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  • 1
    ISSN: 1433-0350
    Keywords: X-linked hydrocephalus ; L1CAM ; Gene mutation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract X-linked hydrocephalus is a genetic form of hydrocephalus that frequently occurs in males. It is characterized by ventricular dilatation, mental retardation, deformity of the thumb and spastic paraparesis. Recently, 23 different mutations of the gene for the neural cell adhesion molecule, L1CAM, located at chromosome region Xq28, have been reported, 16 of which were detected in families with X-linked hydrocephalus. We sequenced the coding region of the L1CAM gene of patients from two different families with X-linked hydrocephalus and found a novel mutation at nucleotide residue 1963 in one family. This mutation from adenine to guanine results in an amino acid change from lysine to glutamic acid at residue 655 of the L1CAM protein, which belongs to the fibronectin type III domain. We report another method for the rapid identification of the mutation based on the polymerase chain reaction. This mutation was not detected among 70 X chromosomes from a healthy population. Ours is the first report demonstrating this gene mutation in X-linked hydrocephalus in an Asian population. Our findings further emphasize the evolving genotypic heterogeneity in X-linked hydrocephalus.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-7276
    Keywords: adhesion ; chemokinesis ; fibronectin ; glioma invasion ; motility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to investigate the biological role of fibronectin in glioma cell invasion, we studied the relation between migratory responses or adhesiveness of glioma cells to fibronectin and the in vitro invasion in three human malignant glioma cell lines, A172, T98G and U373MG. All these cell lines chemotactically migrated in a dose-dependent manner to fibronectin in concentrations ranging from 0.5 to 10 µg/ml, with A172 cells showing the strongest migration and U373 cells the weakest. Checkerboard analyses demonstrated that A172 and T98G cells showed much stronger chemokinetic responses to fibronectin than U373MG cells. In contrast to the migratory responses, A172 and U373MG cells showed an almost equally high adhesion to fibronectin and T98G cells a low adhesion. The degree of expression of the integrin α5 subunit correlated well with the strength of glioma cell adhesion to fibronectin rather than that of migration to the molecule. Furthermore, the cell adhesion to fibronectin was almost completely inhibited by arginine-glycine-aspartic acid (RGD)-containing peptides, but the fibronectin-stimulated cell migration was only partially inhibited. An in vitro invasion assay disclosed that U373MG cells invaded the artificial basement membrane barrier the most and A172 cells the least. However, addition of fibronectin to the glioma cells markedly enhanced the invasive activity of A172 and T98G cells but had little effect on that of U373MG cells. These results indicate that fibronectin-stimulated migration can be one of the factors promoting invasiveness of glioma cells and that the chemokinetic activity of fibronectin may play a crucial role in glioma invasion through conferring motor-driving force on the glioma cells.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-7276
    Keywords: fibronectin ; fibronectin receptor ; malignant glioma ; invasion ; cell migration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to clarify the role of fibronectin in glioma invasion in vivo, we analyzed the relationship between fibronectin-stimulated cell migration and adhesion in 14 primary glioma cells and the expression of fibronectin and the fibronectin receptor in the corresponding tumor tissues. The tumors comprised nine glioblastomas (GB) and five anaplastic gliomas (AG) consisting of two astrocytomas, two oligoastrocytomas and one ependymoma. All glioma cells tested in the primary cell culture were found to migrate to fibronectin in a dose-dependent manner. The extent of cell migration to fibronectin was not significantly different for the GB and AG groups. On the other hand, cell adhesion to fibronectin in the AG was much stronger than that in the GB group. Immunohistochemistry demonstrated that fibronectin positively stained in the extra-cellular matrix (ECM) in eight cases and that the fibronectin receptor was positive in tumor cell membranes in 10 cases. In addition, cellular fibronectin isoforms containing ED-A and ED-B sequences were found to be immunolocalized in the tumor cells and the ECM of GB. These