Search PubMed⌕ Search

Biomedical subjects

L Sachs

Publications and source records attributed to L Sachs.

At least 199 records · Page 11Linked to original sources
PubMed1980

Potential pre-screening for therapeutic agents that induce differentiation in human myeloid leukemia cells.

A cultured line of human myeloid leukemic cells has been used, to test for the ability of compounds used in chemotherapy to induce partial or complete differentiation of these leukemic cells. The compounds differed in their ability to induce specific differentiation-associated properties. Effectiveness of induction of Fc and C3 rosettes was of the order actinomycin C greater than cytosine arabinoside greater than mitomycin-C greater than adriamycin greater than bromodeoxyuridine greater than hydroxyurea. Induction of rosettes by actinomycin-D required a 8212-fold lower concentration than induction by hydroxyurea. All these compounds, except bromodeoxyuridine, induced the synthesis and secretion of lysozyme with the same order of effectiveness as for rosettes, but only actinomycin-D and to a lesser extent bromodeoxyuridine induced the formation of mature granulocytes. Vincristine induced only a small increase in lysozyme. The results indicate that actinomycin-D was the most potent inducer of differentiation in these human myeloid leukemic cells. It is suggested that pre-screening of individual patients for the most effective compounds that can induce differentiation of their myeloid leukemic cells in culture, may prove beneficial for treatment in a form of chemotherapy based on the induction of normal differentiation in leukemic cells.

Antineoplastic Agents↗
PubMed1980

Constitutive uncoupling of pathways of gene expression that control growth and differentiation in myeloid leukemia: a model for the origin and progression of malignancy.

Chemical carcinogens and tumor promoters have pleiotropic effects. Tumor initiators can produce a variety of mutations and tumor promotres can regulate a variety of physiological molecles that control growth and differentiation. The appropriate mutation and the regulation of the appropriate molecules to induce cell growth can initiate and promote the sequence of changes required for transformation of normal cells into malignant cells. After this sequence of changes, some tumors can still be induced to revert with a high frequency from a malignant phenotype to a nonmalignant phenotype. Results obtained from analysis of regulation of growth and differentiation in normal and leukemic myeloid cells, the phenotypic reversion of malignancy by induction of normal differentiation in myeloid leukemia, and the blocks in differentiation-defective leukemic cell mutants have been used to propose a general model for the origin and progression of malignancy. The model states that malignancy originates by changing specific pathways of gene expresion required for growth from inducible to constitutive in cells that can still be induced to differentiate normally by the physiological inducer of differentiation. The malignant cells, unlike the normal cells, then no longer require the physiological inducer for growth. This changes the requirements for growth and uncouples growth from differentiation. Constitutive expression of other specific pathways can uncouple other controls, which then causes blocks in differentiation and the further progression of malignancy. The existence of specific constitutive pathways of gene expression that uncouple controls in malignant cells can also exlain the expresion of fetal proteins, hormones, and some other specialized products of normal development in various types of tumors.

Carcinogens↗
PubMed1980

Desensitization of enucleated cells to hormones and role of cytoskeleton in control of normal hormonal response.

Prostaglandin E1 and the beta-adrenergic hormone l-isoproterenol stimulated cyclic AMP formation in both nucleated and enucleated myeloid leukemic cells that could be induced to differentiate normally to mature cells by the macrophage- and granulocyte-inducing protein MGI (MGI+D+ cells). Enucleated as well as nucleated MGI+D+ cells also desensitized to these hormones, indicating that this desensitization is an extranuclear process. Nucleated or enucleated mutant myeloid leukemic cells that are not induced to differentiate (MGI-D- cells) were not desensitized to these hormones. The antitubulin alkaloids colchicine and vinblastine, but not the antimicrofilament compound cytochalasin B, increased the maximal hormone-induced formation of cyclic AMP in nucleated MGI+D+ cells but not in the MGI-D- cells. These alkaloids also inhibited the development of desensitization to l-isoproterenol and prostaglandin E1 in enucleated MGI+D+ cells. The results indicate that in MGI+D+ cells the cytoskeletal system puts constraints on the cells' ability to respond to these hormones and that these constraints are absent in the mutant MGI-D- cells. Because MGI+D+ but not MGI-D- cells can be induced to differentiate by the macrophage- and granulocyte-inducing protein, cytoskeletal constraints, which are also found in normal myeloid cells, may be necessary for cell competence to differentiate. The results support the suggestion that membrane cytoskeletal constraints generate may control the normal response and desensitization to membrane-mediated cell inducers.

