Search PubMed⌕ Search

Biomedical subjects

Kiyohiko Hatake

Publications and source records attributed to Kiyohiko Hatake.

35 records · Page 2Linked to original sources
PubMed2004

[Rituximab and hematological malignancy].

After genetic recombination with murine and human cDNA, monoclonal antibody has been produced in chimeric form. CD20 is a B cell antigen, which can be a target molecule for antibody therapy. Rituximab is an anti-CD20 monoclonal antibody that has an efficacy against B cell lymphomas. Combination therapy with CHOP regimen as well as single therapy will give rise to new treatment strategy for CD20+B cell lymphomas. Mechanism is not clarified, but induction of apoptosis, complement-mediated cell toxicity, and antibody-dependent cell toxicity are considered. Synergy with chemotherapy agents such as CHOP, ICE, DHAP and stem cell transplantation will help the patients who suffer lymphomas, CLL and Waldenstrom's macroglobulinemia. Treatment with rituximab is well tolerated and we must be careful about infusion reaction after administration.

Antibodies, Monoclonal↗
PubMed2003

Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling.

Erythropoietin (EPO) can rescue erythroid cells from apoptosis during erythroid development, leading to red cell production. However, the detailed mechanism of how EPO protects erythroid cells from apoptosis is still open to question. To address this problem, we used a human EPO-dependent leukemia cell line UT-7/EPO and normal erythroid progenitor cells. After deprivation of EPO, UT-7/EPO cells underwent apoptosis, accompanied by down-regulation of the Bcl-xL protein. In addition, the cleaved products of caspase-3, p11 and p21, and a few cleaved forms of inhibitor of caspase-activated DNase (ICAD) were detected in these cells. When the cells were pre-treated with the pancaspase inhibitor Z-VAD-FMK, the ratio of apoptotic cells was significantly reduced, suggesting that EPO protects the UT-7/EPO cells from apoptosis via inhibition of caspase activities. When an MEK 1/2 inhibitor U0126 inhibited activities of extracellular signal-regulated kinases (ERKs), the expression of Bcl-xL protein was down-regulated and subsequently apoptosis was induced. Interestingly, Z-VAD-FMK blocked U0126-induced down-regulation of Bcl-xL protein and apoptosis, strongly suggesting that Bcl-xL expression is regulated by caspases which lies downstream of ERK activation pathway in EPO signaling. Importantly, these findings were also observed in normal erythroid progenitor cells. In conclusion, the activation of ERKs by EPO up-regulates Bcl-xL expression via inhibition of caspase activities, resulting in the protection of erythroid cells from apoptosis.

Apoptosis↗
PubMed2003

Severe infusion reaction induced by trastuzumab: a case report.

We report a case of a severe infusion reaction caused by trastuzumab. A 59-year-old woman with metastatic breast cancer was treated with trastuzumab. During the first infusion, initial symptoms such as severe headache and general fatigue developed. Blood pressure fell 90 minutes after these initial symptoms. A collapsed lung was demonstrated by chest X-ray and computed tomography. Steroid therapy was successfully used for these reactions. Careful monitoring of vital signs, examination of the respiratory system, and the use of steroids are recommended for severe infusion reaction.

Anaphylaxis↗
PubMed2003

In vitro platelet activation by an echo contrast agent.

OBJECTIVE: We investigated whether an ultrasonic echo contrast agent containing microbubbles (Levovist [SH U 508A]; Schering AG, Berlin, Germany) could in routine use activate platelets. METHODS: Levovist and its main component, galactose, were mixed with separate samples of whole blood (1.5-75 mg/mL) from 5 healthy volunteers to form a 1-mL suspension sample. After in vitro exposure to ultrasound emitted from a commercial ultrasonic scanner at a pulse frequency of 3.5 MHz with a mechanical index of 1.9 and an exposure duration of 5 minutes, 5 microL of the sample was incubated for 20 minutes with the fluorescein isothiocyanate-labeled CD61 antibody, which is a platelet-specific antigen, and the phycoerythrin-labeled CD62P (P-selectin) antibody, an activation-specific antigen, both on the platelet surface. After more than 30 minutes of fixing in 1% paraformaldehyde, flow cytometric analysis was performed. RESULTS: The percentage of CD62P-expressing platelets increased according to the concentrations of Levovist and galactose, which showed almost equal effects. Ultrasound exposure did not enhance the effect except at the highest concentration of Levovist (75 mg/mL). CONCLUSIONS: In vitro, a galactose-based echo contrast agent could not activate the platelets at its routine concentration.