isoforms were also specifically expressed in tumor vessels within tumor tissues, but not in those within normal brain tissues. Cell migration tended to be expressed more strongly by glioma cells derived from tumor tissues in which fibronectin was posi-tively immunolocalized in the ECM than from tissues with negative fibronectin in the ECM. Four glioma cells derived from GB whose tumor cells did not positively stain for fibronectin receptors migrated much less extensively to fibronectin than other glioma cells whose tissues showed positive staining for the fibronectin receptor. Of these four GB, two had loss of heterozygosity in the locus of fibronectin receptor b1 gene. These results suggest that fibronectin deposited in the extracellular matrix of tumors, which can be derived from both plasma and the tumor cell itself, strongly promotes the migration of glioma cells, and that expression of the fibronectin receptor may play a critical role in the biological behavior of the tumor cells, particularly in fibronectin-stimulated cell migration in vivo.© Kluwer Academic Publishers 1998
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Neurosurgical review 7 (1984), S. 3-12 
    ISSN: 1437-2320
    Keywords: Chemotherapy of gliomas ; pharmacokinetics ; cell kinetics — clinical studies — side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Chemotherapy of malignant glioma has been discussed in relation to recent advances in experimental and clinical studies. It is now obvious that chemotherapy is of increasing importance in the multidisciplinary treatment of malignant gliomas. Survival time of patients was prolonged by intensive and prolonged chemotherapy and by second treatment upon tumour recurrence. Further progress of chemotherapy will be gained by the progressive accumulation of all experiences, however small, in all the varied routes of approach.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-7373
    Keywords: intrathecal chemotherapy ; ACNU ; pharmacokinetics ; leptomeningeal tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of intrathecal 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were studied in female Wistar rats by macroscopical autoradiography using14C labeled ACNU. In normal rats, ACNU rapidly distributed in the subarachnoid space and ventricles after intracisternal administration. Diffusional transport into the brain tissue was limited to a depth of 1 or 2 mm from the cerebrospinal fluid (CSF) surface of the brain. Clearance of ACNU from the CSF space and brain was relatively fast and the half time of ACNU concentration at the cortical or ventricular surface was 10 min. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, the distribution pattern of ACNU after intracisternal administration was essentially the same as in normal rats until the tumor had grown in the subarachnoid space to form more than 10 or 20 layers of tumor cells. ACNU was distributed in the tumor as well. When the tumor had grown to form masses in the subarach-noid space, ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface. Our results suggest that intrathecal ACNU administration may have no, or minor side effects on the brain and that it can eliminate floating or thin layered tumor cells in the subarachnoid space but not bulky tumors.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-7373
    Keywords: malignant glioma ; chemotherapy ; anthracyclines ; KRN8602(MX2) ; phase II study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood–brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma. The 44 patients enrolled received at least 2 cycles of KRN8602 35 mg/m2/day at 3–4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma. Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed. The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Journal of neuro-oncology 45 (1999), S. 9-17 
    ISSN: 1573-7373
    Keywords: ACNU ; MTX ; 5-FU ; pharmacokinetics ; leptomeningeal tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2 mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110 min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-7373
