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Biomedical subjects

J Takeuchi

Publications and source records attributed to J Takeuchi.

At least 55 records · Page 3Linked to original sources
PubMed1995

Interleukin-1 beta-converting enzyme mediates cisplatin-induced apoptosis in malignant glioma cells.

Increasing the susceptibility of tumor cells to apoptotic cell death following chemotherapy is of importance to the outcome of cancer treatment. Although the tumor suppressor gene p53 is required for efficient induction of apoptosis by chemotherapeutic agents, it is not the only apoptosis mediator gene. The molecular mechanisms mediating apoptosis following chemotherapy via p53-dependent or p53-independent pathways remain unclear. We show here that cis-diamminedichloroplatinum (cisplatin) induces the expression of interleukin-1 beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, in murine and human malignant glioma cells during apoptosis regardless of their p53 status. Furthermore, overexpression of the murine ICE gene induces apoptosis in these tumor cells. The apoptosis induced by cisplatin treatment or murine ICE overexpression can be suppressed by the tetrapeptide ICE inhibitor Ac-YVAD-CMK or the apoptosis inhibitors bcl-2 or bcl-2-related bcl-XL gene. These findings suggest that ICE may mediate apoptosis induced by chemotherapy, and its induction could represent a novel approach for the effective treatment of malignant glioma.

Amino Acid Sequence↗
PubMed1995

MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis.

Induction of apoptosis in tumor cells is an important mechanism of chemotherapy-induced cell death. The tumor-suppressor gene p53 is required for the efficient activation of apoptosis following chemotherapy. However, the molecular mechanism regulating p53-associated apoptosis remains controversial. In this study, we show that the expression of both wild-type p53 and MDM2 (murine double minute 2) proteins was induced when cis-diamminedichloroplatinum (cisplatin) caused apoptosis in human glioblastoma U87-MG cells, which expressed neither wild-type p53 nor MDM2 protein prior to treatment. Overexpression of MDM2 in U87-MG cells transfected with human mdm2 expression vector conferred the resistance of tumor cell to cisplatin-induced apoptosis. In contrast, the treatment with mdm2 antisense oligonucleotide targeted against mdm2 mRNA increased the susceptibility of tumor cells to apoptosis. Changes in expression level of MDM2 protein, however, did not affect the expression of wild-type p53 protein. These findings suggest that MDM2 protein may act as a negative regulator of cisplatin-induced apoptosis, and moreover, may play an important role in the development of resistance to cisplatin in human tumors.

Apoptosis↗
PubMed1995

The SMS1 gene encoding a serine-rich transmembrane protein suppresses the temperature sensitivity of the htr1 disruptant in Saccharomyces cerevisiae.

A new gene (SMS1; serine-rich multi-copy suppressor) of Saccharomyces cerevisiae was isolated by the ability to suppress the temperature sensitivity of the htr1 disruptant (Kikuchi et al. (1994) Mol. Gen. Genetics, in press) by increasing its gene dosage. The predicted gene product contains a serine-rich domain followed by a putative transmembrane region. The SMS1 gene was physically and genetically mapped in the region near cdc3 on chromosome XII R.

Amino Acid Sequence↗
PubMed1995

Relationship between responsiveness to colony stimulating factors (CSFs) and surface phenotype of leukemic blasts.

We examined the responsiveness of leukemic cells to colony stimulating factors (CSFs) as determined by 3H-TdR incorporation and surface phenotypes of leukemic blasts. In acute myeloid leukemia (AML), CD13 and/or CD33 positive and HLA-DR negative M1 and M3 cases tended to show high response to G-CSF, GM-CSFs and IL-3, however, all HLA-DR positive M1, M2, M4 and M5 cases were unresponsive to CSFs but showed high autonomous growth. In acute lymphocytic leukemia (ALL), no response was observed to any CSFs but high autonomous growth was found in mixed leukemia cases. Sole T or B lineage cases showed low autonomous growth. These results suggest the varied nature of the proliferative state in leukemia and the existence of a subgroup in M1.