Animals↗
PubMed1979

[Does low-dosage heparin treatment require serial haematological controls? (author's transl)].

Blanket serial controls are not necessary in low-dosage heparin treatment. It would, in any case, be difficult under normal clinical conditions and would run counter to the whole conception of low-dose heparin treatment. However, in problem cases with an increased thrombo-embolic risk, sensitive methods for monitoring the heparin effect are recommended. A study on 150 patients has indicated that the most sensitive method is the use of chromogenic substrates. Thrombin time, using low-concentration thrombin solution of 1.5 NIH units/ml, thrombelastogram and activated partial thromboplastin time are less sensitive. Antithrombin III levels should be determined in all cases of increased heparin tolerance. With reduced antithrombin III levels and higher body weight an increase of the standard dose from 5000 U.S.P. units heparin t. i. d. subcutaneously to 7500 U.S.P. units t. i. d. should be considered.

Antithrombins↗
PubMed1979

Activation of normal genes in malignant cells: activation of chemotaxis in relation to other stages of normal differentiation in myeloid leukemia.

Genetically differerent clones of myeloid leukemic cells have been used to study the activation of normal genes in these malignant cells by the normal physiological inducer of myeloid cell differentiation, the protein MGI. In appropriate clones, MGI induced the normal differentiation-associated property of chemotaxis to a variety of compounds including the steroid hormone dexamethasone. The induced cells could also distinguish among different steroids by chemotaxis, suggesting that there are specific membrane interaction sites for steroids. The sequence of differentiation in these cells was the formation of C3 and Fc rosettes leads to phagocytosis of these rosettes and chemotaxis leads to synthesis and secretion of lysozyme leads to mature macrophages or granulocytes. The use of appropriate mutants and the comparison of induction by MGI and dexamethasone has shown that chemotaxis to casein can be dissociated from: chemotaxis to dexamethasone, ATP, and bacterial factor; formation of C3 or Fc rosettes; phagocytosis of these rosettes; synthesis of lysozyme; and the formation of mature cells. It is suggested from this dissection of normal differentiation that there are different membrane changes for specific chemotaxis, formation of these rosettes, and their phagocytosis, and that induction of each of these properties requires activation of different genes.

Animals↗
PubMed1979

Regulation of normal differentiation in mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion.

The control of cell multiplication and differentiation by tumor-promoting phorbol esters including 12-O-tetradecanoylphorbol-13-acetate (TPA) has been studied with different clones of mouse myeloid leukemic cells, a line of human myeloid leukemic cells, and normal mouse bone marrow myeloblasts. TPA induced normal cell differentiation in one of the mouse leukemic clones and this was mediated by induction of the protein inducer of differentiation to macrophages or granulocytes (MGI) in the cells that then differentiated. Other mouse clones were not induced to differentiate by TPA. In one of these clones, TPA induced cell susceptibility to externally added MGI. This effect was not due to a general induction of susceptibility to all compounds because TPA did not induce susceptibility to lypopolysaccharide or dexamethasone in this clone. In the human leukemic cell line, TPA also induced differentiation with the induction of MGI activity and enhanced susceptibility to added MGI. It is suggested that the clonal differences in induction of MGI activity and increased susceptibility to MGI may be associated with differences in receptors for TPA and the ability of TPA to modify receptors for MGI. Studies with normal bone marrow cells have indicated that TPA stimulated MGI activity and also increased susceptibility of normal myeloblasts to induction of multiplication by MGI. The ability of different phorbol esters to produce these effects on normal myeloblasts and myeloid leukemic cells paralleled their ability to act as tumor promoters. The results indicate that a tumor promoter such as TPA can induce the production of and increase cell susceptibility to a normal regulator of cell multiplication and differentiation. TPA has pleiotropic effects. It is suggested that, by these mechanisms, TPA may thus act as a tumor promoter by increasing cell multiplication in initiated cells, induce differentiation in some cells, or inhibit differentiation in other cells, depending on which molecules are being regulated in the TPA-treated cells.

