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Biomedical subjects

A D Ho

Publications and source records attributed to A D Ho.

At least 235 records · Page 13Linked to original sources
PubMed1984

Plasma and intracellular levels of lactate dehydrogenase, phosphohexose isomerase and lysozyme activity in acute leukemia.

Plasma and intracellular levels of lactate dehydrogenase (LDH), phosphohexose isomerase (PHI) and lysozyme activities were investigated in 20 patients with acute myelocytic leukemia (AML), 18 patients with acute lymphatic leukemia (ALL) and 10 patients with chronic myelocytic leukemia in blast transformation (CML/BT). Though the plasma levels of LDH and PHI in all patients with acute leukemia were elevated as compared to control persons there was no distinctive pattern which could be of use in the classification of acute leukemia. On the other hand the intracellular levels of these enzymes could be of value in classifying acute leukemia. The leukemic lymphoblasts were characterized by low levels of PHI and lysozyme as compared to leukemic myeloblasts or to normal lymphocytes (p less than 0.01). The LDH/PHI ratio is also significantly higher in leukemic lymphoblasts than in leukemic myeloblasts or in normal lymphocytes (p always less than 0.01). These characteristics might also be made use of in identifying the blasts of CML/BT als "lymphoid" or "myeloid" in corresponding cases.

Acute Disease↗
PubMed1984

Cytostatic activity of steroid linked nitrosoureas.

First investigations on the therapeutic activity of a new group of steroid-linked N-(2-chloroethyl)-N-nitrosocarbamoyl-L-alanine esters (CNC-L-alanine esters) in a nitrosourea-sensitive rat leukemia (L 5222) characterized by a relatively high content of glucocorticoid binding sites are presented. Despite a considerable range of optimal and toxic doses of the different analogs, the respective therapeutic ratios do not appear to be significantly influenced by the nature of the carrier molecules to which CNC-L-alanine is attached. However several steroid-linked representatives are distinctly more active than CNC-L-alanine. The androsterone-3-ester and the dihydrotestosterone-17-ester, in particular effected high percentages of cures in contrast to CNC-L-alanine.

Animals↗
PubMed1984

DNA strand breakage and ADP-ribosyl transferase mediated DNA ligation during stimulation of human bone marrow cells by granulocyte-macrophage colony stimulating activity.

ADP-ribosyl transferase (ADP-RT) is a chromatin-bound nuclear enzyme catalysing the transfer of ADP-ribose from NAD+ to chromatin proteins. The enzyme is activated by DNA strand breaks and has been suggested to have roles in both DNA repair (via its effect on DNA ligase II) and in differentiation. We recently demonstrated that specific inhibitors of ADP-RT preferentially inhibit differentiation of human granulocyte-macrophage progenitor cells to the macrophage lineage and that the specific proliferation/differentiation stimulus granulocyte-macrophage colony stimulating activity (GM-CSA) activates ADP-RT in human marrow cells within 3 h of exposure. The purpose of this study was to investigate the role of ADP-RT in monocyte-macrophage differentiation. By altering the time of addition of ADP-RT inhibitor it was demonstrated that maximal inhibition of macrophage differentiation only occurs when the inhibitor is added within the first 24 h of culture. This suggests that it is an early event during the induced differentiation of granulocyte-macrophage progenitor cells which requires ADP-RT. Fluorometric assay of the level of DNA strand breaks showed that GM-CSA induces DNA strand breaks which are rapidly ligated only if ADP-RT is available. These data and those of our earlier studies suggest that DNA rearrangement may be involved in differentiation of granulocyte-macrophage progenitors to the monocyte-macrophage pathway. Such a DNA rearrangement could provide a molecular basis for commitment of multipotent progenitors to a single lineage.

Bone Marrow↗
PubMed1984

Mitoxantrone in relapsed and refractory acute leukemia.