Cell Division↗
PubMed1995

Combination therapy with cisplatin and nifedipine induces apoptosis in cisplatin-sensitive and cisplatin-resistant human glioblastoma cells.

We attempted to determine whether calcium channel blockers (CCBs) enhance the anti-tumour activity of cis-diamminedichloroplatinum (cisplatin) against both cisplatin-sensitive human glioblastoma U87 MG cells and cisplatin-resistant U87-MG-CR cells, the latter of which we developed for resistance to cisplatin. Nifedipine, a dihydropyridine class CCB, significantly enhanced the anti-tumour effect of cisplatin on these two cell types in vitro and in vivo. Our findings also indicated that, in the absence of normal extracellular Ca2+ nifedipine was capable of enhancing the cytotoxicity of cisplatin. In addition, this anti-tumour activity was partially inhibited by actinomycin D and cycloheximide, suggesting that it is possibly dependent upon new RNA and protein synthesis. Interestingly, ultrastructural analysis, DNA fragmentation assay and cell cycle analysis demonstrated that synergism between cisplatin and nifedipine results in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. Furthermore, we demonstrated that nuclei from these cells lack a Ca(2+)-dependent endonuclease that degrade chromatin in the linker region between nucleosomes. In conclusion, our studies suggest that the non-cytotoxic agent nifedipine is able to synergistically enhance the anti-tumour effects of cisplatin on U87-MG and U87-MG-CR cells lacking a Ca(2+)-dependent endonuclease and subsequently to induce apoptosis via interaction of nifedipine with an as yet uncharacterised functional site other than a calcium channel on target cells.

Animals↗
PubMed1995

Complete remission in a patient with hypoplastic acute lymphoblastic leukemia induced by granulocyte-colony-stimulating factor.

We report here a case of hypoplastic leukemia with T cell markers in whom complete remission was obtained with granulocyte-colony-stimulating factor (G-CSF) alone. A 23-year-old male was diagnosed with hypoplastic leukemia: Hb 2.6 g/dl, platelet count 29.0 x 10(9)/l after transfusion, WBC 2.9 x 10(9)/l, hypocellular bone marrow with 70.7% blasts. He was given G-CSF 300 micrograms/day by intravenous drip infusion without antileukemic agents for severe pneumonia. After the administration of G-CSF for 15 days, hematological examination and bone marrow findings had improved to normal, and complete remission was obtained. However, the patient relapsed 45 days after discontinuation of G-CSF. The characteristics of the relapsed leukemia cells were similar to those on admission: negative for myeloperoxidase and positive for T cell markers (CD2 and CD7). The possibilities for the differentiation of leukemic cells and the recovery of normal hematopoiesis with G-CSF are discussed.

Adult↗
PubMed1995

Tumor necrosis factor-alpha induces p53-dependent apoptosis in rat glioma cells.

In this study, we demonstrated that tumor necrosis factor (TNF)-alpha inhibited the viability of rat glioma (C6) cells and induced apoptosis but did not affect the viability of rat newborn brain, mainly astroglial cells. The antitumor activity of TNF-alpha against C6 cells was partially inhibited by actinomycin D and cycloheximide, suggesting that it is possibly dependent upon new ribonucleic acid and protein synthesis. The results of immunoblotting assay demonstrated that TNF-alpha decreased the expression of mutant p53 protein but induced the expression of wild-type p53 in C6 cells during apoptosis. We suggest that TNF-alpha may activate the function of wild-type p53 protein by the suppression of mutant p53, at least indirectly, and induce p53-dependent apoptosis in glioma cells.

Animals↗
PubMed1995

Activation mechanism of phospholipase D involved in the generation of lipid mediators in cultured Madin-Darby canine kidney cells.

