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Biomedical subjects

M G Macey

Publications and source records attributed to M G Macey.

At least 73 records · Page 4Linked to original sources
PubMed1992

Evaluation of the in vitro antiproliferative properties of four novel anthracyclines YM1, 3, 4 and 6 in human leukemia cell lines.

The antitumor activity of novel doxorubicin analogues YM1, YM3, YM4 and YM6 was evaluated against drug sensitive U937 monocytic leukemia and CCRF-CEM lymphoid leukemia cell lines, as well as drug resistant CEM/VLB100 lymphoid multidrug resistant leukemia cell line by a [3H]thymidine incorporation assay. Different antileukemic activities of these new anthracyclines were observed in our studies. These novel anthracyclines produced a dose- and time-dependent inhibition in all the leukemic cell lines tested, while YM1 and YM3 were more effective than YM4 and YM6 against all the leukemic cell lines. The antitumor activity of all these novel analogues was lower than that of doxorubicin or epidoxorubicin in drug sensitive leukemic cells. The relative resistance values (IC50 of resistant cell line/IC50 of sensitive parental cell line) of YM1, 3, 4 and 6 were 27, 7, 5 and 14 respectively. These were lower than the resistance values for ADM and EDR which were 45 and 40 respectively. YM3 had a similar antileukemic activity against the CEM/VLB100 drug resistant leukemic cell line to ADM or EDR with a lower relative resistance value and a slightly increased IC50 value. Our results suggest that YM3 may be used in high dose for the clinical treatment of leukemias with possible less cardiotoxicity as well as less drug resistance.

Antineoplastic Agents↗
PubMed1991

Is Cyclin Zeuthen's "division protein"?

Biochemical evidence is presented for the presence of cyclin in Tetrahymena. Zeuthen previously postulated the existence of a heat-labile "division protein" to explain heat-shock-induced division synchrony in Tetrahymena [(1964) Synchrony in Cell Division and Growth (Zeuthen, E., Ed.), pp. 99-158, Interscience, New York]. We show that cyclin is heat-labile in Tetrahymena and suggest that cyclin may be Zeuthen's division protein. Cyclin and cell cycle control is of interest in Tetrahymena because the division mechanism drives macronuclear amitosis, closed and acentric micronuclear mitosis, and cortical differentiation in this cell type.

Animals↗
PubMed1991

Multidrug resistance in haematological malignancies.

Many patients with haematological disorders develop resistance to the drugs used in the treatment of their condition. This resistance is often effective against a range of chemotherapeutic agents, hence the term multidrug resistance (MDR) is used. During the past ten years the mechanisms underlying the development of MDR have become better understood, and in this Review the current concepts of the factors contributing to MDR are examined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Gamma interferon augments functional and phenotypic characteristics of vitamin D3-induced monocytoid differentiation in the U937 human leukaemic cell line.

We studied the effect of gamma interferon on 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced differentiation of the human leukaemic cell line U937. Both phenotypic and functional aspects of 1,25(OH)2D3-induced differentiation were significantly augmented by gamma interferon (IFN). Gamma interferon had little effect alone but increased butyrate esterase staining and expression of CD14 antigen and the 40 kD Fc receptor (FcRII) in response to 1,25(OH)2D3. Ability to phagocytose IgG-opsonized bacteria, and superoxide burst in response to both IgG-opsonized bacteria and phorbol ester, was greater after incubation with both IFN and 1,25(OH)2D3 than with either agent alone. The degree of functional activation of cells showed a positive correlation with FcRII expression. In addition, IgG-induced generation of superoxide by differentiated cells was considerably reduced by pre-incubation with the anti-Fc receptor antibody IV3. We conclude that gamma interferon augments 1,25(OH)2D3-induced differentiation and functional activation of the U937 cell line. Increased functional activation may, in part, be due to up-regulation of surface FcR11.

Antigens, Differentiation, Myelomonocytic↗
PubMed1990

CD4 and CD8 subpopulation changes during high dose intravenous immunoglobulin treatment.

High doses of immunoglobulin, when given intravenously (IVIgG), influence lymphocyte subset numbers and function. T-lymphocytes may be subdivided into two functionally different groups, helper/inducer (CD4+) and suppressor/cytotoxic (CD8+). Considerable functional as well as phenotypic heterogeneity exists within the two major subsets. CD4+ cells have been further subdivided into helper/inducer and suppressor/inducer sets by the differential binding of two monoclonal antibodies 4B4 (CDw29) and 2H4 (CD45R). Similarly, the CD8+ subset may be subdivided into suppressor and cytotoxic populations by the differential binding of monoclonal antibodies which identify the C3bi receptor (CD11). During IVIgG treatment of patients with autoimmune thrombocytopenic purpura (ATP) the change in CD4/CD8, due to an absolute increase in CD8+ cells, has been shown to correlate with the response to treatment as determined by platelet increase. However, the total CD4+ and CD8- numbers may not reflect changes in their constituent subpopulations. To examine this possibility the CD4 and CD8 subpopulations were analysed in 15 ATP patients, during IVIgG treatment, using a double fluorescence technique. In 10 of these patients the in vitro response to pokeweed mitogen (PWM) and Staphylococcus aureus Cowan I (STA Cowan I) was determined. There was no correlation between the change in CD8+ subpopulations and response to treatment but there was a correlation between the CD4+ change and platelet increment. In addition there was a correlation between the 4B4/2H4 change and the in vitro response to PWM but no correlation with the response to STA Cowan I. These findings suggest that during IVIgG treatment the CD4+ 4B4+ helper/inducer population is influenced resulting in reduced T-dependent B-cell activation.