Mitoxantrone is a relatively new synthetic anthracenedione derivative with intercalating properties. An in vitro study with established leukemia cell lines indicated that DNA strand breaks were caused by mitoxantrone; when these were progressive after the initial insult, the cell line was sensitive to the drug. Clinical trials involved patients with relapsed and/or refractory acute leukemia. None of the patients receiving a single slow infusion of mitoxantrone achieved a complete remission. A five day treatment regimen produced an overall response rate of 48% with a complete remission rate of 25%. Toxicity in these preliminary studies was limited compared to that expected with the anthracycline antibiotics. Alopecia and nausea were the only commonly observed side effects. The trials were too short, however, to evaluate possible cardiac toxicity. Mitoxantrone is an acute and relatively nontoxic agent that merits further study to identify its role in the first line therapy of acute leukemia; such studies are underway.

Acute Disease↗
PubMed1983

Glucocorticoid receptor level, terminal deoxynucleotidyl transferase activity and initial responsiveness to prednisone and vincristine in leukemia.

We have investigated glucocorticoid receptor (GR) level, terminal deoxynucleotidyl transferase (TdT) activity and the initial responsiveness to prednisone and vincristine in 31 patients with acute lymphatic leukemia (ALL) and with chronic myelogenous leukemia in blast transformation (CML/BT). All 11 patients with low levels of GR (5,000 binding sites per cell) were resistant to this initial treatment whereas 13 of the 20 patients with high levels of GR responded readily. The correlations between clinical responsiveness and TdT activity were significant to the p less than 0.005 level but there was no linear correlation (r = 0.3427) between GR-level and TdT activity. High levels of both GR and TdT seemed to be associated with better prognosis in patients with these leukemias. Thus the determination of GR and TdT might help selection of patients likely to respond to prednisone and vincristine in ALL and CML/BT.

Adolescent↗
PubMed1983

Autologous transplantation of a bone marrow graft manipulated by chemoseparation to eliminate residual tumor cells.

An autologous bone marrow transplantation (ABMT) was performed in a 45-year-old male patient with AML in therapy-resistant first relapse including CNS-disease. The marrow graft was harvested 18 months before, at the beginning of first remission, and was subjected to an in-vitro incubation with 4-hydroperoxycyclophosphamide (4-HC) prior to cryopreservation to eliminate residual clonogenic tumor cells. After myeloablative therapy with high-dose Cyclo-phosphamide (CY), total body irradiation (TBI) and intrathecal application of Methotrexate (MTX), the manipulated marrow graft was reinfused. The myelopoietic reconstitution started already 6 days after ABMT and was completed 40 days thereafter. There is evidence for a complete remission in marrow and spinal fluid observed over a period of 4 months.

Bone Marrow↗
PubMed1983

Effect of thymosin and phorbol ester on purine metabolic enzymes and cell surface phenotype in a malignant T-cell line (MOLT-3).

Previous studies have shown that thymosin (fraction 5) is able to induce surface differentiation markers on normal murine bone marrow T-cell precursors. Phorbol ester (TPA) promotes differentiation of human leukaemic lymphoblasts as assessed by changes in phenotypic surface markers and terminal deoxynucleotidyl transferase (TdT) activity. Changes in levels of purine degradative enzymes occur during T-cell maturation with a fall in adenosine deaminase (ADA) and a rise in purine nucleoside phosphorylase (PNP) and 5'nucleotidase (5'NT) activities. We have now investigated the effect of both thymosin (fraction 5) and TPA on a human leukaemic T-cell line (MOLT-3) in expression of the surface antigenic markers NAI/34 (a marker of immature thymocytes) and OKT11 (which corresponds to the sheep erythrocyte receptor) and of TdT, ADA, PNP and 5'NT. Thymosin (after 96 h incubation) significantly reduced the number of cells positive for NAI/34 from 76.0 +/- 5.0% (mean +/- S.D.) to 51.3 +/- 9.3% (p less than 0.01) but caused no significant change in the percentage of TdT or OKT11 positive cells. ADA levels were significantly reduced (p less than 0.02) and 5'NT levels were significantly elevated (mean increase 303 +/- 142% of control, p less than 0.001) but the increase in PNP level (108 +/- 16.8% of control) was not significant (p greater than 0.05). On the other hand, TPA (after 96 h incubation) significantly reduced cells positive for NAI/34 from 76.0 +/- 5.0 to 30.0 +/- 9.8% and for TdT from 81.7 +/- 6.5 to 17.3 +/- 4.4% and increased OKT11 positive cells from 67.3 +/- 5.5 to 89.0 +/- 2.8% (p less than 0.001). TPA caused no significant change in 5'NT or ADA levels (p greater than 0.05), but an increase in PNP level to 158 +/- 12.9% of control (p less than 0.02). The present study demonstrates for the first time that the normal thymic hormone, thymosin is capable of inducing differentiation changes in thymic derived human leukaemic cells. In addition, it shows that different inducing agents may cause different patterns of differentiation changes in leukaemic cells.

