[Hepatic and hematological toxicities of therapy with H2-receptor antagonists].
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Anti-Ulcer Agents↗
Biomedical subjects
M Hirota
Publications and source records attributed to M Hirota.
Enhanced levels of annexins in pancreatic carcinoma cells of Syrian hamsters and their intrapancreatic allografts.
Annexins are a family of calcium- and phospholipid-binding proteins related by amino acid sequence homology. Annexins I and II are substrates for protein tyrosine kinases. Recent investigations have revealed a possible involvement of annexins I and II in mitogenic signal transduction and cell proliferation. To investigate further the involvement of annexins in cell proliferation, we measured the levels of annexins I and II and the enzyme 3-phosphoglycerate kinase (PGK) (annexin II and PGK are components of the primer recognition protein complex) in normal Syrian hamster pancreas, three hamster pancreatic ductal carcinoma cell lines, and allografts of the three cell lines into hamster pancreas. All three carcinoma cell lines had 5-8-fold higher levels of annexin II compared to normal pancreas. An inverse relationship was seen between level of annexin II and the doubling time of the cell culture. In intrapancreatic allografts, annexin II levels were 3-6-fold higher than in normal pancreas. Annexin I levels were 2-3-fold higher in the allografts. Significant increases (5-6-fold) in specific activity of PGK were seen in all allografts examined. However, the level of PGK, as measured by immunoblotting, was not significantly altered. Immunohistochemical staining revealed heterogeneity in the reactivity of the antiannexin and anti-PGK antibodies with tumor cells. Strikingly, the reactivity and staining intensity were greater in the proliferating regions of the primary tumors and in the metastatic foci. Mitotic cells were either unstained or very weakly stained. We conclude from these findings that annexin II and PGK, as primer recognition proteins, may have a role in cell proliferation.
Animals↗
Modification of blood group A antigen expression in a pancreatic cancer cell line (PC-1) by inhibitors of N-glycan processing.
Pancreatic adenocarcinomas induced in Syrian hamsters by treatment with N-nitrosobis(2-oxopropyl) amine express blood group A antigen, which is absent in normal pancreatic cells. On membrane glycoproteins purified from tumors, blood group A antigen has been found to be expressed on multiantennary Asn-linked complex glycans. In this study, we investigated the effect of inhibitors of Asn-glycan processing on blood group A antigen bearing glycan structures in a cell line (PC-1) established from a primary induced pancreatic cancer. Expression of blood group A antigen on cells and in membrane preparations was blocked by treatment with 1-deoxymannojirimycin, an inhibitor of mannosidase I, but was retained after treatment with swainsonine, an inhibitor of mannosidase II. However, swainsonine treatment altered the glycan structure associated with blood group A antigen from an endoglycosidase H resistant type to a sensitive type, indicating that the blood group A structure might shift from a complex type to a hybrid type glycan by this treatment. These results demonstrate that Asn-linked glycans carry the major blood group A antigens in PC-1 cells.
1-Deoxynojirimycin↗
An experience of cell sorting using samples isolated from paraffin-embedded tissue of neuroblastoma.
Flow cytometric DNA content analyses were performed on samples from 72 patients with neuroblastoma. Nuclear suspensions obtained from paraffin-embedded samples were prepared using the method described by Schutte et al. Determination of DNA ploidy was possible in 62 out of 72 patients. DNA diploidy was detected in 23 (37.1%) and DNA aneuploidy was found in 39 (62.9%) of these 62 patients. Cell sorting was performed on two peak areas of the DNA histogram of samples with aneuploidy. The sorted cells of the first peak area were composed of small round cells and were considered to be normal lymphocytes. The sorted cells of the second peak area were composed of relatively large cells with obvious nucleoli and were considered to be neuroblastoma cells. Thus, two cell components could be distinguished by cell sorting. It is concluded that cell sorting may be of benefit in giving detailed information about DNA histograms, even in samples obtained from paraffin-embedded tissue.
Cell Separation↗
Purification and analysis of glycoproteins bearing blood group-A determinants from hamster pancreatic ductal adenocarcinomas.