Adult↗
PubMed2003

[Gene therapy for breast cancer].

Breast cancer is sensitive to chemotherapy and endocrine therapy, but the prognosis of advanced or relapsed breast cancer is unsatisfactory. Gene therapy is promising as another useful therapeutic approach for advanced breast cancer. Strategies of gene therapy for breast cancer in ongoing clinical protocols can be divided into four: (1) suppression of oncogenes or transduction of tumor suppressors; (2) enhancement of immunological response to cancer cells; (3) transduction of suicide genes; and (4) protection of bone marrow using drug resistance genes. We have started a clinical study of gene therapy for breast cancer using multidrug resistance gene (MDR1), in which advanced or relapsed breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT) with MDR1-transduced hemopoietic cells, and then were treated with docetaxel. Two patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment after PBSCT was seen in both cases. Both patients are in complete remission and have no apparent adverse effect from MDR1 gene transduction.

Antineoplastic Agents, Phytogenic↗
PubMed2003

[Simultaneous detection of both non-Hodgkin's lymphoma cells and breast cancer cells in pleural effusion--a case report].

A 55-year-old woman underwent breast-conserving surgery with irradiation for Stage IIB (T2 N1 M0) breast cancer of her right breast. Thereafter, she was treated orally with oral UFT and tamoxifen. Three years following surgery, she was diagnosed as having a non-Hodgkin's lymphoma. She underwent 6 cycles of EPOCH-G (etoposide, vincristine, adriamycin, cyclophosphamide, prednisolone, G-CSF) therapy, and obtained complete remission. Two years later, her neck and inguinal lymph nodes were swollen. Biopsy confirmed the relapse of NHL. She underwent salvage chemotherapies of MST-16, carboplatin, IVAC, and CPT-11, but the disease was refractory. In May 2000, bilateral pleural effusion was detected. Cytomorphologically, the pleural fluid specimen showed both atypical lymphoid cells and adenocarcinoma cells simultaneously. Existence of double cancer in the pleural effusion has not been reported, suggesting that this case is rare.

Adenocarcinoma↗
PubMed2002

Increased serum granulocyte colony-stimulating factor correlates with coronary artery dilatation in Kawasaki disease.

UNLABELLED: In acute-phase Kawasaki disease, neutrophils cause injury to the coronary arterial endothelium through the production of elastase. Previous research has demonstrated the modulation of neutrophil function and kinetics, such as development and maturation, by granulocyte colony-stimulating factor (G-CSF). To examine the correlation between G-CSF and cardiac complications in Kawasaki disease, functional activity of serum G-CSF and cytokines was measured by enzyme-linked immunosorbent assay in 30 patients with acute-phase Kawasaki disease aged 2 months to 5 years. The mean serum G-CSF was higher in the 1st week of Kawasaki disease than during weeks 2 to 4, and G-CSF was significantly higher in patients with coronary artery dilatation (CAL) than in those without. There was no significant difference in the activity of other cytokines studied or white blood cell counts between the patients with CAL. CONCLUSION: granulocyte colony-stimulating factor is correlated with coronary artery dilatation in acute-phase Kawasaki disease and increased neutrophil function may contribute to the pathogenesis of coronary arterial endothelial injury in these patients.

Arteries↗
PubMed2002

Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells.