5'-Nucleotidase↗
PubMed1983

Sequential studies on the role of mitoxantrone in the treatment of acute leukaemia.

Mitoxantrone, a synthetic and newly available intercalating agent, was shown to have activity in relapsed or refractory acute leukaemia, which is apparently schedule dependent. A 5-day treatment programme demonstrated impressive activity, with a 50% response rate and 24% complete remissions. Toxicity in these preliminary studies was limited compared to that expected with the anthracycline antibiotics. Mitoxantrone is an active and relatively non-toxic agent which merits further assessment prior to its incorporation in first-line therapy of acute leukaemia.

Acute Disease↗
PubMed1983

Biochemical and immunological differentiation of human thymocytes induced by thymic hormones.

Changes in levels of purine degradative enzymes have been shown to occur during T-cell maturation in both rats and humans with a fall in adenosine deaminase (ADA) and a rise in purine nucleoside phosphorylase (PNP) and 5'-nucleotidase (5'NT) activities. We have investigated the effects of four thymic factors: thymosin fraction 5 (TMS-F5); thymosin alpha 1 (TMS-alpha 1); thymopoietin pentapeptide (TP-5); and thymic conditioned medium (CM) on TdT activity, purine enzyme levels and the phenotypic markers OKT3 (a marker for mature T cells) and NA1/34 (which reacts with immature cortical thymocytes) in human thymocytes and in the lymphoid leukaemic cell lines RPMI-8402 and JM1 (derived from Thy-ALL). All four thymic factors caused one or more maturation change in human thymocytes, e.g. TMS-F5 caused a significant increase in OKT3 expression, TMS-alpha 1 a fall in TdT and ADA activities and a rise in OKT3-positive cells, TP-5 an increase in PNP and CM a rise in 5'NT activity. TMS-F5 also caused a marked elevation of 5'NT in both the T lymphoblastic lines (P less than 0.001). On the other hand the non-physiological phorbol ester, 12-O-tetradecanoyl phorbol acetate (TPA), a tumour promotor with potency of inducing differentiation in some leukaemic cell lines, induced changes in both normal thymocytes and in the leukaemic line JM1 were inconsistent with maturation, e.g. a fall in the percentage of OKT3 cells. These observations suggest that maturation of normal thymocytes might proceed stepwise, each step requiring at least one of the thymic hormones. Although thymosin also induces differentiation changes in a malignant lymphoid line, the pattern of these differs from that induced in their normal counterparts.

Animals↗
PubMed1982

Immunocytochemical method for the detection of terminal deoxynucleotidyl transferase in acute leukemia.

Terminal deoxynucleotidyl transferase (TdT) has become an important marker for the classification of acute leukemias. Originally detected by a biochemical assay, the presence of this enzyme in leukemia can now be detected by making use of a highly specific antibody and by applying the immunofluorescence method. In this study, an attempt was made to apply the unlabeled peroxidase-antiperoxidase (PAP) technique for the examination of TdT positive cells. We have optimized this method and have compared the different assays - biochemical, immunofluorescence, and immunocytochemical (PAP) - in ten patients with acute leukemia. The results obtained from all three methods are in accordance with one another, but the PAP method is a further simplification for the detection of TdT in the routine diagnostic of acute leukemias.

Acute Disease↗
PubMed1982

Therapeutic and prognostic implications of glucocorticoid receptors and terminal deoxynucleotidyl transferase in acute leukemia.

