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1.
Int J Oncol ; 29(2): 437-43, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16820887

ABSTRACT

Peroxisome proliferator-activated receptors (PPARs) compose a subfamily of nuclear hormone receptors functioning as transcriptional regulators. Originally, the PPARgamma ligand known as thiazolidinedione (TZD) was used for the treatment of diabetic patients. However, recent studies have shown that TZD also has an antitumor effect that inhibits cell growth in several types of human malignant neoplasms, including leukemia cell lines. Since pioglitazone is the only TZD currently available in clinics in Japan and the role of TZD in normal human hematopoietic cells or primary leukemia cells has not been previously reported, we investigated the effect of pioglitazone on human normal hematopoietic progenitor cells, primary leukemia cells, and leukemia cell lines (HL60, K562, U937, HEL, CEM, Jurkat, and NALM1). Pioglitazone inhibited the proliferation of leukemia cells in a dose-dependent manner. The viable cell numbers of HL60, K562, and Jurkat leukemia cell lines were profoundly reduced when the cells were cocultured with pioglitazone. Colony formation in the leukemia cell lines as well as the primary leukemia cells was significantly inhibited to 20-71% and 1-25% of that in control cultures by the addition of 100 and 300 microM of pioglitazone, respectively. However, the CFU-E and CFU-GM colonies of cells obtained from healthy volunteers were not altered in the presence of 100 microM of pioglitazone. Pioglitazone (300 microM) induced slight decrease of CFU-E and CFU-GM. BFU-E was more sensitive to pioglitazone than CFU-E and CFU-GM. Pioglitazone-induced growth inhibition in HL60 cells was associated with cell cycle arrest at the G1 phase, as has been reported for another TZD, troglitazone. Similar levels of PPARgamma protein were observed in both leukemia and normal bone marrow cells by Western blotting, suggesting that the expression of PPARgamma protein was not associated with the inhibitory potency of pioglitazone. In conclusion, our results suggest that pioglitazone may offer a new therapeutic approach to aid in the treatment of leukemia.


Subject(s)
Hematopoietic Stem Cells/cytology , Leukemia/drug therapy , Leukemia/pathology , Thiazolidinediones/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Erythroid Precursor Cells/metabolism , HL-60 Cells , Humans , Hypoglycemic Agents/pharmacology , Jurkat Cells , K562 Cells , PPAR gamma/metabolism , Pioglitazone
2.
Blood ; 103(8): 3045-50, 2004 Apr 15.
Article in English | MEDLINE | ID: mdl-15070682

ABSTRACT

Thrombophilic dysfibrinogen Tokyo V was identified in a 43-year-old man with recurrent thromboembolism. Based on analyses of the patient fibrinogen genes, the amino acid sequence of the aberrant fibrinogen peptide, and deglycosylation experiments, fibrinogen Tokyo V was shown to have an amino acid substitution of gamma Ala327Thr and possibly extra glycosylation at gamma Asn325 because the mutation confers the N-linked glycosylation consensus sequence Asn-X-Thr. The mutation resulted in impaired function and hypofibrinogenemia (hypodysfibrinogen). Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium, resulting in very low clottability. Additionally, a large amount of soluble cross-linked fibrin was formed upon thrombin treatment in the presence of factor XIII and calcium. However, Tokyo V-derived fibrin was resistant to degradation by tissue plasminogen activator (tPA)-catalyzed plasmin digestion. The structure of Tokyo V fibrin appeared severely perturbed, since there are large pores inside the tangled fibrin networks and fiber ends at the boundaries. Taken together, these data suggest that Tokyo V fibrin clots are fragile, so that fibrinolysis-resistant insoluble fibrin and soluble fibrin polymers may be released to the circulation, partly accounting for the recurrent embolic episodes in the patient.