Addition of 100 nM phorbol 12-myristate 13-acetate (PMA), an active phorbol diester, to quiescent cultured Madin-Darby canine kidney (MDCK) cells caused a maximal stimulation of phosphatidylethanol formation within 1-2 h in the presence of 1% ethanol, indicating the activation of phospholipase D (PLD). The specificity of phorbol diesters for the activation of PLD activation was confirmed by the fact that phorbol 12,13-dibutyrate (PDBu) was effective, whereas 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD) was without effect. Down-regulation caused by the long-term pretreatment of the cells with active phorbol diesters significantly decreased the production of phosphatidylethanol. Staurosporine, a well known protein kinase (PK)C inhibitor at 1 microM, decreased the activation of PLD. Taken together, these observations suggested the involvement of PKC in the activation of PLD. The cellular PLD activity was found to be selectively localized in the particulate fraction by centrifugation at 12,000 x g. The particulate PLD showed the selective substrate specificity for phosphatidylcholine rather than phosphatidylethanolamine. In response to the addition of 100 nM PMA, 1,2-diacylglycerol (DG) increased in a biphasic fashion. In view of the time course of the activation of PLD, the second increase in the 1,2-DG around 20 min was contributed by the activation of PLD. In response to the simultaneous addition of 100 nM PMA and 100 nM A23187, the cultured MDCK cells activated the arachidonate cascades to form prostaglandin (PG)E2 and PGF2 alpha as major products, requiring slower 24 h to reach maximal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Combination therapy with cisplatin and nifedipine inducing apoptosis in multidrug-resistant human glioblastoma cells.

The authors found that multidrug-resistant human glioblastoma GB-1 cells demonstrated significantly more resistance to cisplatin than did nondrug-resistant human glioblastoma U87-MG cells (p < 0.1). They therefore attempted to determine whether calcium channel blockers enhance the antitumor activity of cisplatin against GB-1 cells. Nifedipine, a dihydropyridine calcium channel blocker, significantly enhanced the antitumor effect of cisplatin on GB-1 cells (p < 0.05). In the absence of normal extracellular Ca++, nifedipine enhanced the cytotoxicity of cisplatin. In addition, the antitumor activity of combined cisplatin and nifedipine was inhibited both by actinomycin D and cycloheximide, suggesting that such activity is dependent upon new RNA and protein synthesis. Surprisingly, DNA fragmentation assay demonstrated that synergism between cisplatin and nifedipine resulted in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. In addition, it was demonstrated that nuclei from GB-1 cells lacked a Ca(++)-dependent endonuclease that degrades chromatin into nucleosomes and that calcium ionophore A 23187 did not decrease the viability of GB-1 cells. The above findings suggest the hypothesis that the noncytotoxic agent nifedipine synergistically enhances the antitumor effect of cisplatin on multidrug-resistant GB-1 cells lacking Ca(++)-dependent endonuclease, and subsequently induces apoptosis via its interaction with an as yet uncharacterized functional site other than the calcium channel on GB-1 cells.

Apoptosis↗
PubMed1995

[Aspergillus lumbar discitis in a patient with acute lymphoblastic leukemia following induction therapy].

A 47-year-old female was admitted in October 1988 because of anemia and lymphoblastic cells in peripheral blood. A bone marrow aspirate was hypercellular with 93.9% lymphoblasts negative for peroxidase staining. The case was diagnosed as ALL (L2), and treated with JALSG ALL-87 regimen. She developed spiky fever and endotoxin shock due to bacteremia caused by pseudomonas aeruginosa, then was treated with several antibiotics. With the recovery of leukocytes, the chest X-ray showed an infiltrative shadow and a cavity forming lung abscess resembling aspergilloma in her left lung. The cavity improved of transbronchial infusion following amphotericin B (AMPH-B). Although she achieved complete remission, she felt severe lumbago accompanied by a marked erosion of the vertebral body with disc space narrowing on her X-ray. Then she underwent surgery to remove a disc abscess, and 1 colony of the aspergillus species was cultured from the specimen. She was treated with intravenous AMPH-B, and post remission therapies were performed under the injection of anti-fungal agents. No remarkable symptoms of complications were recognized during the chemotherapy. AMPH-B is useful and safe for the management of aspergillus discitis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

[Natural interferon alpha for chronic myelogenous leukemia in the chronic phase: hematologic, cytogenetic and molecular response].

