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1.
Leukemia ; 19(9): 1558-66, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16034467

ABSTRACT

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.


Subject(s)
Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/immunology , Primary Myelofibrosis/immunology , Thrombopoietin/immunology , Transforming Growth Factor beta/immunology , Adult , Aged , Aged, 80 and over , Antigens, CD34/biosynthesis , Antigens, CD34/genetics , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Cell Count , Enzyme-Linked Immunosorbent Assay , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Megakaryocytes/cytology , Megakaryocytes/pathology , Middle Aged , Myelodysplastic Syndromes/complications , Primary Myelofibrosis/complications , RNA, Messenger/genetics , Thrombopoietin/biosynthesis , Thrombopoietin/blood , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/blood
2.
Ann Hematol ; 82(12): 773-6, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14517692

ABSTRACT

A 55-year-old man developing transfusion-dependant anemia was diagnosed with autoimmune hemolytic anemia (AIHA). Although he received prednisolone (PSL) (daily 60 mg), his hemoglobin level continued to decrease. After 3 weeks of treatment, he presented with a distension of the abdomen. Cytological examination of ascitic fluid revealed large, immunoblastic lymphocytes with plasmacytoid features and abundant IgM chains on the cellular surface; this was diagnosed as primary effusion lymphoma (PEL). Administration of CHOP (cyclophosphamide, Adriamycin, vincristine, and PSL) chemotherapy elicited regression of ascites as well as recovery of hemoglobin level. We hypothesize that PEL cells generated antibodies against red blood cells, resulting in AIHA resistance to PSL.


Subject(s)
Anemia, Hemolytic, Autoimmune/diagnosis , Anemia, Hemolytic, Autoimmune/etiology , Ascitic Fluid/pathology , Lymphoma/diagnosis , Cytodiagnosis , Humans , Lymphoma/pathology , Male , Middle Aged
3.
Ann Hematol ; 81(5): 285-8, 2002 May.
Article in English | MEDLINE | ID: mdl-12029539

ABSTRACT

We report here an autopsy case of true malignant histiocytosis. The patient was a 67-year-old woman who exhibited fever, wasting, hepatosplenomegaly, and progressive pancytopenia. The bone marrow aspiration disclosed hemophagocytosing cells, which resembled histiocytes. The molecular analysis did not show the clonal gene rearrangement of T-cell receptor or immunoglobulin heavy chain. Although the patient had been started on methylprednisolone pulse therapy and chemotherapy with etoposide, she died from cerebral hemorrhage. The autopsy specimens of spleen and liver showed extensive infiltration of atypical cells, for which histiocytic origin was identified with an immunohistochemical method using monoclonal antibodies against CD11c, CD68, macrophage colony-stimulating factor (M-CSF), M-CSF receptor, lysozyme, antitrypsin and alpha1-antichymotrypsin. Recent investigations have disclosed that in most cases diagnosed as malignant histiocytosis, hemophagocytosis was reactive and not evoked by histiocytic malignancy. True malignant histiocytosis, for which histiocytic origin is confirmed, is extremely rare.


Subject(s)
Cytogenetic Analysis , Histiocytic Sarcoma/pathology , Immunohistochemistry/methods , Aged , Antibodies, Monoclonal , Bone Marrow/pathology , Cell Line , Fatal Outcome , Female , Humans , Liver/pathology , Spleen/pathology
4.
Arthritis Rheum ; 44(9): 2160-7, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11592381