Although the hamster pancreas does not express A, B or H blood group antigens, all hamster pancreatic ductal adenocarcinomas induced by treatment with N-nitrosobis(2-oxopropyl)amine express blood group-A antigen. Thus, the acquisition of blood group-A antigen expression in this system is a cancer-associated alteration. We have purified three major blood group-A antigen bearing glycoproteins (gp120, gp135 and gp150) from hamster pancreatic cancer cell membrane preparations using affinity chromatography on DBA (Dolichos biflorus) agglutinin-agarose. When assayed by immunoblotting, gp120 and gp135 showed strong blood group-A reactivity, which was removed by treating membrane samples with peptide-N-glycosidase F. Blood group-A reactivity was unchanged by treatment of the membrane fractions with endoglycosidases F and H. In addition, these two glycoproteins bearing blood group-A antigen also bound L-PHA (Phaseolus vulgaris leucoagglutinin). These results demonstrate that gp120 and gp135 express blood group-A antigen on Asn-linked multi-antennary complex type glycan structures. The gp150 showed weak blood group-A expression. This is the first demonstration of the neoexpression of cancer-associated blood group-A determinants which reside on Asn-linked glycan structures.
ABO Blood-Group System↗
Chalcone tetramers, lophirachalcone and alatachalcone, from Lophira alata as possible anti-tumor promoters.
Two chalcone tetramers were isolated as inhibitors of Epstein-Barr virus (EBV)-activation induced by a tumor promoter, teleocidin B-4, from a medicinal plant in tropical west Africa, Lophira alata (Ochnaceae). One of them was identified as lophirachalcone. The other, named alatachalcone, was new, and the structure was determined by spectral properties. Both compounds also showed potent inhibitory activities against teleocidin B-4-induced inflammation on mouse ear. In an initiation-promotion experiment on mouse skin, alatachalcone (16 nmol) significantly inhibited tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol).
9,10-Dimethyl-1,2-benzanthracene↗
Establishment of a human hepatoblastoma model in athymic nude mice. Producibility of fatty acid-binding protein, alpha-fetoprotein, and alpha 1-acid glycoprotein.
An athymic nude mouse model of human hepatoblastoma, designated HBL-2, was established. HBL-2 produced alpha-fetoprotein (AFP) and the serum level in tumor-bearing mouse was roughly proportional to the tumor weight. Reactivity of AFP to Concanavalin A and Lens culinaris lectins indicated that it contained predominantly fucosylated, non-bisecting N-acetylglucosamine as a sugar moiety. Alpha 1-acid glycoprotein (AAG) was also found in both HBL-2 tumor extract and sera of tumor-bearing mice. The serum level, however, was not proportional to either the tumor weight or the value of the tumor extract. In addition, fatty acid-binding protein (FABP) was detected in approximately 40% of tumor cells and in tumor extract with polyclonal antibody against liver FABP. Thus, HBL-2 is an unique model of human hepatoblastoma, in that it produces FABP in addition to AAG and AFP.
Animals↗
Expression of pS2 gene in human breast cancer cell line MCF-7 is controlled by retinoic acid.
We established a simplified method for the quantitative measurement of pS2 mRNA using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Expression of the pS2 gene, which is transcriptionally induced by estrogen in breast cancer cell line MCF-7 cells, can be repressed by retinoic acid (RA) in unstimulated cells. The suppressive effect of RA on pS2 mRNA was inhibited by cycloheximide.
Breast Neoplasms↗
Inhibitory effects of new types of biflavonoid-related polyphenols; lophirone A and lophiraic acid, on some tumor promoter-induced biological responses in vitro and in vivo.
Lophirone A, isolated as a new type of biflavonoid-related inhibitor of Epstein-Barr virus (EBV) activation, was tested for further inhibitory properties against tumor promotion by short-term system. Lophirone A (200 micrograms) significantly inhibited inflammation of mouse ear (inhibitory effect (IE) = 70%) by 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA, 2 micrograms). It also inhibited both Ca(2+)- and phospholipid-dependent protein kinase C (PKC) activation by 12-O-tetradecanoylphorbol-13-acetate (TPA, IC50 = 50 microM). Application of lophirone A (160 nmol) reduced the number of tumors per mouse (IE = 85%) in an initiation-promotion experiment using dimethylbenz[a]anthracene (DMBA, 0.19 mumol) and TPA (1.6 nmol) on ICR mouse skin. Lophiraic acid, a related polyphenol, was negative in all of the short-term tests. An important chemical factor which may reduce the activities of flavonoid class of inhibitors for tumor promotion was indicated.