Subject(s)
Fibrinogens, Abnormal/genetics , Fibrinogens, Abnormal/physiology , Thromboembolism/blood , Thromboembolism/genetics , Thrombophilia/blood , Thrombophilia/genetics , Adult , Amino Acid Substitution , Calcium/metabolism , Fibrinogens, Abnormal/chemistry , Fibrinolysin/metabolism , Fibrinolysis , Glycosylation , Humans , In Vitro Techniques , Male , Microscopy, Electron, Scanning , Recurrence , Solubility , Tissue Plasminogen Activator/metabolism
3.
Nihon Rinsho ; 61(9): 1504-11, 2003 Sep.
Article in Japanese | MEDLINE | ID: mdl-14515716

ABSTRACT

Allogeneic hematopoietic stem cell transplantation(Allo-HSCT) is a standard therapy for hematological malignancies. However, graft versus host disease(GVHD) remains one of the major obstacles for successful Allo-HSCT. The insight into the pathogenesis of GVHD has been profoundly improved by recent advances in our understanding of the immune system and progress of the molecular biology. A primary causes for GVHD are the inappropriate production of cytokines and dysregulation of complex cytokine network occurs in the three sequential steps: conditioning regimen, donor T cell activation and effector mechanisms. This short review discusses the interaction between the cytokines and the cellular effector of GVHD in each step.


Subject(s)
Cytokines/physiology , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation , Antigen-Presenting Cells/immunology , Hematologic Neoplasms/therapy , Humans , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Transplantation Immunology , Transplantation, Homologous
4.
Rinsho Ketsueki ; 43(10): 918-23, 2002 Oct.
Article in Japanese | MEDLINE | ID: mdl-12462027

ABSTRACT

A 70-year-old man was referred to our hospital in March 2001 for the purpose of evaluation for anemia and thrombocytopenia. Physical examination revealed hepatosplenomegaly, normal skin, and normal neurologic findings. Blood examination showed a white blood cell count of 10,900/microliter, with a differential count of 58.5% eosinophils and 3.5% blast cells. Flow cytometric analysis of eosinophils revealed that they were positive for CD33, CD13, CD25, and HLA-DR. Bone marrow aspiration could not be performed due to dry tap, and bone marrow core biopsy specimen revealed severe myelofibrosis with blastoid cells proliferation. Cytogenetic analysis of bone marrow cells showed isochromosome 17. FISH analysis using a RAR alpha probe (17q21.1) demonstrated 62% of peripheral blood nucleated cells having three signals. BCR/ABL gene rearrangement by FISH analysis was not observed. Allergic disease, infectious disease, parasitic disease, collagen vascular diseases, pulmonary disease, and neoplastic disorders were excluded. Therefore, a diagnosis of chronic eosinophilic leukemia was made. The patient had no symptoms of hypereosinophilia. However, eosinophils with sparse granulation, positivity for CD25, elevated serum levels of soluble IL-2 receptor, and elevated serum levels of eosinophil cationic protein suggested activation of eosinophils. Further analysis is needed regarding the activation of eosinophils in chronic eosinophilic leukemia.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Primary Myelofibrosis/complications , Receptors, Interleukin-2/immunology , Aged , Diagnosis, Differential , Humans , Hypereosinophilic Syndrome/diagnosis , Male
5.
Rinsho Ketsueki ; 43(7): 548-53, 2002 Jul.
Article in Japanese | MEDLINE | ID: mdl-12229124

ABSTRACT

A 58-year-old HIV-negative woman was admitted to our hospital with abdominal distension. She had a 5-year history of hypothyroidism and a 4-year history of diabetes mellitus. Physical examination revealed ascites. There was no lymphadenopathy or splenomegaly. Laboratory examination showed elevated levels of serum LDH and Al-p, polyclonal hypergammaglobulinemia, and was positive for anti-nuclear antibody, several autoantibodies and HCV-RNA. A computed tomographic scan of the abdomen and chest showed massive ascites, but there was no evidence of tumor masses or lymph node enlargement. Cytologic examination of the ascitic fluid revealed numerous abnormal lymphocytes which by flow cytometry demonstrated expression of CD5, CD19, CD20, and CD4. Cytogenetical analysis demonstrated a hyperdiploid karyotype, with numerical abnormalities. Southern blot analysis demonstrated rearranged monoclonal bands in JH and c-mycgenes. Polymerase chain reaction (PCR) analysis failed to detect the genomes of EBV and HHV-8 in the abnormal lymphocytes. A diagnosis of primary effusion lymphoma of B cell lineage was made. Following abdominal paracentesis, the patient remained in complete clinical remission for 7 months and died of an unrelated cause (cerebral bleeding). The present case demonstrated an HIV-, HHV-8-, and EBV-negative, and HCV-positive primary effusion lymphoma of B cell lineage, with a unique clinical course.