ABSTRACT

UNLABELLED: OBJECTIVE; Superoxide dismutase (SOD) is a potent antiinflammatory enzyme that has received growing attention for its therapeutic potential. This study was undertaken to examine the efficacy of extracellular SOD (EC-SOD) gene therapy in murine collagen-induced arthritis. METHODS: Embryonic DBA/1 mouse fibroblasts were infected with a recombinant retrovirus expressing human EC-SOD. DBA/1 mice that had been treated with type II collagen were administered subcutaneous injections of 2 x 10(7) EC-SOD-expressing fibroblasts on day 29, when symptoms of arthritis were already present. The severity of arthritis in individual mice was evaluated in a double-blind manner; each paw was assigned a separate clinical score, and hind paw thickness was measured with a caliper. Mice were killed on day 50 for histologic examination of the joints. RESULTS: High serum concentrations of EC-SOD were maintained for at least 7 days. Mice treated with the transgene exhibited significant suppression of clinical symptoms such as disabling joint swelling, deformity, and hind paw thickness, compared with the untreated group (mean +/- SD maximum clinical score in the untreated and the transgene-treated groups 2.71 +/- 1.08 and 1.35 +/- 1.22, respectively; P < 0.01, and hind paw thickness 3.04 +/- 0.18 mm and 2.56 +/- 0.12 mm, respectively; P < 0.05). Histologic abnormalities, including destruction of cartilage and bone, infiltration of mononuclear cells, and proliferation of synovial cells, were also markedly improved in the EC-SOD-treated mice compared with the control group (histopathologic score 7.50 +/- 1.13 and 4.13 +/- 1.88 in the untreated and transgene-treated groups, respectively; P < 0.05). CONCLUSION: These results indicate that EC-SOD gene transfer may be an effective form of therapy for rheumatoid arthritis.


Subject(s)
Arthritis, Rheumatoid/therapy , Genetic Therapy , Superoxide Dismutase/genetics , Animals , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/pathology , Cells, Cultured , Collagen/pharmacology , Culture Media , Extracellular Space/enzymology , Female , Fibroblasts/cytology , Fibroblasts/enzymology , Gene Expression Regulation, Enzymologic , Hindlimb/pathology , Humans , Interleukin-1/blood , Joints/pathology , Mice , Mice, Inbred DBA , Pregnancy , RNA, Messenger/analysis , Superoxide Dismutase/blood , Tumor Necrosis Factor-alpha/metabolism
5.
Bone Marrow Transplant ; 28(6): 619-21, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11607778

ABSTRACT

A 54-year-old woman with peripheral T cell lymphoma in second complete remission (CR) received an autologous peripheral blood stem cell transplant (PBSCT). Antibiotic-resistant bloody diarrhea, and fever developed 110 days after transplant. Blood and stool cultures were negative. Skin rash was not observed. Barium enema and colonoscopy showed typical features of pancolonic-type ulcerative colitis (UC). Endoscopic biopsies confirmed the diagnosis of UC. Mesalazine and immunosuppressive therapy improved symptoms dramatically. We detected serum antibodies against synthetic tropomyosin (TM) peptide when UC was diagnosed. We postulate that autoimmunity including autoreactive anti-TM antibodies may be involved in the pathogenesis of UC after autologous PBSCT in this patient.


Subject(s)
Colitis, Ulcerative/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoma, Non-Hodgkin/complications , Autoantibodies/blood , Autoimmunity/immunology , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Female , Humans , Lymphoma, Non-Hodgkin/therapy , Lymphoma, T-Cell, Peripheral/complications , Lymphoma, T-Cell, Peripheral/therapy , Middle Aged , Transplantation, Autologous/adverse effects , Tropomyosin/immunology
6.
Gastroenterology ; 121(4): 865-74, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11606500

ABSTRACT

BACKGROUND & AIMS: In colorectal adenoma and carcinoma, glutathione S-transferase-pi (GSTP1-1) is highly expressed. K-ras mutation is also known to occur frequently in colorectal adenoma and carcinoma, as well as in the putative precursor of adenoma, aberrant crypt foci (ACF). Further, forced expression of v-H-ras in rat liver epithelial cells has been shown to enhance rat pi-class GST expression. The aim of the present study is, therefore, to investigate the causative relationship between GSTP1-1 overexpression and K-ras mutation in these lesions. METHODS: Twenty-seven specimens of colorectal carcinoma, 24 of adenoma, and 28 of ACF were examined in this study. The expression of GSTP1-1 or p21(K-ras) was examined by immunohistochemistry. The GSTP1-1 messenger RNA levels were measured by TaqMan reverse-transcription polymerase chain reaction (PCR). K-ras mutation was detected by two-step PCR restriction fragment length polymorphism. v-K-ras transfection to RPMI-4788 colon carcinoma cells was carried out by the lipofection method. Activities of GSTP1-1 promoters containing AP-1 and Sp1 responsive elements in the v-K-ras transfectants were measured by a secreted form of human placental alkaline phosphatase (SEAP) assay. Nuclear protein from these transfectants bound to the GSTP1-1 promoter was analyzed by electrophoretic mobility shift assay (EMSA). RESULTS: In human colorectal carcinoma, adenoma, and ACF, close association of increased expression of GSTP1-1 with K-ras mutation was observed. v-K-ras transfectants showed significantly higher SEAP activity than that of mock-transfectant activity. EMSA showed specific interaction of AP-1 with promoter of GSTP1-1. CONCLUSIONS: It is highly plausible that GSTP1-1 overexpression in ACF, colorectal adenoma, and carcinoma is induced by K-ras mutation via AP-1 activation.