9,10-Dimethyl-1,2-benzanthracene↗
Serological and immunohistochemical studies on sialylated carbohydrate antigens in colorectal carcinoma.
Sialylated carbohydrate antigens, such as CA19-9 (sialyl Lea), CA-50 (sialyl Le4), CSLEX1 (sialyl Lex) and SLX (sialyl Lex-i), were assayed in the same preoperative serum samples of 63 patients with colorectal cancer, and compared with CEA. In addition immunohistochemical expressions of sialyl Lea, sialyl lex and sialyl Lex-i antigens were studied in 62 colorectal carcinomas and 42 normal mucosal sites remote from the malignant lesion using monoclonal antibodies CSLEA1, CSLEX1 and FH-6, respectively, in order to elucidate their tumor-specificity and clinical usefulness as a tumor-associated antigen. Serologically, the percent positive rates of CA19-9, CA-50, CSLEX1, SLX and CEA were 30.2%, 17.7%, 23.8%, 16.1% and 44.4%, respectively. In dukes' A and B, these sialylated carbohydrate antigens, especially CSLEX1 and SLX, showed low positive rates, but the percent positive rates of CSLEX1 and SLX correlated with operative radicality. The positive spectrum of CSLEX1 differed from that of CA19-9 in sera, and CEA had no correlation with these two antigens. The immunohistochemical expression rates of sialyl Lea, sialyl Lex and sialyl Lex-i were 88.1%, 17.0% and 9.5% in normal mucosa, but were 77.8%, 90.5% and 71.4% in carcinoma, respectively. These data suggested that the type 2 chain antigens CSLEX1 and SLX, which have high tumor-specificity compared with CA19-9, may be useful in preoperative diagnosis for extension of carcinoma and operative radicality, although early diagnosis using these sialylated carbohydrate antigens may be difficult, while the combined use of CA19-9, CSLEX1 and CEA should make it possible to detect a wide range of colorectal cancer patients.
Antibodies, Monoclonal↗
The patterns of beta-cell regeneration in untreated diabetic and insulin-treated diabetic Syrian hamsters after streptozotocin treatment.
Our previous study showed that Syrian hamsters recover from streptozotocin (SZ)-induced diabetes spontaneously and that insulin therapy adversely affects diabetes. The recovery and lack of recovery was associated with beta-cell regeneration and lack of regeneration. In this study, we examined the patterns of beta-cell regeneration in hamsters by using an immunohistochemical-autoradiographical method. We used tritiated thymidine to examine the DNA synthesis in islet cells and evaluated the number of labeled cells that were or were not immunoreactive with antiinsulin, antiglucagon, and anatisomatostatin. The results showed that, in untreated control hamsters, beta-cell regeneration took place both from preexisting beta cells and from undifferentiated cells (labeled cells unstained with any of the three antibodies) in equal proportions. In the SZ-treated hamsters, however, most regenerating cells seemed to derive from undifferentiated cells within the islets. Insulin therapy inhibited beta-cell regeneration from both the preexisting cells, but more so from the undifferentiated cells. The number of extrainsular islet cell foci was the same in all treatment groups and paralleled the number of islets in each animal during the entire experiment. We concluded the following about diabetic hamsters: 1. beta-Cell regeneration occurs primarily from undifferentiated cells within the islet; 2. Exogenous insulin inhibits beta-cell differentiation from the precursor cells; and 3. The response of intrainsular and extrainsular islet cells to SZ and insulin therapy is similar and the number of extrainsular islet cell foci per pancreas parallel the changes in the number of islets.
Animals↗
Flow cytometric DNA analysis of neuroblastoma: prognostic significance of DNA ploidy in unfavorable group.
Flow cytometric DNA content analyses were performed on samples of 54 patients with neuroblastoma. DNA aneuploidy was detected in 55.6% of the 54 patients. A high incidence of DNA aneuploidy was observed in patients with prognostically favorable variables such as age (less than 1 year), clinical stage (I, II, or IVs), and primary site (extraadrenal sites). DNA aneuploidy was predominant in surviving patients, even in those with unfavorable variables. In patients 1 year old or more, the survival rate among those with DNA aneuploidy was 58.8% compared with 28.6% in patients with diploidy. Likewise, in patients with advanced stage (III or IV) neuroblastoma, the survival rate among those with DNA aneuploidy was 63.2% compared with 30.4% in patients with DNA diploidy. It is concluded that DNA content analysis is of value in predicting the prognosis of patients with neuroblastoma.
