Biomedical subjects

T Hotta

Publications and source records attributed to T Hotta.

At least 217 records · Page 12Linked to original sources

PubMed1992

Treatment of hairy cell leukemia with deoxycoformycin (YK-176). The Deoxycoformycin (YK-176) Study Group.

Eleven patients with hairy cell leukemia (HCL) were treated with YK-176 (2'-deoxycoformycin) at a dose of 5 mg/m2 by intravenous injection every week or every other week. Patients received a median of eight (range 4-19) injections of YK-176. Five patients had previously been untreated, four of whom had massive splenomegaly. Six patients had previously been treated, four with interferon-alpha (IFN-alpha) or IFN-alpha and chemotherapy and two with prednisolone. Two patients had had splenectomies. Five patients achieved complete remission (CR) and six, partial remission (PR) according to WHO criteria (remission rate 100%, 95% confidence interval (CI) 74-100%). All six neutropenic patients recovered > 1,500/microliters neutrophils, six of seven anemic patients recovered > 12.0 g/dl hemoglobin and five of nine thrombocytopenic patients recovered > 100,000/microliters platelets following the treatment. According to the response criteria for HLC, five patients achieved CR, two PR and four minor response. The overall remission (CR + PR) rate was 64% (95% CI 35-85%). The CR and PR have lasted from > 30 to > 718 days (median, > 281 days) so far with no relapses. Of four patients previously treated with IFN-alpha, two achieved CR and one, PR. All patients were alive with a median survival time of > 290 days from treatment (range > 50- > 763 days). The treatment was generally well tolerated. Mild to moderate nausea, vomiting, appetite loss and general fatigue were experienced in two patients, skin rash in one and a transient fever in three. YK-176 was a highly active agent in the treatment of HCL.

Adult↗

PubMed1992

Remission induction of acute promyelocytic leukemia by all-trans-retinoic acid: molecular evidence of restoration of normal hematopoiesis after differentiation and subsequent extinction of leukemic clone.

Sequential molecular and cellular changes during remission induction were investigated in a case of acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA). By means of clonality analysis, the assessment of the retinoic acid receptor alpha gene alterations, as well as conventional cytologic studies, it was demonstrated that remission induction of APL by ATRA proceeds in two steps: first, the differentiation of the leukemic clone to mature granulocytes and its subsequent extinction; second, proliferation/differentiation of the residual normal clones to restore polyclonal hematopoiesis.

Adult↗

PubMed1992

[A case of multiple myeloma with intracerebral metastasis].

Compared to leukemia, malignant lymphoma and other hematogenous tumors, multiple myeloma rarely metastasizes to the central nervous system. Intracerebral metastasis without involvement of the cranium itself is rarer. We report a case of Ig-G k-type multiple myeloma with metastasis to the left frontal lobe extending to the right basal ganglia without involvement of the cranium. A 71-year-old male complained of exertional dyspnea and lumbago. His laboratory data revealed hyperproteinemia and an abnormal increase in Ig-G (6117mg/dl) in his serum. Serum protein immunoelectrophoresis revealed an IgG k-type band, and Bence-Jones protein was detected in his urine. MMPP, VMCP, VIPP and MP chemotherapy was given, and serum IgG level decreased to a normal range. 21 months after his first admission, incontinence, disorientation, gait disturbance and apathy developed. CT-scan showed an isodense lesion with massive edema in the left frontal lobe and right basal ganglia. On MRI, a Gd-DTPA enhancing lesion was detected extending from the left frontal to the opposite frontal lobe through the splenium. No abnormal skull punched out lesions were noted. Left frontal lobectomy was performed. Histopathology revealed plasmablastic myeloma cells with clear nucleole and eccentric nucleus in the cerebrum. He was diagnosed as having intracerebral metastasis of multiple myeloma without involvement of the cranium. Unfortunately, he died of pancytopenia and pneumonia. Our case suggests the possibility of metastasis via blood into the cerebrum.

Aged↗

PubMed1992

[Hairy cell leukemia successfully treated with 2'-deoxycoformycin following refractoriness to splenectomy and alpha-interferon therapy].