Subject(s)
Colonic Neoplasms/enzymology , Gene Expression Regulation, Enzymologic , Genes, ras , Glutathione Transferase/genetics , Mutation , Adenoma/enzymology , Adenoma/pathology , Base Sequence , Carcinoma/enzymology , Carcinoma/pathology , Colonic Neoplasms/pathology , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay , Glutathione S-Transferase pi , Humans , Isoenzymes/genetics , Molecular Sequence Data , Polymorphism, Restriction Fragment Length , Promoter Regions, Genetic , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Transfection , Tumor Cells, Cultured
7.
Gastroenterology ; 121(3): 599-611, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11522744

ABSTRACT

BACKGROUND & AIMS: We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS: The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS: In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS: The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.


Subject(s)
Adenomatous Polyposis Coli/genetics , Colorectal Neoplasms/genetics , Cytoskeletal Proteins/genetics , Genes, ras/genetics , Trans-Activators , Adenomatous Polyposis Coli/pathology , Adenomatous Polyposis Coli Protein , Adult , Aged , Biopsy , Colorectal Neoplasms/pathology , Cytoskeletal Proteins/analysis , Disease Progression , Endoscopy, Gastrointestinal , Female , Genetic Testing , Humans , Immunohistochemistry , Intestinal Mucosa/chemistry , Intestinal Mucosa/pathology , Male , Middle Aged , Mutation , Polymorphism, Restriction Fragment Length , beta Catenin
8.
Clin Chem ; 47(7): 1297-301, 2001.
Article in English | MEDLINE | ID: mdl-11427462

ABSTRACT

BACKGROUND: The significance of serum concentrations of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of inflammatory bowel disease (IBD) is uncertain. We measured TNF-alpha in serum from IBD patients by immuno-PCR to analyze the relationship between TNF-alpha and pathophysiologic state in IBD. METHODS: Serum samples were collected from 54 healthy blood donors, 29 patients with ulcerative colitis (UC; 46 samples), and 7 patients with Crohn disease (CD; 8 samples). DNA label was generated by PCR amplification using biotinylated primer and was bound with streptavidin to biotinylated third antibody. TNF-alpha sandwiched by antibodies was detected by PCR amplification of the DNA label. RESULTS: TNF-alpha could be measured in all samples. The median serum concentration in IBD patients overall was approximately 390-fold higher than in healthy donors (median increase, 380-fold for UC, 640-fold for CD). The median serum TNF-alpha concentration was 1.7-fold higher in the active stage of UC than in the inactive stage (P <0.05), and this difference could be detected in individual patients. CONCLUSIONS: Sensitive measurement of serum TNF-alpha could provide an important pathophysiologic marker for the presence and activity of IBD.


Subject(s)
Inflammatory Bowel Diseases/blood , Tumor Necrosis Factor-alpha/analysis , Adult , Aged , Antibodies , Biomarkers/blood , Biotinylation , Colitis, Ulcerative/blood , Colitis, Ulcerative/pathology , Crohn Disease/blood , Crohn Disease/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Inflammatory Bowel Diseases/pathology , Male , Middle Aged , Polymerase Chain Reaction/methods , Sensitivity and Specificity , Streptavidin
9.
Int J Hematol ; 73(2): 251-7, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11372740