BACKGROUND: Attachment of leukemic cells to vascular endothelial cells induces the vascular endothelial cells to release endothelial cell-derived interleukin 8 (endothelial IL-8), which then induces leukemic cells to undergo apoptosis. NB4, a human promyelocytic leukemic cell line that expresses high levels of cell-surface CD13/aminopeptidase N, does not undergo endothelial IL-8-induced apoptosis. Consequently, we investigated the relationship between cell-surface aminopeptidase activity and endothelial IL-8 induction of apoptosis in various leukemic cell lines. METHODS: CD13/aminopeptidase N activity and IL-8-induced apoptosis were examined in leukemic cell lines. Endothelial IL-8-induced apoptosis was examined further in NB4 cells, K562 cells (human chronic myelogenous leukemic cells expressing low levels of CD13/aminopeptidase N), CD13/aminopeptidase N-transfected K562 (K562/CD13) cells that overexpress aminopeptidase, and mock-transfected K562 cells (vector only). These cells were also cocultured with a vascular endothelial cell layer to investigate the association between aminopeptidase activity and apoptosis in this system. All statistical tests were two-sided. RESULTS: Endothelial IL-8 induced apoptosis in K562 cells but not in K562/CD13 cells. A combination of an aminopeptidase inhibitor (such as bestatin) and endothelial IL-8 induced apoptosis in NB4 cells and K562/CD13 cells (2.88-fold difference [95% confidence interval [CI] = 1.82-fold to 3.94-fold], P =.004 for bestatin-treated NB4 cells and 4.31-fold difference [95% CI = 3.52-fold to 5.10-fold], P<.001 for bestatin-treated K562/CD13 cells). When aminopeptidase activity in NB4 cells was modulated by aminopeptidase inhibitors, a statistically significant correlation was found between aminopeptidase activity and the proportion of apoptotic cells induced by endothelial IL-8 (r = -.837, P<.001 by Pearson's correlation coefficient; r = -.697, P =.013 by Spearman's correlation analysis by ranks). K562/CD13 cells cocultured with vascular endothelial cells did not undergo apoptosis, but the addition of bestatin resulted in the induction of apoptosis in K562/CD13 cells (2.70-fold difference [95% CI = 1.77-fold to 3.63-fold], P<.001). Bestatin treatment increased the level of IL-8 mRNA in and the amount of IL-8 secreted by vascular endothelial cells. CONCLUSIONS: High levels of cell-surface CD13/aminopeptidase N appear to allow leukemic cells to resist endothelial IL-8-induced apoptosis. The combination of endothelial IL-8 and bestatin induce leukemic cells expressing high levels of CD13/aminopeptidase N to undergo apoptosis. Bestatin may be useful for treating patients with leukemia.

Antibiotics, Antineoplastic↗
PubMed2002

New human myelodysplastic cell line, TER-3: G-CSF specific downregulation of Ca2+/calmodulin-dependent protein kinase IV.

We have established a new hematopoietic cell line from a patient with myelodysplastic syndrome (MDS), which was refractory anemia with excess blasts (RAEB). This cell line, designated TER-3, depends on several cytokines for long-term survival and growth, and requires interleukin-3 (IL-3) for continuous growth. Cytochemical analysis revealed that TER-3 cells are weakly dianisidine positive and nonspecific esterase positive, but peroxidase negative. The surface marker profile shows that the TER-3 cells are strongly positive for myeloid, lymphoid, and megakaryocytic antigens such as CD15, CD19, and CD61, and negative for some common multilineage antigens such as CD13, CD33, and CD34. Thus, this cell line has a multilineage phenotype, suggesting that the transformation event occurred in multipotent stem cells. Dianisidine- and nonspecific esterase-positive TER-3 cells increase with granulocyte-colony stimulating factor (G-CSF) rather than with IL-3. These results suggest that the cell line is useful for understanding the mechanism underlying G-CSF-associated hematopoietic cell differentiation and activation in the patient with MDS.

Antigens, Surface↗
PubMed2002

Macrophage colony-stimulating factor restored chemotherapy-induced granulocyte dysfunctions: role of IL-8 production by monocytes.

We evaluated the influence of M-CSF treatment on granulocyte functions in patients with ovarian cancer. Eighteen patients with ovarian cancer received two consecutive courses of chemotherapy (16 cases, CAP therapy and two cases, CP therapy) at 4-week intervals. M-CSF (8 million U/day) was infused for 7 days starting from the next day after chemotherapy. Superoxide anion production by isolated peripheral blood granulocytes, their phagocytosis, and expression of cell adhesion molecules such as CD11a, CD11b, and CD18 on granulocytes were measured by flow cytometry. Cytokine (IL-8, G-CSF, and GM-CSF) levels in peripheral blood monocyte (PBM) culture supernatants were measured by enzyme-linked immunosorbent assay in 5 out of 18 cases. The levels of CD11a, CD11b and CD18 expression on peripheral blood granulocytes and superoxide anion production by granulocytes were significantly suppressed by chemotherapy without CSF support. The levels of CD11a and CD18 expression on granulocytes were significantly enhanced by administration of M-CSF. When M-CSF was added to cultured PBM, the level of IL-8 in the supernatant increased with the concentration of M-CSF. When IL-8 was added to cultured granulocytes, the levels of CD18 expression on granulocytes and superoxide anion production by granulocytes were significantly increased. These observations suggest that M-CSF enhances the production of IL-8 from monocytes in vivo, thereby improving chemotherapy-induced granulocyte dysfunction.