Adult↗
PubMed1990

Flow cytometric analysis of the functional ability of neutrophils from patients with autoimmune neutropenia.

Flow cytometry has been used to evaluate the functional ability of neutrophils and the expression of IgG Fc receptors (FcRII and FcRIII) in autoimmune neutropenia. Quantification of the neutrophil oxidative burst was made by assaying the production of 2'7'-dichlorofluorescein (DCF) from non-fluorescent 2'7'-dichlorofluorescein trapped within the cell, by flow cytometric analysis of cellular fluorescence. In the present study the DCF assay was used to examine the response of neutrophils to stimulation by opsonized and non-opsonized Staphylococcus aureus. In addition, the rate of uptake of S. aureus labelled with the red nuclear dye propidium iodide was determined. The presence of surface-bound immunoglobulin, which may affect the phagocytic capacity of the neutrophil, was also measured. No correlation between the neutrophil count and level of membrane-bound IgG or the rate of bacterial uptake was found. The studies were performed on twenty patients with autoimmune neutropenia, twelve with other autoimmune disorders and fourteen normal controls. The rate of uptake of bacteria was considered in relation to the expression of FcRII and FcRIII. Good correlation was found with the level of expression of FcRII, the major receptor for neutrophil activation, and the rate of uptake of bacteria (r = 0.64).

Autoimmune Diseases↗
PubMed1990

Effects of Porphyromonas gingivalis culture products on human polymorphonuclear leukocyte function.

Porphyromonas gingivalis culture supernate was found to induce homotypic agglutination of human polymorphonuclear leukocytes (PMN). Pretreatment of PMN with P. gingivalis supernate inhibited both the rate and the degree of agglutination induced by the secretagogues PMA and FMLP. Lipopolysaccharide from P. gingivalis upregulated the CR3 (Mac-1, CD11b) receptors on PMN. Treatment of glass-adherent PMN with P. gingivalis supernate did not alter their phagocytic capacity for P. gingivalis cells but when PMN were pretreated in suspension the cells adhered less well to glass and phagocytosis of those PMN that did adhere was reduced. P. gingivalis supernate treatment of PMN induced lysozyme release but the amount released during phagocytosis when supernate was present did not change. Neither P. gingivalis supernate nor LPS were cytotoxic for PMN. The data suggest that P. gingivalis factors could interfere with PMN elimination of this organism at the site of infection by inappropriately stimulating PMN, depressing phagocytosis and causing enhanced CR3 expression. The consequent agglutination or enhanced adherence could also lead to decreased phagocytic capacity of the adherent or agglutinated cells.

Antigens, Differentiation↗
PubMed1990

Interleukin-2 (IL-2) immunotherapy.

Various forms of immunotherapy have been employed for the treatment of cancer patients during the past 5 years, with recombinant interleukin-2 (IL-2) having been widely used in these treatment regimes. The progress of IL-2 immunotherapy is discussed.

Humans↗
PubMed1989

Role of the membrane-associated folate binding protein (folate receptor) in methotrexate transport by human KB cells.

The uptake of methotrexate by KB cells was observed to be dependent on time, temperature, and concentration of extracellular methotrexate. The Kd for methotrexate surface binding to KB cells was approximately 200 nM. Following exposure of KB cells to trace quantities of [3H]methotrexate for periods ranging from 6 min to 24 h, the cellular methotrexate was progressively formed into methotrexate polyglutamates and was bound to dihydrofolate reductase as well as to a particulate folate binding protein. To further study the mechanism of methotrexate uptake in KB cells, the N-hydroxysuccinimide ester of methotrexate was used to covalently label the surface of KB cells and to inhibit transport of methotrexate. The N-hydroxysuccinimide ester of methotrexate was bound to a species of protein with an apparent molecular weight of 160,000 in 1% (v/v) Triton X-100 that bound folic acid and was specifically precipitated by antiserum raised against the previously purified high-affinity folate binding protein (the folate receptor) from human KB cells. In addition, trypsin was utilized to remove surface-accessible covalently bound methotrexate. The amount of covalently bound methotrexate that could be released by trypsin initially decreased on incubation at 37 degrees C, suggesting that the methotrexate and binding protein were internalized. However, with time, trypsin could again release the covalently bound methotrexate, suggesting that the binding protein cycles from the external cell surface to the inside of the cell and out again.