Subject(s)
Herpesvirus 8, Human , Lymphoma, B-Cell/therapy , Lymphoma, B-Cell/virology , Ascites/therapy , Female , Humans , Middle Aged , Paracentesis , Remission Induction
6.
Leuk Res ; 26(5): 477-82, 2002 May.
Article in English | MEDLINE | ID: mdl-11916522

ABSTRACT

In this study, we show potent in vitro purging induced by adenosine triphosphate (ATP) for leukemic cells. The treatment of murine L1210 leukemic cells with 2mM of ATP in vitro for 3h was able to reduce the number of leukemic clonogenic cells by about one order of magnitude presumably by changing the permeability of the leukemic cell membrane. Furthermore, the incubation of L1210 cells with ATP (2mM) and low dose 4-hydroperoxycyclophosphamide (4-HC, 2 microg/ml) for 3h resulted in at least a four-log reduction of clonogenic L1210 cells. Only a slight degree of toxicity to pluripotent hematopoietic stem cells (CFU-S) was observed in both treatment protocols. To determine the efficacy of pharmacological purging by ATP, we designed a murine system to mimic the conditions expected in the clinical setting of autologous transplantation using simulated partial remission marrow (SPRM) which was prepared by mixing normal marrow cells and L1210 cells at a ratio of 9:1. After the SPRM cells were incubated in vitro at a concentration of 1 x 10(6)/ml with both ATP (2mM) and low dose 4-HC (2 microg/ml) for 3h, 5 x 10(4) of the cells were then injected into lethally irradiated 9 weeks male BDF1 mice. All the mice given untreated-SPRM died of leukemia by day 27, whereas none of the recipients transplanted treated-grafts had died by day 70, thus suggesting that the combination use of ATP and 4-HC may be a potentially effective way to purge leukemic cells in autologous stem cell transplantation. The mechanism of the selective killing of leukemic cells is assumed that 4-HC is effectively incorporated into leukemic cells by increasing the permeability of the cell membrane by ATP. Taken together, this simple and rapid procedure is able to purge leukemic cells from autologous bone marrow grafts.


Subject(s)
Adenosine Triphosphate/therapeutic use , Bone Marrow Purging/methods , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia L1210/therapy , Animals , Hematopoietic Stem Cells/drug effects , Male , Mice , Transplantation, Autologous
7.
Rinsho Ketsueki ; 43(12): 1037-44, 2002 Dec.
Article in Japanese | MEDLINE | ID: mdl-12607992

ABSTRACT

Airway hyperreactivity (AHR) was studied with an astograph for 34 sequential hematopoietic stem cell transplantation (HSCT) patients before and after HSCT. The percentage of Dmin positive patients was 25.0% before HSCT and 25.0-57.1% after HSCT, while all normal subjects were negative for Dmin. The mean Dmin of post HSCT patients was 22.7 u in days 501-1000 and 19.3 u after 1001 days, which was significantly lower than the 45.2 u of normal controls. The patients were divided into two groups according to the treatment before HSCT, strongly treated (S, acute leukemia and non-Hodgikin lymphoma) and weakly treated (W, chronic myelogenous leukemia and aplastic anemia) patients. The ratio of Dmin positive patients and mean Dmin in the W group after HSCT (38.9%, 27.8 u), and the S group before and after HSCT (55.6%, 20.5 u and 45.5%, 23.8 u, respectively), were significantly impaired compared with the findings in the normal controls (0%, 45.2 u). The mean sGrs/Grs count was higher in the W group before HSCT than in the other groups (W before and after HSCT, 0.58 and 0.19, respectively; S before and after HSCT, 0.21 and 0.22, respectively). Taken together, AHR was observed in HSCT patients, particularly for patients in the S group. These data indicate that high dose chemo-radiotherapy including conditioning regimen causes AHR. The mechanisms leading to AHR may be infection, inflammation, and remodeling of the airway.


Subject(s)
Hematopoietic Stem Cell Transplantation , Respiratory Hypersensitivity/physiopathology , Adolescent , Adult , Female , Humans , Leukemia/drug therapy , Leukemia/therapy , Lymphoma/drug therapy , Lymphoma/therapy , Male , Middle Aged
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