Adult↗
PubMed2002

HTLV-I carrier status disclosed at diagnosis of cytomegalovirus gastric ulcer.

A 50-year-old man experienced epigastric pain and gastrofiberscopy (GF) disclosed A2 to H1 stage multiple ulcerative lesions in the stomach. Inclusion bodies were found in the gastric mucosal cells of the biopsy specimen and the cells were positive for monoclonal antibody against cytomegalovirus. Serum HTLV-I antibody was positive and no atypical lymphocytes were seen in the peripheral blood. Gancyclovir and lansoprazole were given. A follow-up GF showed good ulcer healing with immunohistological improvement. The patient died from acute hepatic failure of undetermined cause eleven months after diagnosis. This is the first case report where a cytomegaloviral-induced gastric ulcer disclosed HTLV-I carrier state.

Antibodies, Monoclonal↗
PubMed2002

Differentiation of monoblastic cell line UG3 into leukemic dendritic cells.

Dendritic cells (DCs) are known to be generated from leukemic clone from patients with acute and chronic leukemia when cultured in the presence of combination of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-4. However, there have been few reports that showed DCs could be effectively differentiated from human leukemia cell lines. In this study, we have shown that a human monoblastic cell line, UG3, was inducible to differentiate into DCs in the presence of GM-CSF and TNF-alpha along monocyte-macrophage lineage. These DCs, consistently displayed dendritic morphology, phenotypes and allogeneic T-cell stimulating capacity. UG3 cells thus may represent a suitable model to further elucidate characteristics of DC differentiation.

Antigen Presentation↗
PubMed2002

Interleukin-10 differently regulates monocyte chemoattractant protein-1 gene expression depending on the environment in a human monoblastic cell line, UG3.

Interleukin (IL)-4, IL-10, and IL-13 affect monocyte/macrophage functions including regulation of cytokine production. We analyzed the regulatory effects of these cytokines on cytokine production using a human monoblastic cell line, UG3. It is interesting that IL-10 up-regulated, whereas IL-4 and IL-13 down-regulated monocyte chemoattractant protein-1 (MCP-1) production by unstimulated UG3 cells. IL-10-induced expression of MCP-1 mRNA occurred without de novo protein synthesis at transcriptional and post-transcriptional levels. The enhancement of binding activity of nuclear factor Sp1 (Sp-1) and signal transducer and activators of transcription (STAT)1 and 3 but not nuclear factor kappaB (NF-kappaB) was associated with this IL-10-induced MCP-1 expression. Furthermore, IL-10 suppressed lipopolysaccharide (LPS)-induced NF-kappaB binding but not Sp-1. The present results suggest IL-10 has two contrasting actions on the MCP-1 production of monocytes/macrophages, between the resting and activated conditions. The combination of activated Sp-1 and STATs is important for IL-10-induced MCP-1 expression in resting monocytes/macrophages, and the inhibition of LPS-induced NF-kappaB binding is crucial for down-regulation of MCP-1 by IL-10 in stimulated monocytes/macrophages.

Cell Line↗
PubMed2002

[Pancreatic islet cell carcinoma with multiple hepatic metastases successfully treated with a streptozocin/5-FU regimen--a case report].

A 53-year-old woman was hospitalized because of lientery and steatorrhea. CT scans revealed a pancreatic head tumor along with multiple liver tumors. The pancreatic head tumor had spread to the duodenum. Following tumor biopsy with gastrointestinal fiberscopy, we diagnosed a pancreatic malignant islet cell tumor with multiple liver metastases. Since there was no clinical evidence of recognized endocrinopathy, we diagnosed "nonfunctioning" tumor. At first we administered only 5-FU at a dose of 370 mg/m2/day continuously for two weeks. However, neither the pancreatic head tumor nor the metastatic liver tumors changed in size. We then administered streptozocin and 5-FU at doses of 1,000 mg/m2 and 370 mg/m2, respectively, every week. The patient received a total of 10 g/m2 of streptozocin. After this treatment, the enlarged metastatic liver tumors were reduced in size, with marked improvement in liver enzyme. Toxic reactions to this regimen were mild. Only grade 1 nausea and alopecia were observed during the treatment. No hematological toxicity was observed, nor, with sufficient diuresis, was nephrotoxicity, demonstrating that this regimen can be administered safely.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Paclitaxel administered weekly in patients with docetaxel-resistant metastatic breast cancer: a single-center study.