ABSTRACT

The antitumor effect of high-dose chemotherapy (HDC) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) is considered superior to that of conventional chemotherapy. However, the long-term benefits of this strategy in Japan remain unclear. Therefore, in this study, 109 cancer patients enrolled between 1989 and 1999 were treated with HDC and auto-PBSCT. Patients were evaluated for long-term survival and late-onset complications, including secondary malignancy. The mean number of CD34+ cells harvested per apheresis was larger in the group receiving high-dose cytosine arabinoside or high-dose etoposide plus granulocyte colony-stimulating factor (G-CSF) than in the group receiving conventional chemotherapy plus G-CSF. The 5-year overall survival rates for non-Hodgkin's lymphoma patients in first complete remission (CR) (83.2%), second or subsequent CR (74.1%), or first partial remission (PR) (66.7%) at the time of transplantation were significantly higher than those with no remission (35.7%) at the time of transplantation (first CR, P < .05; second or subsequent CR, P < .05; first PR, P < .05). The 5-year overall survival (OS) rates for breast cancer was 40.8%, and the disease-free survival rate was extremely low (8.8%). The 5-year OS rates for chemotherapy-sensitive and chemotherapy-resistant diseases at the time of transplantation were 32.7% and 35.7%, respectively, a difference that was not considered significant. The 5-year OS for germ cell tumor was 80.0%, and the disease-free survival rate was 77.9%. The rate of therapy-related death was 8.2%. The occurrence rate of secondary malignancy was 0.9%. Late-onset complications were observed in 4 cases (glomerulonephritis, interstitial pneumonitis, ulcerative colitis, and acute myelogenous leukemia). At 3.7%, the occurrence rate was not very high, but most complications of auto-PBSCT were life threatening and interfered with patients' quality of life. A careful follow-up is required for at least 2 years after transplantation, because the mean occurrence time of late-onset complications is 16.7 months posttransplantation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/complications , Neoplasms/therapy , Transplantation, Autologous/methods , Adult , Antigens, CD34/blood , Antineoplastic Combined Chemotherapy Protocols/toxicity , Blood Component Removal , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/standards , Humans , Male , Middle Aged , Neoplasms, Second Primary , Survival Rate , Transplantation, Autologous/standards , Treatment Outcome
10.
Gene Ther ; 8(2): 149-56, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11313784

ABSTRACT

We have previously reported that superoxide stimulates the motility of tumor cells and the administration of Cu-Zn superoxide dismutase (SOD) significantly suppresses metastasis. However, ideally, anti-metastatic therapy should be long-lasting, systemically effective and have low toxicity. The half-life of Cu-Zn SOD in plasma is so short that it cannot provide long-lasting effects. Therefore, in this study we have developed a gene therapy in a mouse model utilizing extracellular SOD (EC-SOD), which is the most prevalent SOD isoenzyme in extracellular fluids. We retrovirally transfected fibroblasts (syngeneic) with the EC-SOD gene and established EC-SOD-secreting fibroblasts. Inoculation of EC-SOD-secreting fibroblasts suppressed both artificial and spontaneous metastatic lung nodules in mouse metastasis models. These data indicate the feasibility of anti-metastatic gene therapy utilizing the EC-SOD gene.


Subject(s)
Genetic Therapy/methods , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Superoxide Dismutase/genetics , Transduction, Genetic , Animals , Carcinoma, Lewis Lung/pathology , Carcinoma, Lewis Lung/secondary , Carcinoma, Lewis Lung/therapy , Cell Culture Techniques , Cell Division , Culture Media , DNA, Complementary/genetics , Feasibility Studies , Fibroblasts/transplantation , Gene Expression , Isoenzymes/genetics , Isoenzymes/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred Strains , Neoplasm Transplantation , RNA, Messenger/genetics , Sarcoma, Experimental/pathology , Sarcoma, Experimental/secondary , Sarcoma, Experimental/therapy , Superoxide Dismutase/metabolism
11.
J Gastroenterol ; 36(2): 129-32, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11227670

ABSTRACT

A 21-year-old man with diarrhea and edema was admitted to our hospital and diagnosed with protein-losing enteropathy caused by primary intestinal lymphangiectasia. He was placed, in turn, on a low-fat diet, an elemental diet, and, subsequently, fasting therapy with total parenteral nutrition (TPN) support. However, his symptoms were not relieved, but, rather were exacerbated. On the 45th day of hospitalization, octreotide therapy was initiated. After 2 weeks of treatment, his clinical symptoms, as well as hypoproteinemia and hypoalbuminemia, gradually became alleviated. The improvement was confirmed in terms of scintigraphy, endoscopy, and histology of the duodenum. The patient remained healthy until 6 months after the commencement of octreotide treatment, when he discontinued octreotide at his own discretion, at which point the symptoms recurred. Resumption of the drug, however, again brought about remission, which has continued until the present, March 2000. Thus, octreotide therapy is one modality which may be useful for refractory primary intestinal lymphangiectasia.