Animals↗
PubMed1979

Increase of normal myeloblast viability and multiplication without blocking differentiation by type C RNA virus from myeloid leukemic cells.

Clones of mouse myeloid leukemic cells that differ in their competence to be induced for normal cell differentiation by the protein inducer MGI produce type C virus. These viruses have been studied for their effect on the viability, multiplication, and differentiation of normal bone marrow cells either with or without the addition of MGI. Virus from leukemic clones that can differentiate normally to mature macrophages and granulocytes (MGI+D+ clones) induced some multiplication of myeloblasts in the bone marrow, but the cells did not differentiate without adding MGI. In the presence of MGI, this virus then induced an increased number of colonies whose cells differentiated to mature macrophages or granulocytes as in colonies of uninfected cells. Virus infection also resulted in a decrease in the amount of MGI and fetal calf serum that was required for colony formation. Virus from MGI+D+ clones, in the presence of MGI, was 500-fold more effective in increasing colony formation than virus from the differentiation-defective MGI-D- clones, although both types of virus replicated with equal efficiency in the normal bone marrow cells. No such increase was obtained after infection with the Friend leukemic virus complex or the Moloney murine leukemia virus. Infection with virus from a MGI+D+ clone that was differentiated by MGI mainly to macrophages induced a higher percentage of macrophage colonies than virus from MGI+D+ clones that were differentiated by MGI to granulocytes and macrophages. Studies with isolated myeloblast colony-forming cells from the bone marrow have indicated that these are the target cells for the virus. Infections of these isolated myeloblasts with virus from MGI+D+ clones induced some multiplication without differentiation in the absence of MGI, and increased the viability and multiplication of the myeloblasts without inhibiting their ability to differentiate in the presence of MGI. The results, therefore, indicate that virus from MGI+D+ cells can increase the viability and multiplication of normal myeloblasts in the bone marrow without blocking the ability of these cells to be induced to differentiate by MGI, and that this effect was directly related to the competence of the leukemic host cells to be induced for normal differentiation. It is suggested that the difference between the effect of virus from MGI+D+ and MGI-D- cells may be due to a difference in their integration sites in relation to the genes that control cell viability, multiplication, and differentiation.

Animals↗
PubMed1979

Bromocriptine suppression of TRH-stimulated prolactin and thyrotrophin release and accompanying inhibition of bromocriptine induced growth hormone release by TRH in normal man.

Six normal fasting males received on four separate occasions in random order (1) a placebo tablet followed 60 min later by 200 microgram of TRH intravenously (2) bromocriptine 2.5 mg orally followed by TRH intravenously (3) bromocriptine 2.5 mg orally followed by a placebo injection and (4) placebo tablet followed by placebo injection. Plasma prolactin and TSH responses to TRH were decreased following bromocriptine pretreatment. The rise of plasma growth hormone after bromocriptine was inhibited by TRH. The rise in plasma FSH seen after TRH injection was not influenced by bromocriptine pretreatment. Circulating LH and insulin concentrations were unaffected by any drug administration. These results suggest a dopaminergic influence on prolactin and TSH release in normal men, an inhibitory effect of TRH on bromocriptine stimulated growth hormone secretion, and no dopaminergic modulation of basal insulin secretion.

Adult↗
PubMed1979

Difference in the cell proliferation and colony-forming ability of normal human T lymphocytes.

Cell transfer experiments were carried out with phytohaemagglutinin-induced normal human T lymphocyte colonies after 2--10 days of primary colony growth. The cells gave a cloning efficiency of 15% after 2 days of incubation and this decreased to 0.2% with the progressive growth of the colonies. The primary colonies had a proliferative capacity to give about 240 cells after 10 days of incubation, but only contained 0.5 to one cell per colony that could form a new colony. This number of colony-forming cells per colony did not change with an increase in colony size. These results indicate that colonies maintained the same number of colony-forming cells that they started with and that the other cells could proliferate but not form colonies. It is suggested that this ability to distinguish between colony-forming and proliferative T cells may be useful for determining specific deficiencie in either cell type in various diseases.

Cell Division↗