AIMS AND BACKGROUND: We evaluated retrospectively the efficacy and toxicity of paclitaxel in patients with docetaxel-resistant metastatic breast cancer. STUDY DESIGN: Paclitaxel (80 mg/m2) was administered weekly to 44 patients who had previously received chemotherapy regimens for metastatic breast cancer. All patients had progressive disease in spite of having received docetaxel therapy. RESULTS: Treatment was repeated until there was evidence of disease progression. Objective responses were obtained in 14 of 44 assessable patients (31.8%; 95% confidence interval, 17.5-46.1). Fourteen patients had partial responses; none responded completely. Seven of 14 responders had primary resistance to docetaxel therapy. The median duration of response was 6.1 months (range, 2.1-12.7). The median time to progression was 5.0 months. Clinically severe adverse events (grade 3 or 4) included neutropenia (27.2%), leukopenia (25.0%), neuropathy-sensory (13.6%), febrile neutropenia (6.8%), anemia (2.2%), constipation (2.2%), and edema (2.2%). Treatment was generally well tolerated and could be continued on an out-patient basis. CONCLUSIONS: Weekly paclitaxel is effective in patients with docetaxel-resistant metastatic breast cancer. This observation suggests partial cross-resistance between paclitaxel and docetaxel. There was no evidence for additive cumulative toxic effects of the two taxanes.

Adult↗
PubMedDate not supplied

Efficacy and safety of trastuzumab as a single agent in heavily pretreated patients with HER-2/neu-overexpressing metastatic breast cancer.

AIMS AND BACKGROUND: The human epidermal growth factor receptor 2 (HER2) protein is a unique and useful target for antibody therapy against breast cancers that overexpress the HER-2/neu gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, was approved for clinical use in the United States in 1998. It became available in Japan in June 2001. This study focuses on the efficacy and safety of trastuzumab as a single agent in second-third line treatment of HER2/neu-overexpressing metastatic breast cancer. STUDY DESIGN: Between June 2001 and May 2002, we treated 62 patients with trastuzumab, as a single agent or in combination chemotherapy, for second-third line treatment of HER2-overexpressing metastatic breast cancer. Twenty-seven of 62 patients were treated with trastuzumab as a single agent. We reviewed retrospectively the efficacy and safety of the drug given as a single agent. The expression of HER2 was determined by immunohistochemical staining. All patients received a standard loading dose of 4 mg/kg followed by 2 mg/kg weekly. RESULTS: Patients received a median of 16.7 weekly infusions (range, 1-66 infusions). Trastuzumab therapy was generally well tolerated. Clinically severe adverse events (grade 3 or 4) included hypotension (7.4%), and hypoxia (3.7%). Grade 1 to 2 toxicity included fever (11.1%) and diarrhea (3.7%). Infusion-related reactions were infrequent, as were serious hematologic complications. Cardiotoxicity did not occur in the study. Three patients had a complete and 3 a partial response, 3 had no change, 17 had progressive disease, and one was not evaluated. The overall response rate in the 26 patients with available data was 23.1% (95% confidence interval, 5.7-40.4). The median duration of response was 6.4 months (range, 2.5-14.0). The median time to progression was 3.1 months (range, 0.2-16.7). Response rates differed by metastatic site as follows: lung 0% (0/12), bone 10.0% (1/10), liver 0% (0/8), skin 50.0% (4/8), lymph nodes 42.9% (3/7), brain 0% (0/2). CONCLUSIONS: Molecular target therapy with trastuzumab appears safe and is generally well tolerated. For treatment of metastatic breast cancer, single agent therapy produces a durable response in some patients but lacks sufficient efficacy. Single agent use of trastuzumab is a viable option for treatment in cases with non-life-threatening disease without visceral metastasis.

Adult↗