A 34-year-old man was admitted in May, 1989 because of severe left upper abdominal pain, which was caused by advanced splenomegaly. On initial examinations, peripheral blood showed leukocytosis (13,400/ml) including 60% hairy cell which also infiltrated in bone marrow (64%). The patient was diagnosed as having hairy cell leukemia (Japanese type) of B-cell lineage. Splenectomy was performed as an initial treatment. The effect of splenectomy was only palliative and transient leukocytosis progressed thereafter. alpha-interferon and bestrabucil (KM 2210) were then adopted for 4 months respectively. The effects were, however, unsatisfactory. Subsequently the patient was treated successfully with 2'-deoxycoformycin (DCF). Complete remission was attained following 12 injections of 7.5 mg/body of DCF during 5 months and durable remission persists for more than 6 months without maintenance therapy. The side effect was minimum.

Adult↗

PubMed1991

Aphidicolin, an inhibitor of DNA replication, blocks the TPA-induced differentiation of a human megakaryoblastic cell line, MEG-O1.

The commitment process of a human megakaryoblastic cell line (MEG-O1) induced with phorbol ester, TPA, was investigated with special reference to glycoprotein (GP) IIb/IIIa expression, multinuclear formation, and DNA replication. TPA (10(-7) mol/L) completely inhibited cellular division in MEG-O1, but did not suppress de novo DNA synthesis. Two days' culture with 10(-7) mol/L TPA was sufficient for MEG-O1 cells to initiate an irreversible commitment process. These cells could not resume cell growth and expressed GP IIb/IIIa antigen; some of them showed multinuclear form and DNA polyploidy even after removal of TPA from the culture medium. DNA histogram analysis showed that, upon treatment with TPA, the percentage of cells whose DNA ploidy was more than 8N was 5 to 10 times higher than that of control cells. Precise analysis using cell size fractionation by centrifugal elutriation method showed that there was strong correlation between the percentage of multinuclear cells and DNA polyploidy in TPA-treated cells. The percentage and staining intensity of GP IIb/IIIa and other megakaryocytic phenotypes such as von Willebrand factor and PAS staining were highest in large multinuclear cell populations, suggesting that these cells are the most differentiated population in this system. In TPA-treated cells, the activity of DNA polymerase alpha, a marker for cell growth, remained at the same level as in control cells. Aphidicolin, a specific inhibitor of DNA polymerase alpha, completely inhibited the differentiation induction of MEG-O1 cells with TPA measured by either GP IIb/IIIa expression or multinuclear cell formation. Therefore, DNA replication appears to be involved in the process of phenotypic expression as well as endomitosis in megakaryocyte differentiation of MEG-O1 cells. Aphidicolin was also effective in inhibiting megakaryocytic differentiation of other leukemia cell lines such as human erythroleukemia (HEL) and K562 cell lines induced with TPA, suggesting the close interplay of DNA replication and phenotypic expression in megakaryopoiesis.

Aphidicolin↗

PubMed1991

Augmentation of cytotoxic activity by combination with interleukin 2 and interferon gamma.

The synergy of cytotoxic activity by interleukin 2 (IL-2) and interferon gamma (IFN-gamma) was evaluated in human peripheral blood mononuclear cells (PBMC) and spleen cells. PBMC incubated with IL-2 (10 IU/ml) and IFN-gamma (200 IU/ml) for 4 days showed the stronger cytotoxic activity against K562, MOLT-4 and Daudi cells. Combination with IL-2 and IFN-gamma induced stronger activity than IL-2 or IFN-gamma alone. In order to investigate the sequential roles of IL-2 and IFN-gamma in the killer cell function, the cells were stimulated with IFN-gamma after washing of IL-2 or stimulated by IFN-gamma at various timing and duration without washing of IL-2. IL-2 was essential to induce the synergistic effect of IL-2 and IFN-gamma to cytotoxic activity. The similar augmentation of cytotoxic activity was observed by the addition of IFN-gamma at any incubation periods with IL-2, compared with stimulation with IL-2 or IFN-gamma alone. The phenotypes of the killer cells by stimulation with IL-2, IFN-gamma alone or IL-2 plus IFN-gamma were mainly CD2+, CD16+, indicating the activated natural killer cells.

Cytotoxicity, Immunologic↗

PubMed1991

von Recklinghausen neurofibroma produces neuronal and glial growth-modulating factors.