Adrenal Gland Neoplasms↗
Disturbed metabolism of glucose and related hormones in familial amyloidotic polyneuropathy: hypersensitivities of the autonomic nervous system and therapeutic prevention.
Regulation of glucose metabolism was evaluated by oral glucose tolerance test (OGTT) in patients with familial amyloidotic polyneuropathy (FAP). Upon oral administration of a loading dose of glucose, plasma levels of glucose, insulin and glucagon changed abnormally in all FAP patients tested. Although plasma levels of glucose and insulin in the fasted patients were within normal ranges, 33% of FAP patients showed hypoglycemia after transient hyperinsulinemia during the examination. Furthermore, another three patients showed transient hypoglycemia during their daily life. Thus, perturbed glucose metabolism should be taken into account for treating patients with FAP. The salivary glands as well as the lacrimal glands showed transient hypersecretion after chewing a gum. Histochemical analysis at autopsy revealed significant amyloid deposition in the stroma, nerves and vessels of the pancreas, but not in Langerhans islets. Similar appearance was recognized in the salivary glands. These results suggest that denervation supersensitivity might occur not only in the exocrine glands but also in the endocrine gland.
Administration, Oral↗
Immunohistochemical expression of blood group substances and related carbohydrate antigens in breast carcinoma.
In forty-one carcinomas and sixteen benign lesions (fibroadenoma and mastopathy) of the human breast, immunohistochemical expression of sialylated and non-sialylated forms of both Lea and Lex, and the A, B, and H type 2 blood group substances were studied by using an indirect immunoperoxidase staining. In normal ductal epithelium and benign lesion of breast, Lewis-related antigens were mostly expressed. Breast carcinomas showed these antigens with the following frequencies: Lea, 31.7% (13/41); sialyl Lea, 56.1% (23/41); Lex, 46.3% (19/41); sialyl Lex, 68.3% (28/41); A/B/H type 2, 38.1% (16/41). Sialylated forms of Lea and Lex were observed more frequently than their respective non-sialylated forms in breast carcinomas. In both one normal epithelium and four carcinomas of breast with Le(a-b-) phenotype, the expressions of type 2 antigens were observed, while type 1 antigens were not consistently expressed. Although compatible expression was observed in all specimens of both normal epithelium and benign lesion of breast, twenty-four cases with the deletion of A and/or B antigens, six cases with H type 2 accumulation and one case with incompatible expression were demonstrated in breast carcinoma. Thirty-one breast carcinomas which showed the deletion of A/B/H type 2 expressed the Lewis-related antigens more frequently than nine cases which showed compatible expression. These results suggested that the activation of terminal fucosyltransferase and sialyltransferase as well as inactivation of some glycosyltransferases had occurred in cancer cell membrane, and sialyl Lex, defined by a new monoclonal antibody CSLEX1, may be useful as a tumor-associated antigen independent of Lewis blood group type in breast cancer.
Antigens, Tumor-Associated, Carbohydrate↗
[Two cases of interstitial pneumonitis with marked increase of tumor-associated carbohydrate antigens in serum].
Tumor-associated carbohydrate antigens, CA19-9 and SLEX have been used clinically as markers for malignancy. However, it is also known that these antigens are frequently elevated in the serum of patients with benign lung diseases. We have experienced two cases of interstitial pneumonitis with marked increase of carbohydrate antigens in serum, the level of which changed according to their clinical course. Case 1. A 64-year-old woman was admitted because of a cough and exertional dyspnea. Despite treatment with various antibiotics and prednisolone, she died of respiratory failure approximately two months after admission. Her CA19-9 and SLEX in serum elevated from 500 U/ml to 5506 U/ml and 167 U/ml to 1187 U/ml respectively in accordance with clinical deterioration. Autopsy revealed no malignancy. Case 2. A 57-year-old woman, who had been suffering from interstitial pneumonitis associated with rheumatoid arthritis, was admitted with a cough and fever. She responded to prednisolone therapy, however two years later she readmitted because of exacerbation and died of respiratory failure. The initial CA19-9 level in serum was 876 U/ml and dropped to 42 U/ml with prednisolone therapy. The serum antigen level again increased during the period of exacerbation, and showed 133 U/ml immediately before death. An immunohistochemical study of CA19-9 and SLEX in various tissues obtained by autopsy was performed in case 1. The distribution of these antigens in tissue was similar to that of normal individuals. The exceptions were the expression of these antigens on epithelial cells of microscopic honeycombing and on mucinous exudates in air spaces.