Subject(s)
Gastrointestinal Agents/therapeutic use , Lymphangiectasis, Intestinal/drug therapy , Octreotide/therapeutic use , Adult , Humans , Lymphangiectasis, Intestinal/diagnosis , Male
12.
Blood ; 97(4): 1123-30, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11159546

ABSTRACT

Acute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-gamma or tumor necrosis factor-alpha have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4(+) helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.


Subject(s)
Graft vs Host Disease/prevention & control , Immunosuppressive Agents/therapeutic use , Quinolines/therapeutic use , Th1 Cells/drug effects , Triazoles/therapeutic use , Acute Disease , Administration, Oral , Animals , Bone Marrow Transplantation/adverse effects , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacology , Intestines/pathology , Liver/pathology , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Quinolines/administration & dosage , Quinolines/pharmacology , Radiation Chimera , Skin/pathology , Spleen/transplantation , Th1 Cells/metabolism , Transplantation, Homologous/adverse effects , Triazoles/administration & dosage , Triazoles/pharmacology
14.
Intern Med ; 40(11): 1136-9, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11757771

ABSTRACT

We report a patient with an initial relapse of acute promyelocytic leukemia (APL) who achieved a second complete remission (CR) after treatment with arsenic trioxide. The patient, a 66-year-old woman diagnosed as having relapsed APL, received arsenic trioxide intravenously at a dose of 10 mg/day. At day 36, the patient achieved a second CR. The side effects were slight neuralgia and mild skin erythematous changes, which improved following cessation of the drug. Although arsenic trioxide may be effective for relapsed APL, it should be used with caution because of various complications.


Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Bone Marrow/drug effects , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Aged , Arsenic Trioxide , Bone Marrow/pathology , Female , Humans , Leukemia, Promyelocytic, Acute/pathology , Recurrence , Remission Induction , Treatment Outcome
15.
Rinsho Ketsueki ; 41(9): 750-4, 2000 Sep.
Article in Japanese | MEDLINE | ID: mdl-11070938

ABSTRACT

A 62-year-old woman was admitted because of leukocytosis, systemic lymph node swelling and erythroderma. Laboratory data disclosed a WBC count of 15,600/microliter (CD4-positive cells: 91%). CD25 and HTLV-1 were negative. A skin biopsy revealed the involvement of T cells. These data and findings were consistent with a diagnosis of Sézary syndrome. Although the patient was treated with 2 courses of CHOP, the leukocyte count did not decrease. We then treated the patient orally with etoposide (25 mg/day) and methotrexate (10 mg/week), and this resulted in reduction of the leukocyte count and lymph node swelling, and amelioration of the erythroderma. As Sézary syndrome is an extremely rare disease, it is worthwhile reporting cases like the present one, where therapy was successful.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Sezary Syndrome/drug therapy , Skin Neoplasms/drug therapy , Administration, Oral , Etoposide/administration & dosage , Female , Humans , Methotrexate/administration & dosage , Middle Aged , Time Factors
16.
Rinsho Ketsueki ; 41(8): 648-52, 2000 Aug.
Article in Japanese | MEDLINE | ID: mdl-11020992

ABSTRACT

A 48-year-old woman, who had been suffering from systemic lupus erythematosus (SLE), developed normochromic normocytic anemia after receiving clomipramine hydrochloride. Her reticulocyte count was low, and a bone marrow aspirate revealed erythroid hypoplasia without involvement of other cell lines. Thus a diagnosis of pure red cell aplasia (PRCA) was made. The anemia gradually resolved following withdrawal of the drug. Although several drugs are known to cause PRCA, this is the first time that clomipramine hydrochloride has been reported to have such an effect. The underlying SLE in this case suggested the possible immunological pathogenesis of drug-induced PRCA.