Two kinds of novel neural trophic factors were currently detected in von Recklinghausen neurofibroma (NF1) extracts. One of the two was a growth factor, neuroblastoma growth factor (Mr less than 5 kDa), which promotes the proliferation of human neuroblastoma cell and survival and neurite-extension of rat cortical neurons, but differently from nerve growth factor (NGF) or NGF-like factors. The other one was a glial growth inhibitor (Mr = 100 kDa), which suppresses the growth of glioma cell lines, astrocytoma, glioblastoma, oligodendroglioma and Schwannoma. These factors do not appear to be previously identified cytokines or growth factors such as interleukins, granulocyte colony-stimulating factor, NGF and fibroblast growth factor. There was also detectable ciliary neurotrophic factor-like activity in the extracts. The primary cause of high contents of these factors in NF1 is not known, but may relate to fundamental mechanisms controlling growth and differentiation of neurons and glias during development of nervous system.

Animals↗

PubMed1991

Glutathione and cellular response of ACNU-resistant rat glioma sublines to drugs and radiation.

Three ACNU-resistant sublines (R1, R3 and R12) from rat glioma 9L cells showed cross-resistance to vinblastine, adriamycin, and VP-16. Among these, the R3 subline also acquired radioresistance under aerobic conditions. Total glutathione levels in these sublines were elevated 2- to 3-fold. Treatment of the cells with BSO, a specific inhibitor of GSH synthesis, resulted in decreased intracellular total glutathione levels in all 4 cell lines to about 10% of control levels. However, sensitivity to radiation or to chemicals did not change accordingly. Treatment of 9L cells with OTZ, a precursor of cysteine, resulted in a rise in intracellular GSH levels but it did not correlate with sensitivity to X-ray or to ACNU. These results suggest that, in terms of cellular sensitivity to radiation or ACNU, total glutathione level alone cannot serve as a predictive indicator.

Animals↗

PubMed1991

Chemosensitivity testing with highly purified fresh human tumour cells with the MTT colorimetric assay.

A major problem associated with the succinate dehydrogenase inhibition (SDI) test using tetrazolium dye (MTT) as a cancer chemosensitivity testing is the contamination of non-malignant cells in the tumour tissues. Highly purified fresh human tumour cells from 44 solid tumours and 24 malignant ascites were used for the MTT assay. The purity of tumour cells was greater than 90% after separation on Ficoll-Hypaque and Percoll discontinuous gradients. The OD570 obtained from tumour cells alone was higher than that from non-malignant cells. The chemosensitivity of tumour cells was distinct from that of non-malignant cells. Moreover, the chemosensitivity of highly purified tumour cells was also distinct from that of non-purified cells just separated from tumour tissues. 31 of the 68 patients had evaluable lesions, and received cancer chemotherapy according to the results of MTT assay using highly purified tumour cells. A clinical response was obtained in 10 of the 31 patients (response rate = 32.3%, 5 complete responses, 5 partial responses).

Adolescent↗

PubMed1991

Augmented production of granulocyte-macrophage colony-stimulating factor and alpha/beta interferon in mice inoculated with heat-killed Corynebacterium liquefaciens.

We demonstrated that heat-killed Corynebacterium liquefaciens bacteria, as a known potent host immune activity modulator, stimulate spleen cells to produce granulocyte-macrophage (GM) colony-stimulating factor (CSF) and another CSF with similar activity, as well as alpha/beta interferon, when injected intravenously into mice. Alpha/beta interferon was shown to be produced by C. liquefaciens-activated plastic-G-10 column-adherent cells (A cells) in a thymus-independent manner. In contrast, augmented production of GM-CSF required the action of C. liquefaciens-activated T lymphocytes that collaborated with normal A cells. Non-T spleen cells from C. liquefaciens-stimulated athymic mice, however, produced an alternative CSF that partially replaced GM-CSF. Correspondingly, the numbers of GM-producing CFU developing in cultures of spleen cells from C. liquefaciens-treated euthymic or athymic mice were 10 to 30 times higher than those in cultures of spleen cells from untreated mice. These results suggest that gram-positive rods such as C. liquefaciens activate T and A cells for production of multiple cytokines and that potential cooperative actions of these cytokines underlie the known immunomodulatory action of coryneforms.

Animals↗

PubMed1991

Successful treatment of hemosiderosis with regular phlebotomy and recombinant human erythropoietin. Case report and ferrokinetic studies.