Binding, Competitive↗
PubMed1989

Cellular changes during the infusion of high dose intravenous immunoglobulin.

With the ever widening group of autoimmune conditions that are beneficially affected by infusions of high dose immunoglobulin the possible mechanisms of action of such therapy appear increasingly complex. Fc mediated blockade of the mononuclear phagocyte system is an acknowledged early effect. This is, however, accompanied by a decrease of neutrophil counts which suggests that IgG binding to the neutrophil may be a mechanism of action. The decrease of neutrophil counts is transient but in immune thrombocytopenia is inversely proportional to the platelet response observed. In parallel to the effect on the neutrophil there are changes in the lymphocyte subsets with reversal of the T helper/suppressor ratio and alterations in the individual cellular constituents of each subset that correlate with the clinical response. The observed changes in B cell numbers and function suggest that T dependent and independent antibody production is effected by intravenous immunoglobulin. It is increasingly clear that in ITP at least the clinical response to IV IgG is a summation of several cellular events and their balance reflects the ultimate outcome. It may eventually be possible to use these observations to predict the likely outcome in the individual patient of this mode of therapy.

Antigens, Differentiation↗
PubMed1988

Effect of intravenous immunoglobulin on a spontaneous inhibitor to factor VIII.

A 71-year-old woman with a spontaneous anti-factor VIII inhibitor fractured her right wrist and 2 months later her left femur. She received treatment with porcine factor VIII for the first fracture and developed a secondary anti-porcine antibody response (from 10 to 200 Bethesda units). Following the second fracture she received intravenous immunoglobulin (i.v. IgG) (0.4 g/kg day for 5 days) in an attempt to reduce antibody activity. Despite further treatment with porcine factor VIII, the antibody level declined instead of rising as expected and the anti-human antibody activity also declined. We were not able to demonstrate neutralizing activity to her antibody but did demonstrate a reduced helper: suppressor ratio and reduced B-cell numbers and function after treatment with i.v. IgG. These changes were transient and as B-cell function improved over the following 4 months, her anti-human activity returned toward its previous level. Anti-porcine activity remained at its previous low level. We speculate that one of the mechanisms of action of i.v. IgG may be a direct cellular effect influencing both T-suppressor and B-lymphocyte function.

Aged↗
PubMed1986

Red cell sequestration during high dose intravenous immunoglobulin in idiopathic thrombocytopenic purpura.

The cellular interactions involved in the platelet response after immunoglobulin infusion in acute and chronic idiopathic thrombocytopenic purpura (ITP) are unknown. There have been a number of theories including the competitive inhibition of platelet-binding to macrophages by the preferential sequestration of immunoglobulin coated red cells. We report a study to examine this hypothesis. Adult acute and chronic patients were given infusions of immunoglobulin at a rate of 0.4 g/kg body weight, daily for 5 days. Serum haptoglobin, lactate dehydrogenase and the absolute reticulocyte counts were monitored and no significant change in any value was seen during the period of study. A red cell survival was performed on four of the patients and no increase in the rate of red cell clearance occurred during the infusion period. We conclude from this that in these patients no significant degree of haemolysis was provoked by the infusion although this does not preclude this as a mechanism of action in some individuals.

ABO Blood-Group System↗
PubMed1985

Lymphocyte subpopulations in bronchoalveolar lavage fluid in asbestos workers.

We examined peripheral blood and bronchoalveolar lavage (BAL) fluid lymphocyte subpopulations in 29 asbestos workers, 10 with and 19 without clinical or radiologic evidence of asbestosis. Peripheral blood lymphocyte subpopulations were also measured in 13 control subjects. The mean OKT4:OKT8 (T-helper/inducer:T-suppressor/cytotoxic lymphocyte) ratio in BAL fluid in the 29 asbestos workers was 0.96 (range, not detected to 3.33), significantly less than 1.76 (1.33 to 2.67) in peripheral blood (p less than 0.001). There were no significant differences in OKT4:OKT8 ratios in peripheral blood between the 10 patients with asbestosis, the 19 asbestos workers without asbestosis, and the 13 normal control subjects or in the OKT4:OKT8 ratios in BAL fluid between patients with asbestosis and asbestos workers without asbestosis. In the group as a whole, 83% of those who had suffered more than 5 yr of exposure to asbestos showed OKT4:OKT8 ratios less than 1.2, whereas in those who had suffered fewer than 5 yr of exposure, 80% showed ratios greater than 1.2 (p less than 0.02). No other relationships between OKT4:OKT8 ratios and clinical, radiographic, or physiologic variables were observed.

Adult↗