    Keywords: DNA topoisomerase II ; etoposide ; glioma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have established an in vivo etoposide-resistant glioma cell line (C6/VP) from C6 rat glioma cells by stepwise exposure to increasing doses of etoposide. The C6/VP cells were 10 times more resistant to etoposide than the parental C6 cells. In addition C6/VP cells demonstrated cross-resistance to vincristine and vinblastine, but not to ADM or m-AMSA. Interestingly, the cells had collateral sensitivity to ACNU, cisDDP and Ara-C. The C6/VP cells did not express the MDR gene or p-glycoprotein, while they showed 16 times less topoisomerase II catalytic activity compared to the C6 cells. Although there was no significant difference between C6 and C6/VP cells in amounts of topoisomerase II in nuclear extracts, the C6/VP cells had 2.9 times higher amounts of the enzyme than C6 cells in nuclear scaffold prepared from a relatively low-salt buffer (0.5 M NaCl). Northern blot analysis demonstrated that mRNAs of topoisomerase IIα isoforms were expressed both in C6 and C6/VP cells, and that the amounts of topoisomerase IIα in C6/VP cells were 14 times greater than in C6 cells. The total uptake of etoposide in tumor tissues derived from C6/VP cells was 3 times less than those derived from parental C6 cells. These results indicate that the C6/VP acquired a multi-drug resistance phenotype by a reduction of the catalytic activity of topoisomerase II and/or diminished accumulation of drugs. This phenotype did not involve the p-glycoprotein. Alterations of topoisomerase II in the C6/VP cells also were accompanied by an increased amount of the topoisomerase IIα isoform, most of which was localized in the nuclear scaffold (matrix). This suggests that altered binding of topoisomerase II to topologically organized DNAs in the nuclear scaffold may be the molecular basis of this multi-drug resistance phenotype.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-7373
    Keywords: angiogenesis ; angiogenesis inhibitor ; TNP-470 ; malignant glioma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A novel angiogenesis inhibitor TNP-470 was investigated for its anti-tumor activity against malignant gliomas bothin vitro andin vivo. TNP-470 cytostatically inhibited the growth in all of the seven glioma cell lines in culture including anticancer drug resistant cells. The 50% inhibitory concentrations (IC50) of these glioma cell lines were 10 to 30 Μg/ml and they were 10 to 20 times higher than IC50 of normal endothelial cells. TNP-470 (30 mg/kg, i.p., every other day) also significantly inhibited the tumor growth of T98G-transplanted nude mice. Microscopically, tumor vessels after the treatment of the tumor-bearing mice with TNP-470 became fewer in number and smaller in diameter than those without treatment. Furthermore, there appeared extensive necrotic areas in the tumor with TNP-470. These results indicate that TNP-470 is a potent angiogenesis inhibitor for malignant gliomas. In addition, the studies of labeling index of BrdU and Ki67 suggest that TNP-470 may act mainly on tumor endothelial cells, thus resulting in reduction of the tumor growth.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-7373
    Keywords: leptomeningeal tumor ; intrathecal chemotherapy ; ACNU ; nitrosourea ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pharmacokinetics, toxicity and therapeutic efficacy of intrathecal ACNU, 3-((4-amino-2-methyl-5-pyrimidinyl)methyl)-1-(2-chloroethyl)-1-nitrosourea, were studied in rats to determine if it is a new and effective method for the treatment of malignant leptomeningeal tumors. Pharmacokinetics of intracisternally administered ACNU was studied by macroscopial autoradiography using 14C-labeled ACNU. It was demonstrated that intracisternally administered ACNU distributed in the subarachnoid space and subpial layer of the brain in high concentration and was rapidly eliminated into the systemic circulation. The diffusional transport of ACNU into the deeper part of the brain was limited. More than 3.0 mg/kg of intracisternal ACNU induced progressive loss of the weight of body in normal rats, and 80% of the rat given 6.0 mg/kg died. Increase of capillary permeability, neuronal loss and gliosis were observed in the marginal layer of the brain facing to the subarachnoid space in the rat given more than 3.0 mg/kg of ACNU. Systemic and local toxicity was not observed in the rat given less than 1.5 mg/kg. Therapeutic effect of intrathecal ACNU against leptomeningeal tumors was evaluated in the rat with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells. The median survival time of the rat treated with 1.5 mg/kg of intracisternal ACNU once on day 2 or on day 5 after tumor inoculation was significantly prolonged by 173%, and 214% at maximum, respectively, as compared with that of the untreated animal. These findings suggest that intrathecal ACNU may be of value for clinical trial against leptomeningeal tumors.
    Type of Medium: Electronic Resource
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