS.

Animals↗