Twenty one patients with Philadelphia chromosome positive CML were treated with natural interferon alpha. All patients were in the chronic phase, 5 were untreated and 16 had been previously treated with busulfan or hydroxyurea. Eight patients in complete remission (CR) were given IFN subcutaneously at a dose of 5 x 10(6) unit per day as maintenance therapy, whereas 13 non-CR patients were given 2. 5 approximately 10 x 10(6) units for remission induction. Doses and intervals of IFN were adjusted to maintain the WBC count below 5 x 10(9)/l, but additional drugs were given when the WBC count could not be controlled with IFN alone. Six out of 10 evaluable non-CR patients attained CR with IFN only and 4 others achieved with additional drug. Cytogenetic responses were evaluated in 15 patients. CCR, PCR and MCR were attained in 5, 2 and 1 patients respectively. Southern blotting method showed that the BCR gene rearrangement disappeared in 5 out of 13 patients. Cytogenetic response rate was not different between untreated and previously treated patients, however it differed between patients with or without additional drug. The time to first cytogenetic effect was within 12 months in almost all effective cases. Fever and general fatigue were seen in almost all patients. IFN administration was discontinued only patients with severe skin eruption (3 patients) and bone marrow aplasia (1 patient).

Adult↗
PubMed1995

[Structure and function of extracellular matrix with special references to proteoglycan].

To clarify the physiological significance of extracellular matrix components, biochemical and histochemical characterization of glycosaminoglycan and proteoglycan was performed. The glycosaminoglycan, chondroitin sulfate, was favorable to the growth of Ehrlich ascite tumor cells inoculated into the subcutaneous space of the mouse's back. The glycosaminoglycan content and its synthesis by gastric carcinoma tissue were compared with those of non-neoplastic mucosa, after incubation of tissue segments in medium containing 35SO4. The rate of glycosaminoglycan synthesis by medullary carcinoma tissue was much higher than that by the non-neoplastic mucosa, although no significant difference was found in the amount of glycosaminoglycan between them. Using human gastric carcinoma cell lines, the interaction of fibroblasts (cell line WI-38) with carcinoma cells was studied in vitro. In well-differentiated adenocarcinoma, the amount of glycosaminoglycan secreted into the interface between carcinoma cells and fibroblasts was much larger (about 20-fold) than that into the interface between the carcinoma cells and the bare culture dish. However, in poorly differentiated adenocarcinoma cells, glycosaminoglycan secretion was not affected by the presence of fibroblasts. The effects of the extracellular matrix produced by carcinoma cells on the attachment and growth of fibroblasts were also examined in vitro. The attachment-promoting and growth-promoting activities of the matrix substance produced by poorly differentiated carcinoma was about 10 times greater than that caused by the well-differentiated adenocarcinoma cell matrix substance. Proteoglycan and glycosaminoglycan were identified in malignant and benign non-epithelial tumors. More proteoglycans containing mainly chondroitin sulfate could be detected in malignant tumors than in benign tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Transfection with a bcl-2 expression vector protects transplanted bone marrow from chemotherapy-induced myelosuppression.

The use of cytokines such as granulocyte-colony-stimulating factor (G-CSF) to ameliorate chemotherapy-induced myelosuppression may not only stimulate the recovery of normal hematopoietic cells but may also enhance the proliferation of the tumor cells with functional receptors for these cytokines. In this study, we show that administration of recombinant human (rh) G-CSF decreased the in vitro and in vivo cytotoxic effects of Adriamycin or etoposide on L1210 murine leukemic cells with receptors for rhG-CSF. Transplantation of bone marrow cells expressing high levels of bcl-2 from a retroviral construct [MPZenNeo(bcl-2)] (bcl-2-BMT) did not decrease the in vivo cytotoxic effect of etoposide on L1210 cells, but enabled recovery of myelopoiesis following etoposide-induced myelosuppression to almost the same extent as did the administration of rhG-CSF. These findings suggest the possibility that bcl-2 transfection could be used to protect transplanted bone marrow from chemotherapy-induced myelosuppression on behalf of administration of rhG-CSF, in case of treatment of tumors with functional receptors for rhG-CSF.