Glucocorticoid receptors (GR) have been reported to predict clinical responsiveness to glucocorticoid therapy and to possess prognostic significance in leukemia. A raised level in terminal deoxynucleotidyl transferase (TdT) also seems to suggest clinical responsiveness to prednisone and vincristine therapy. We have investigated these two biochemical markers in the leukemic blasts in 23 patients with acute myeloid leukemia (AML) and in 19 patients with acute lymphoblastic leukemia (ALL) and have compared the binding data with clinical glucocorticoid sensitivity, with response to chemotherapy, with survival and with TdT. In 25 of these patients we have also investigated the in vitro glucocorticoid sensitivity by measuring dexamethasone inhibition of radiolabelled uridine and thymidine incorporation into the leukemic blasts. In patients with AML, GR levels were mostly high but did not correlate with the in vitro sensitivity, response to chemotherapy or survival. On the other hand, in the 19 patients with ALL there seemed to be a correlation between GR and in vitro sensitivity and between GR and clinical responsiveness to glucocorticoid therapy. Furthermore, patients with low levels of either TdT or GR seemed to be associated with poor prognosis. TdT activity and GR, however, did not associate with one another. TdT is a useful marker for the identification of lymphoblasts but, by itself, is not connected with glucocorticoid sensitivity. Gr, when applied to ALL, could supplement TdT determination by predicting response to therapy.

Adolescent↗
PubMed1982

Intracellular lactic dehydrogenase and phosphohexose isomerase activity in leukaemia and malignant lymphoma.

Intracellular activities of total lactic dehydrogenase (LDH) and phosphohexose isomerase (PHI) were investigated in the leukaemic cells of 14 patients with acute myeloid leukaemia (AML), five with chronic myeloid leukaemia (CML), seven with acute lymphoblastic leukaemia (ALL), 19 with chronic lymphocytic leukaemia (CLL), 16 with leukaemic non-Hodgkin's lymphoma (NHL) and in the lymphocytes of 14 normal persons. Intracellular total LDH-activity of the blasts of AML and ALL was in the same range as the normal lymphocytes. Patients with CLL and NHL had significantly lower levels (P less than 0.01) of total intracellular LDH than the controls. Intracellular PHI activity was consistently lower in the lymphoid malignancies (ALL, CLL, NHL) than in normal lymphocytes (P less than 0.05), or in leukaemic myeloblasts (P less than 0.01). The intracellular LDH/PHI index of the leukaemic lymphoblasts was significantly elevated as compared to lymphocytes from normal subjects (P less than 0.0001) or to leukaemic cells from patients with AML (P less than 0.001), with CLL (P less than 0.0001) or with NHL (P less than 0.001). The patients with CLL and NHL, on the other hand, had significantly lower levels of LDH/PHI ratio than the normal subjects (P less than 0.0001 and P less than 0.025 respectively).

Adolescent↗
PubMed1981

[Significance of terminal deoxynucleotidyl transferase in patients with acute leukemia and malignant lymphoma: results obtained by immunofluorescence assay (author's transl)].

Deoxynucleotidyl transferase (TdT) is of diagnostic and therapeutic importance in acute leukaemia and malignant lymphoma. Previous methods for determining TdT activity by biochemical assay are complex and require the use of radioactive substances. There now is available a specific antibody for immunofluorescent demonstration of TdT. The two methods were compared on samples from 43 patients with leukemia or malignant lymphoma. There was very good agreement. High TdT activity was found in 12 of 14 patients with acute lymphatic leukemia and in one of two with acute undifferentiated leukaemia. TdT activity was absent with acute and chronic myeloid leukaemia, chronic lymphatic leukaemia and non-Hodgkin's lymphoma of low malignancy. Immunofluorescence assay, although its results are of similar significance to that obtained with the biochemical tests, is simpler to do. Furthermore, it can be done on normal bone-marrow smear or lymph-node preparations and can be correlated with the morphological findings.

DNA Nucleotidylexotransferase↗
PubMed1981

Glucocorticoid receptors and sensitivity in leukemias.