Subject(s)
Antidepressive Agents, Tricyclic/adverse effects , Clomipramine/adverse effects , Lupus Erythematosus, Systemic/complications , Red-Cell Aplasia, Pure/chemically induced , Female , Humans , Middle Aged
17.
FASEB J ; 14(13): 2108-18, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11023995

ABSTRACT

To target disseminated tumors in vivo, transgenes [beta-galactosidase gene, green fluorescence protein (GFP) gene, herpes simplex virus thymidine kinase (HSV-TK)] were conjugated to transferrin (Tf) by a biotin-streptavidin bridging, which is stoichiometrically controllable, and Tf receptor (Tf-R) affinity chromatography, which selects Tf conjugates with intact receptor bindings sites from reacting with the linker. Tf-beta-galactosidase plasmid conjugate thus constructed was specifically transfected to human erythroleukemia cells (K562) via Tf-R without the aid of any lysosomotropic agents. The transfection efficiency of the conjugate was superior to those of lipofection (1% staining) and retroviral vector (5%) and slightly lower than that of adenovirus (70%). The high level of expression with our conjugate was confirmed using other tumor cells (M7609, TMK-1) whereas in normal diploid cells (HEL), which express low levels of Tf-R, expression was negligible. When GFP gene conjugates were systemically administered through the tail vein to nude mice subcutaneously inoculated with tumor, expression of GFP mRNA was found almost exclusively in tumors and to a much lesser extent in muscles, whereas GFP revealed by fluorescence microscopy was detected only in the former. To exploit a therapeutic applicability of this method, suicide gene therapy using Tf-HSV-TK gene conjugate for massively metastasized k562 tumors in severe combined immune-deficient mice was conducted, and a marked prolongation of survival and significant reduction of tumor burden were confirmed. Thus, this method could also be used for gene therapy to disseminated tumors.


Subject(s)
Biotin , Drug Carriers/pharmacology , Gene Targeting/methods , Leukemia, Erythroblastic, Acute/therapy , Streptavidin , Thymidine Kinase/therapeutic use , Transferrin/pharmacology , Animals , Biotinylation , DNA , Genetic Therapy/methods , Green Fluorescent Proteins , Humans , K562 Cells/drug effects , Leukemia, Erythroblastic, Acute/mortality , Leukemia, Experimental/drug therapy , Leukemia, Experimental/mortality , Luminescent Proteins/genetics , Mice , Neoplasm Metastasis/drug therapy , Plasmids/pharmacology , Simplexvirus/enzymology , Thymidine Kinase/genetics , beta-Galactosidase/genetics
18.
Hepatology ; 32(5): 916-23, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11050039

ABSTRACT

Most cases of cholangiocarcinoma have reached an unresectable stage by the time they are discovered despite significant progress of diagnostic modalities. Many of these patients with obstructive jaundice are often treated by biliary drainage using stents to relieve the jaundice. However, the stent patency period is as short as 3 to 9 months because of tumor ingrowth or overgrowth, and mean survival is at most 12 months. Therefore, both continuous relief of obstructive jaundice and local control of the tumor are required in the treatment for advanced cholangiocarcinoma. In this investigation, we developed a new percutaneous transhepatic biliary drainage tube coated with carboplatin (carboplatin-coated tube; CCT). CCT continuously released a fixed amount of carboplatin for 4 weeks and showed an antitumor effect on human cholangiocarcinoma cell line HuCC-T1 in vitro. When CCT was embedded in subcutaneous tumor inoculated in nude mice, a significant reduction of tumor size with no apparent damage to normal adjacent tissue was observed. On the basis of these studies, 5 patients with inoperable cholangiocarcinoma were treated with CCT for 4 weeks. Overall efficacy rate of 5 patients with cholangiocarcinoma was 60% (partial response in 3 and no change in 2). No apparent side effect was observed in these patients. Thus, CCT may provide a new treatment modality for this disease. Randomized controlled trials comparing CCT therapy with palliative stenting are required to confirm these results.


Subject(s)
Antineoplastic Agents/administration & dosage , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic , Carboplatin/administration & dosage , Cholangiocarcinoma/drug therapy , Coated Materials, Biocompatible/therapeutic use , Stents , Aged , Aged, 80 and over , Animals , Antineoplastic Agents/therapeutic use , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/surgery , Carboplatin/therapeutic use , Cholangiocarcinoma/pathology , Cholangiocarcinoma/surgery , Delayed-Action Preparations , Equipment Design , Female , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Transplantation , Tumor Cells, Cultured/drug effects
19.
Hum Gene Ther ; 11(12): 1671-81, 2000 Aug 10.
Article in English | MEDLINE | ID: mdl-10954901