Animals↗
PubMed1994

Induction of apoptosis in murine ACTH-secreting pituitary adenoma cells by bromocriptine.

Bromocriptine, a dopamine agonist, is now an accepted primary therapeutic agent for patients with prolactinomas and other pituitary adenomas. In this study, we demonstrated that bromocriptine inhibited the proliferation of murine ACTH-secreting pituitary adenoma (AtT-20) cells. In addition, the antitumor activity of bromocriptine was inhibited both by actinomycin D and cycloheximide, suggesting that it was dependent on new RNA and protein synthesis. Interestingly, the results of DNA fragmentation assays and cell cycle analysis clearly demonstrated that bromocriptine induced apoptosis in AtT-20 cells.

Adenoma↗
PubMed1994

bcl-2 gene prevents apoptosis of basic fibroblast growth factor-deprived murine aortic endothelial cells.

Growth factors such as basic fibroblast growth factor (bFGF) have been found to promote the survival and proliferation of endothelial cells. However, the mechanism by which growth factors control the regeneration and degeneration of the endothelial cells remained poorly understood. In this study, we demonstrated that apoptosis of murine aortic endothelial (MAE) cells was induced by deprivation of bFGF but required new RNA and protein synthesis. Furthermore, enforced expression of bcl-2 gene in MAE cells using gene transfer techniques decreased apoptosis induced by deprivation of bFGF. These findings suggest that bcl-2 interferes with a pathway for endothelial cell death that is induced by deprivation of bFGF.

Animals↗
PubMed1994

Temporal regulation of light-induced Fos and Fos-like protein expression in the ventrolateral subdivision of the rat suprachiasmatic nucleus.

We measured c-fos messenger RNA levels and Fos protein immunoreactivity in the suprachiasmatic nucleus of rats as a function of light and time of day. Immunohistochemistry demonstrated a daily rhythm of immunoreactive Fos in the ventrolateral subdivision of the suprachiasmatic nucleus of animals entrained to a 12 h/12 h light-dark cycle; expression was low during the dark phase, peaked about 2 h after light onset at dawn, and remained elevated at an intermediate level for the remainder of the light phase. Immunoblots of nuclear extracts showed a 54,000 mol. wt band that increased in density from the dark phase to the early light phase and decreased again during the late light phase. In situ hybridization using a radiolabeled cDNA probe revealed a c-fos messenger RNA signal that was detected as early as 15 min after dawn, prominent at 30 min, and absent by 2 h. The expression of c-fos messenger RNA and Fos immunoreactivity in the suprachiasmatic nucleus depended on the presence of ambient light. In rats entrained to two daily 1-h light pulses corresponding to dawn and dusk ("skeleton" photoperiod) instead of the complete light-dark cycle, immunoreactive Fos was elicited by the dawn pulse alone and was less persistent than during the complete photoperiod. In rats free-running in constant darkness, c-fos messenger RNA and Fos immunoreactivity were stimulated by 2-h light pulses administered only during the subjective night and early subjective day, but not by light pulses during the middle or late subjective day or in the absence of light pulses.

Animals↗
PubMed1994

Tumour necrosis factor-alpha induces an increase in susceptibility of human glioblastoma U87-MG cells to natural killer cell-mediated lysis.

The mechanism by which tumour necrosis factor (TNF)-alpha increases the susceptibility of U87-MG human glioblastoma cells to lysis by natural killer (NK) cells was studied. Treatment with TNF-alpha (100 units ml-1) for 48 h enhanced the susceptibility of tumour cells to lysis by NK cells. Increased susceptibility to lysis was associated with enhanced expression of intercellular adhesion molecule 1 (ICAM-1) and HLA class I antigen. Antisense ICAM-1 oligonucleotide inhibited lysis by NK cells of TNF-alpha-treated tumour cells. In contrast, acid treatment following TNF-alpha treatment increased lysis by NK cells. These findings indicate that TNF-alpha treatment of glioblastoma cells increased their susceptibility to lysis by NK cells, since ICAM-1 up-regulation would have more profound effects on NK susceptibility than would HLA class I antigen up-regulation.

Antigens, Neoplasm↗