In an attempt to investigate the utility of glucocorticoid receptor determination to predict clinical responsiveness in human leukemias we have studied glucocorticoid receptors in the leukemic cells from 46 patients and in the lymphocytes from 18 normal donors. In the normal lymphocytes there were 3,875 (Median) specific binding sites per cell. The blasts from 17 patients with ANLL had on average higher levels of binding sites per cell (Median = 7,250, range: 0 to 15,295) than the other leukemias. Of the 15 patients with CLL, six had received glucocorticoid treatment for 3 to 5 years. Their lymphocytes had lower number of receptors (Median = 2,000) than the other cases which were newly diagnosed (Median = 4,500). Four patients had ALL/AUL, three patients had blast crisis as terminal phase of CML, and seven had leukemic Non-Hodgkin lymphomas (Median = 3,500 sites/cell). In 24 patients we have also studied the in vitro sensitivity of the leukemic cells to dexamethasone. There was no marked correlation between glucocorticoid receptor levels and in vitro sensitivity. An attempt to correlate receptor levels with clinical responsiveness demonstrated that glucocorticoid receptor determination might be of value in patients with lymphoid malignancies but probably not in patients with other leukemias.

Adult↗
PubMed1980

[Cholelithiasis in a previously not described case of congenital erythropoietic porphyria (author's transl)].

The signs of congenital erythropoietic porphyria (Günther) had their onset at the age of two in a male patient born in 1934: there were blisters and scars after exposure to sunlight, red urine, marked cutaneous pigmentation, acral mutilation, lanugo and erythrodontia. Porphyrin levels in red blood cells and urine confirmed the diagnosis. Splenectomy was performed in 1966 for hypersplenism and haemolysis. No transfusion has been necessary since and the haemolysis has completely disappeared, but signs of ineffective erythropoiesis have continued. Cholecystectomy with choledochal revision was performed because of right upper abdominal colics, fever and biliary stasis in 1977: five partly pigmented, partly mixed gall-stones were removed. The latter had a black, friable centre with high porphyrin content and a cholesterol coating. Thus, as in other chronic haemolyses, pigmented gall-stones may also occur in congenital erythropoetic porphyria.

Adult↗
PubMed1980

Capping of lymphocytes in patients and carriers of Duchenne muscular dystrophy.

Recent results showed that Duchenne muscular dystrophy is probably associated with a generalized membrane defect. The capping phenomenon in lymphocytes indicates normal intramembrane protein mobility and disturbances of this phenomenon are is believed to reflect membrane alterations. We have investigated capping in lymphocytes from 19 patients with Duchenne muscular dystrophy, 13 carriers, 8 patients' sisters, 14 patients' aunts and 52 normal controls. All 19 patients showed a reduction in capping both with fluorescein conjugated polyvalent goat antiserum (mean +/- SD = 18.5 +/- 5.1% and with fluorescein labeled Concanavalin A (mean +/- SD = 10.8 +/- 3.1%) as compared to controls. Normal persons (n = 52) have a mean of 50.2 +/- 9.9% (SD) capping with polyvalent anti-immunoglobulin (range: 32--72.5%) and 25.6 +/- 3.6% with F-Con A (range: 18.5--31.5%). 12 of the 13 mothers, as well as 5 of the 8 patients' sisters, also exhibited decreased lymphocyte capping to the same extent as the patients. Creatine kinase activity (CK) was elevated only in 4 mothers and 2 of the sisters. Our results indicate that this method might be of value in detecting carriers and can yield less false negative results as the CK-activity test.

Adult↗
PubMed1980

Determination of glucocorticoid receptors in human leukemias.

Determination of steroid receptors has been used to predict steroid sensitivity in various neoplasias. In an attempt to investigate its applicability in human leukemias we have studied glucocorticoid receptors in the leukemic cells from 23 patients with various hematologic neoplasias and in the lymphocytes from 18 normal donors. Specific glucocorticoid binding in intact cells was determined by a whole cell competitive binding assay. Normal lymphocytes have about 4,611 specific binding sites per cell. The blasts from 9 patients with acute myelogenous leukemias (AML) have strongly varying high levels of specific binding sites, ranging from 4,817 to 15,416 per cell. Of the 13 patients with chronic lymphocytic leukemia (CLL), 5 have received glucocorticoid treatment for years and were clinically resistant to glucocorticoid. Their lymphocytes have lower specific binding sites (range: 2,047 to 3,999) than the other CLL cases which were newly diagnosed (range: 3,734 to 11,020). Our results suggest that determination of glucocorticoid receptors might be of value in predicting clinical responsiveness in leukemias.

Dexamethasone↗