ABSTRACT

Autologous transplantation of bone marrow cells (BMCs) transduced with the multidrug resistance 1 (MDR1) gene or dihydrofolate reductase (DHFR) gene has already been applied in clinical chemoprotection trials. However, anticancer drugs frequently used in high-dose chemotherapy (HDC), such as alkylating agents, are not relevant to MDR1 or DHFR gene products. In this context, we have previously reported that glutathione S-transferase-pi (GST-pi) gene-transduced human CD34(+) cells showed resistance in vitro against 4-hydroperoxicyclophosphamide, an active form of cyclophosphamide (CY). In the present study, a subsequent attempt was made in a murine model to evaluate the effectiveness of transplantation of GST-pi-transduced BMCs to protect bone marrow against high-dose CY. The gene transfection was carried out retrovirally, employing a recombinant fibronectin fragment. Transfection efficiency into CFU-GM was 30%. After the transplantation, recipient mice (GST-pi mice) received three sequential courses of high-dose CY. As the chemotherapy courses advanced, both shortening of recovery period from WBC nadir and shallowing of WBC nadir were observed. In contrast to the fact that three of seven control mice died, possibly due to chemotoxicity, all seven GST-pi mice were alive after the third course, at which point the vector GST-pi gene was detected in 50% of CFU-GM derived from their BMCs and peripheral blood mononuclear cells. When BMCs obtained from these seven mice were retransplanted into secondary recipient mice, 20% of CFU-GM from BMCs showed positive signals for vector GST-pi DNA after 6 months. These data indicate that the GST-pi gene can confer resistance to bone marrow against CY by being transduced into long-term repopulating cells.


Subject(s)
Antineoplastic Agents, Alkylating/toxicity , Bone Marrow/drug effects , Cyclophosphamide/toxicity , Gene Transfer Techniques , Glutathione Transferase/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/drug effects , Isoenzymes/genetics , Animals , Female , Glutathione S-Transferase pi , Glutathione Transferase/metabolism , Humans , Isoenzymes/metabolism , Leukocyte Count , Mice , Mice, Inbred BALB C , Polymerase Chain Reaction
20.
Gut ; 47(2): 236-41, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10896915

ABSTRACT

BACKGROUND AND AIMS: Recent studies suggest that tropomyosin (TM) may act as a putative autoantigen in ulcerative colitis (UC). Recently, we identified, by computer homology analysis, a specific peptide (HIAEDADRK) in human TM that can bind to HLA-DPw9. The aim of this study was to investigate the presence of autoantibodies against this peptide in UC. METHODS: Antibodies were measured by ELISA with a synthetic peptide in 20 healthy volunteers, 48 patients with UC, 26 with Crohn's disease (CD), eight with primary sclerosing cholangitis (PSC), and six with primary biliary cirrhosis (PBC). The functional significance of antibodies was investigated by antibody dependent cell mediated cytotoxicity (ADCC) against DPw9 transfected L cells using a standard (51)Cr release assay. RESULTS: Optical density values (mean (SD)) of sera from patients with UC (1.40 (0. 52)) and PSC (1.65 (0.12)) were significantly higher than those from healthy volunteers (0.32 (0.28)) (p<0.05), CD (0.50 (0.34)) (p<0.05) and PBC (0.14 (0.09)) (p<0.05). Values in UC decreased with clinical improvement. The ADCC activity of UC sera correlated well with antibody titre against this synthetic peptide. CONCLUSIONS: Anti-TM antibody was detected in UC sera by a specific peptide based ELISA with high reproducibility. This peptide may be an antigenic epitope of TM involved in the immunopathogenesis of UC and, perhaps, PSC.


Subject(s)
Antibody-Dependent Cell Cytotoxicity/immunology , Autoantibodies/immunology , Colitis, Ulcerative/immunology , HLA-DP Antigens/immunology , Tropomyosin/immunology , Adolescent , Adult , Aged , Animals , Case-Control Studies , Cholangitis, Sclerosing/immunology , Crohn Disease/immunology , Enzyme-Linked Immunosorbent Assay/methods , Epitopes/immunology , Female , Humans , L Cells/immunology , Liver Cirrhosis, Biliary/immunology , Mice , Middle Aged , Reproducibility of Results
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