A 55-year-old female patient with hemosiderosis induced by administration of excessive doses of parenteral iron was successfully treated with regular phlebotomy combined with recombinant human erythropoietin (rHuEPO). Ferrokinetic data before therapy showed 28.0 mumol/l of serum iron, 4.1 mumol/l of unsaturated iron-binding capacity, 4,060 ng/ml of serum ferritin, 148 min of plasma iron disappearance time, 45% of red cell iron utilization and 0.4 mg/kg/day of plasma iron turnover rate. She had 300-ml phlebotomies, first every other week then weekly, and subcutaneous injections of rHuEPO twice a week. Two years later, the total volume of phlebotomized blood reached 31 liters and her ferrokinetic data showed: serum iron 8.6 mumol/l, iron-binding capacity 39.6 mumol/l, serum ferritin 277 ng/ml, plasma iron disappearance time 52 min, red cell iron utilization 100% and plasma iron turnover rate 0.5 mg/kg/day. During the phlebotomy therapy, her hemoglobin levels were maintained above 12 g/dl. No adverse effect due to rHuEPO occurred. These findings provide evidence for the efficacy of rHuEPO in multiple phlebotomy therapy for hemosiderosis and may open new avenues for its clinical application.

Bloodletting↗

PubMed1991

Outcome of primary central nervous system lymphoma--a study of 32 patients.

The outcomes in 32 cases of histologically diagnosed primary central nervous system lymphoma were investigated. The 1-, 2-, and 5-year survival rates were 54, 36, and 8%, respectively. Good outcome was indicated by extensive surgical removal with 50-Gy irradiation and lower ages. 61% of patients receiving radiation therapy suffered recurrence within 1 year. The incidence of multiple lesions increased at recurrence. These lesions were almost all remote from the initial site in the brain, occurring more frequently in the central part of the supratentorial regions near the ventricle. Multiple lesions recurred more rapidly than single lesions. Longer survival times were indicated by a long tumor-free period after initial treatment. Extensive surgical removal results in long survival times for patients with a localized single tumor in the early stage. Radiochemotherapy should be given as part of the initial treatment.

Adolescent↗

PubMed1991

[Establishment of ACNU-resistant rat gliosarcoma cell lines and their characteristics].

One of the most serious problems in cancer chemotherapy is the acquired drug resistance of tumor cells. In order to investigate the mechanism of acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), nine resistant cells were isolated from rat gliosarcoma 9L cells and characterized. ACNU-resistant cells were easily isolated after a single treatment even with low-dose ACNU (5 micrograms/ml). However, in spite of repeatedly high-pressure dose of ACNU, more than 30 fold increase to parental 9L cell resistance was not achieved. At this time, further increase in selection pressure resulted in cell death. The resistant ratios of these resistant cells were stable in the absence of ACNU for more than 1 year. Luria and Delbrück's fluctuation test indicated that the appearance of ACNU-resistant cells occurred spontaneously at a rate of (4.40-8.02) x 10(-7)/cell/generation. In karyotypic analysis, the mode was higher in the resistant cells than in 9L cells, but a homogeneously staining region or double minute chromosome, which was considered to be a result of gene amplification, was not observed. In growth kinetics, all the resistant cells except R1 and R12 cells had higher saturation density and plating efficacy than parental 9L cells. These findings seemed to be due to cellular modification associated with ACNU resistance.

Animals↗

PubMed1991

Cross-resistance patterns in ACNU-resistant glioma sublines in culture.

Three ACNU-resistant clones (R1, R3, and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU), no cross-resistance was observed for other alkylating agents, while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine, Adriamycin, and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells, and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study, this multidrug resistance could be explained by reduced intracellular uptake of these drugs, but there seemed little possibility that membrane P-glycoprotein, which usually is observed in typical multidrug-resistant cells, was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.

Animals↗

PubMed1991

Hypersensitivity of rat glioma sublines with acquired ACNU resistance to L-asparaginase.

Cell lines resistant to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) show a high degree of collateral sensitivity to L-asparaginase. The mechanism for this phenomenon was investigated by comparing the nutritional requirements and asparagine synthetase activity of the resistant sublines to those of parent cells. Nine ACNU-resistant sublines were isolated from rat glioma 9L cells after incubation with various concentrations of ACNU in Ham's F-12 medium. The 9L cells grew independently of asparagine, developing well in asparagine-deficient Dulbecco's modified Eagle's medium. In contrast, the growth rates of all nine ACNU-resistant sublines decreased under the same conditions and required the addition of 10(-4) M asparagine for maximum growth. Asparagine synthetase activity in the ACNU-resistant cells was much lower than in the 9L cells, suggesting that the requirement for asparagine in the resistant sublines was due to reduced activity of this enzyme. A growth-inhibition assay showed that the ACNU-resistant sublines were more sensitive to L-asparaginase than 9L cells by up to 2 x 10(5)-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.