Antigens, Tumor-Associated, Carbohydrate↗
[A case of lung sarcoidosis which was clinically difficult to distinguish from hypersensitivity pneumonitis].
A case of pulmonary sarcoidosis (stage III), in which the abnormal chest shadow disappeared within two weeks was reported. A 35-year-old male was admitted for further examination of bronchial asthma. He stayed overnight at home after he received inhalation provocation test of sulpyrin. Returning to the hospital, he had a fever (38 degrees C) with diffuse small nodular shadows on the chest roentgenogram. The onset and clinical features of the disease suggested hypersensitivity or drug induced pneumonitis rather than sarcoidosis. Bronchoalveolar lavage fluid (BALF) analysis showed an increase of total cell counts and lymphocytes. The surface marker of lymphocytes in BALF revealed that the CD4/8 ratio was remarkably elevated to 6.2. Both transbronchial lung and scalene node biopsy specimens revealed numerous non-caseous granulomas, and a diagnosis of sarcoidosis was confirmed. The chest infiltrates disappeared spontaneously within two weeks. This case was reported because of its rare natural course as stage III pulmonary sarcoidosis.
Adult↗
[Analysis of cellular and biochemical contents of broncho-alveolar lavage fluid from patients with pulmonary tuberculosis].
To evaluate the local immune response in lung and activity of pulmonary tuberculosis. Broncho-alveolar lavage (BAL) was performed on 15 patients with pulmonary tuberculosis. Patients consisted of nine in the active stage and six in the inactive stage. Acid-fast bacilli (AFB) in BAL fluid (BALF) were found in six out of nine active stage patients (BAL-AFB positive group). The results obtained were as follows; 1) The number of total cells in BALF increased significantly in BAL-AFB positive group. BALF from two patients of this group, who were in the very early stage, revealed that the lymphocytes increased predominantly whereas neutrophils were dominant in BALF from the other four patients. 2) No case showed increase of B cells in BALF. Lymphocytes surface markers were compared between BAL-AFB positive and negative groups. No difference was found in the numbers of OKT3, OKT4 and OKT8. The positive rates of OKIal, and OKT4/8 ratio were both increased in BALF compared to the BAL-AFB positive group. 3) The numbers of OKT4 and OKT4/8 ratio in peripheral blood, which were taken simultaneously with BAL, were decreased in patients in the active stage. 4) Protein, albumin, IgG, IgA, lysozyme and alpha 1-antitrypsin levels in BALF were all increased in tuberculous patients. No correlation between the activity of tuberculosis and levels of protein, albumin, IgG and IgA was observed. Lysozyme level increased in the inactive stage of patients. On the other hand alpha 1-antitrypsin level increased in the active stage. Fibronectin level in BALF from patients was lower than that from normal controls. 5) Smoking habit had no influence on the above results. 6) Only one case showed the appearance of new lesions after BAL procedure as a complication.
Adult↗
[The usefulness of pleural biopsy in benign or malignant pleurisy].
Retrospective studies of pleural biopsy, cytology and ADA in pleural effusion were performed in 116 patients with pleural effusion between 1980 and 1988. Pleural malignant disease was diagnosed in 25 patients (75.8%) by cytology, in 19 patients (57.6%) by pleural biopsy. Thus, cytology should be performed first in patients with pleurisy. Both of cytologic study and CEA in pleural effusion were negative in 3 cases of squamous cell carcinoma. Tuberculous pleuritis was diagnosed in 24 patients (50.0%) by pleural biopsy, in 5 patients (10.4%) by isolation of Mycobacterium tuberculosis. Both pleural biopsy and adenosine deaminase activity (ADA) were examined in 19 cases of tuberculous pleuritis and ADA was elevated in 16 patients (84.2%). These data suggested that pleural biopsy was useful for diagnosis of pleuritis and the combination of cytology, tumor markers and ADA with biopsy improved diagnostic rates of pleuritis.
Adult↗