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Keizo Kaba, Eiichi Tani, Tatsuo Morimura, and Tsuyoshi Matsumoto

✓ The effects of calcium channel blockers and calmodulin inhibitors on vincristine cytotoxicity were studied in vitro with five glioma cell lines: three human glioblastomas, one rat glioma, and one mouse ependymoblastoma. One human glioblastoma and the rat glioma were resistant to vincristine in contrast to other glioma cells. The resistance to vincristine was considerably decreased by nontoxic or marginally toxic concentrations of calcium channel blockers or calmodulin inhibitors, although the former was more effective than the latter. In the presence of verapamil, the vincristine cytotoxicity, as measured by cell doubling times, increased 90- and 84-fold in the vincristine-resistant human glioblastoma and rat glioma, respectively. The decrease in the resistance to vincristine was related to a marked increase in the intracellular level of that drug, probably mediated by inhibiting its outward transport. The in vivo studies showed that verapamil or nicardipine administered daily with vincristine for 10 days significantly enhanced the chemotherapeutic effect of vincristine in an intracranially transplanted rat glioma model. An approximately 32% to 118% increase in life span occurred with 15 mg/kg/day of verapamil, depending on the doses of vincristine.

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Katsuya Miyaji, Eiichi Tani, Atsuhisa Nakano, Hideyasu Ikemoto, and Keizo Kaba

✓ Stimulation of three human glioma cell lines with basic fibroblast growth factor (bFGF) led to the enhancement of cell growth and the rapid tyrosine phosphorylation of cellular proteins, including major substrates of 90 kD. A methyltransferase inhibitor, 5′-methylthioadenosine (MTA), inhibited dose dependently the bFGF-stimulated cell growth and protein tyrosine phosphorylation in glioma cells by blocking both receptor autophosphorylation and substrate phosphorylation, as shown by immunoblotting with antiphosphotyrosine antibodies and cross-linking bFGF to receptors. The antiproliferative activity of MTA correlated quantitatively with its potency as an inhibitor of bFGF-stimulated protein tyrosine kinase activity. The methyltransferase inhibitor MTA had no effect on either epidermal growth factor— or platelet-derived growth factor—stimulated protein tyrosine phosphorylation in glioma cells, but inhibited specifically bFGF-stimulated protein tyrosine kinase activity. The concentration of MTA required for inhibition of protein methylation correlated well with the concentration required for inhibition of bFGF-stimulated cell growth and protein tyrosine phosphorylation. Because MTA had no effect on numbers and dissociation constants of high- and low-affinity bFGF receptors, the inhibition of bFGF-stimulated bFGF receptor tyrosine kinase activity is not likely to be the result of a reduction in bFGF receptor and bFGF binding capacity. In fact, MTA delayed and reduced the internalization and nuclear translocation of bFGF, and the internalized bFGF was submitted to a limited proteolysis that converted it to lower molecular peptides whose presence remained for at least 22 hours. The effect of MTA on bFGF-stimulated tyrosine phosphorylation was immediate and readily reversible.

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Tsuyoshi Matsumoto, Eiichi Tani, Keizo Kaba, Hideki Shindo, and Katsuya Miyaji

✓ The expression of P-glycoprotein, a product of multidrug resistance gene 1, was studied by Western blotting and immunohistochemistry in five human glioma cell lines. One glioma cell line was resistant to vincristine, Adriamycin (doxorubicin), and etoposide, and the other four glioma cell lines were sensitive to each drug. The multidrug-resistant cell line showed a high expression of P-glycoprotein in Western blot analysis and a positive immunostaining for P-glycoprotein mainly along the cell membrane, whereas all multidrug-sensitive glioma cell lines demonstrated no expression of P-glycoprotein in Western blotting and no immunostaining for P-glycoprotein, thus showing a good correlation between the expression level of P-glycoprotein and the extent of multidrug resistance.

In 18 human surgical glioma specimens, there was no evidence of complete absence of immunostaining for P-glycoprotein. With a definition of more than 20% of P-glycoprotein-positive cells as positive, from 10% to 20% as intermediate, and less than 10% as negative, immunostaining for P-glycoprotein was positive in one specimen and intermediate in six of 15 specimens taken from virgin gliomas, and positive in two specimens and intermediate in one of three recurrent gliomas treated previously with irradiation, ACNU (1-(4-amino-2-methyl-pyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), cisplatin, vincristine, and/or procarbazine.

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Ikuya Yamaura, Eiichi Tani, Masayuki Yokota, Atsuhisa Nakano, Masahiro Fukami, Keizo Kaba, and Tsuyoshi Matsumoto

Object. Surgical or endovascular occlusion of the parent artery proximal to an aneurysm has been recommended for treatment of dissecting aneurysms of the intracranial posterior circulation. However, dissecting aneurysms may rupture even after proximal occlusion because distal progression of thrombus is necessary to occlude the dissecting aneurysm completely, and this may be delayed by the presence of retrograde flow. In this article the authors present their experience in treating six patients with ruptured dissecting aneurysms.

Methods. The authors report on six patients with a ruptured dissecting aneurysm in the posterior fossa who were successfully treated by endovascular occlusion of the aneurysm by using Guglielmi detachable coils. The procedure was particularly aimed at occluding the dissected site.

Conclusions. At the present time, endovascular occlusion of the dissected site is a safe, minimally invasive, and reliable treatment for dissecting aneurysms when a test occlusion is tolerated and adequate collateral circulation is present.

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Tsuyoshi Matsumoto, Eiichi Tani, Keizo Kaba, Nobuo Kochi, Hideki Shindo, Yoshihiro Yamamoto, Hiromi Sakamoto, and Junichi Furuyama

✓ Two human glioma cell lines were examined for multidrug resistance (MDR). A vincristine (VCR)-resistant glioma cell line showed a cross resistance to Adriamycin (doxorubicin, ADR) and etoposide (VP-16) to varying extents, suggesting the presence of MDR; the resistance to VCR was considerably decreased by calcium entry blockers. On the other hand, another VCR-sensitive glioma cell line exhibited no cross resistance to ADR or VP-16. Double minute chromosomes and homogeneously staining regions as well as clonal aberrations of chromosome 7 were not observed in cytogenetic studies of multidrug-resistant and multidrug-sensitive glioma cell lines. In Northern and Southern blot analyses, MDR gene 1 (MDR1) messenger ribonucleic acid (mRNA) was shown to be overexpressed without any amplification of the MDR1 gene in multidrug-resistant glioma cell lines as compared to multidrug-sensitive glioma cell lines. It would be reasonable to suggest that amplification of the MDR1 gene may not be a sine qua non for acquisition of MDR and that the MDR1 mRNA level may be well correlated with the extent of MDR.