Animals↗

PubMed1991

Cisplatin treatment renders tumor cells more susceptible to attack by lymphokine-activated killer cells.

We investigated whether tumor cell lysis by lymphokine-activated killer (LAK) cells was enhanced by treatment of the tumor cells with cisplatin (CDDP) in vitro. Tumor cells were treated with CDDP in vitro, and the cytotoxic activity for LAK cells was measured by 4-h 51Cr-release assay. The alterations of succinate dehydrogenase (SD) activity, and DNA,RNA synthesis of tumor cells were analysed. The susceptibility of CDDP-treated (2 micrograms/ml, 2h) Daudi and KATO-III cells to lysis by short term-cultured LAK cells was enhanced, as was the susceptibility of CDDP-treated (2 micrograms/ml, 12h) autologous tumor and Daudi cells to lysis by long term-cultured LAK cells. SD activity and DNA synthesis in tumor cells were impaired by 12-h treatment with 2 micrograms/ml of CDDP, whereas those were not altered by 2-h treatment with 2 micrograms/ml of CDDP. The enhancement of the susceptibility of CDDP-treated tumor cells to long term-cultured LAK cells was thus elucidated; it was shown to be due to alterations of the tumor cells with regard to their SD activity and DNA synthesis. It is suggested that the combined therapy with CDDP and LAK cells offers hope for increasing the response rate and the long-term survival of cancer patients.

Cisplatin↗

PubMed1991

[A case of RAEB-t treated by G-CSF showing complete remission after MST-16 treatment for subsequent reversible leukemia].

A seventy-five-year-old female with general fatigue, high fever and anemia was admitted. Her chest X-ray film revealed pneumonia. She was diagnosed as RAEB-t with the normal karyotype by peripheral blood film and bone marrow aspiration; 125 micrograms/ml of G-CSF was administered s.c. daily in order to increase neutrophil count because of the prolongation of pneumonia. Her blast cells in both peripheral blood and bone marrow showed a remarkable increase by G-CSF. After the cessation of G-CSF administration, blast cells decreased rapidly, and neutrophil count in the peripheral blood increased. Her pneumonia was then cured. After 5 months of stable hematological state, 60% of her bone marrow cells became occupied by blast cells again. So 2 consecutive courses of 14 days p.o. administration of 1,200 mg MST-16/day were tried. Three months after the first MST-16 trial, her bone marrow showed complete remission (CR) which lasted about 4 months. But she died of sepsis after the first relapse. Her bone marrow in CR still revealed several features of dyspoiesis.

Acute Disease↗

PubMed1991

Iron balance following recombinant human erythropoietin therapy for anemia associated with chronic renal failure.

Erythrokinetic changes before and after rHuEPO therapy in 15 anemic patients with chronic renal failure undergoing maintenance hemodialysis were analyzed by means of ferrokinetics and measurement of red cell mass and survival. To estimate the change in iron status no exogenous iron was administered during the observation period unless a lack of response due to iron deficiency was confirmed. During 13-29 weeks of therapy there was an increase in red cell mass from 12.5 +/- 1.7 mg/kg to 20.1 +/- 3.6 ml/kg, compatible with the increase in hematocrit from 21.5% to 31.8%. In ferrokinetics the plasma iron disappearance time (t1/2) shortened from 163 +/- 44 min to 92 +/- 24 min. The plasma iron turnover rate rose from 0.39 +/- 0.10 mg/dl per day to 0.56 +/- 0.11 mg/dl per day. Serum ferritin levels were decreased from 160 +/- 115 ng/ml to 26 +/- 22 ng/ml, although there was only one patient showing poor response to rHuEPO because of iron deficiency. The increase in red cell volume correlated with the decrease in serum ferritin levels (p less than 0.02). There was no significant difference in these ferrokinetic parameters between transfused and non-transfused patients not only before, but also after, rHuEPO therapy. It is suggested that an elevation of about 8 ml/kg of red cell mass (approx. 10% as hematocrit) exhausts iron stores in the majority of patients.

Adult↗