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Biomedical subjects

L Sachs

Publications and source records attributed to L Sachs.

At least 73 records · Page 4Linked to original sources
PubMed1993

The cellular and molecular environment in leukemia.

Identification of normal viability-, growth-, and differentiation-inducing cytokines, the cells that produce them, and how cytokines interact in normal development, has made it possible to identify the cellular and molecular basis of normal development and changes in the developmental program that result in leukemia. When normal cells have been changed into leukemic cells, the malignant phenotype can again be suppressed in various ways. Results on the molecular control of growth, differentiation, and apoptosis in normal myeloid hematopoietic cells, changes in the normal developmental program in myeloid leukemia, and the suppression of malignancy in myeloid leukemia, have shown that (A) malignancy can be suppressed either with or without genetic changes in the tumor cells, (B) suppression of malignancy by inducing differentiation does not have to restore all the normal controls, and (C) genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation and apoptosis which stop cells from multiplying.

Animals↗
PubMed1993

The molecular control of hemopoiesis and leukemia.

The establishment of a cell culture system for the clonal development of hemopoietic cells made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hemopoietic cell lineages and the molecular basis of normal and abnormal development in blood-forming tissues. These regulators include cytokines now called colony stimulating factors (CSFs) and interleukins (ILs). Different cytokines can induce cell viability, multiplication and differentiation, and hemopoiesis is controlled by a network of cytokine interactions. This multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor. The cytokine network which has arisen during evolution allows considerable flexibility depending on which part of the network is activated and the ready amplification of response to a particular stimulus. The CSFs and ILs induce cell viability by inhibiting programmed cell death (apoptosis). Programmed cell death is also regulated by the genes wild-type and mutant p53, c-myc and bcl-2, and suppression or induction of this program can result in tumor promotion or tumor suppression. Cytokines that regulate normal hemopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation. Genetic abnormalities that give rise to malignancy in these leukemic cells can be by-passed and their effects nullified by inducing differentiation and programmed cell death. The hemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in hemopoiesis.

Animals↗
PubMed1993

Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and -defective myeloid leukemic cells.

Myeloid leukemias that differ in their competence for induction of differentiation were analyzed for expression of bcl-2 and c-myc and for their sensitivity to induction of apoptosis by heat shock and cancer chemotherapy compounds. The M1 leukemia expressed a high level of bcl-2 and showed a much lower susceptibility to induction of apoptosis by heat shock, Adriamycin, 1-beta-D-arabinofuranosylcytosine, methotrexate, and cycloheximide, compared to five other leukemias which expressed a low level of bcl-2. There was no association between susceptibility to induction of apoptosis and competence for induction of differentiation. The difference in susceptibility to methotrexate, which is not regulated by the multidrug resistance (MDR) genes, and treatment with verapamil, which blocks MDR activity, have indicated that the higher resistance of the M1 leukemia to these agents was not due to MDR activity. The results indicate that the level of regulated bcl-2 expression in these myeloid leukemias was associated with cell susceptibility to induction of apoptosis by different apoptosis-inducing agents. Screening for expression of bcl-2 may thus be useful to characterize leukemias regarding susceptibility to induction of apoptosis by different agents. The level of regulated c-myc expressed in these leukemias was not associated with susceptibility to induction of apoptosis. Transfection with a deregulated mutant p53 into the M1 leukemia did not change susceptibility to apoptosis induction, but transfection with deregulated c-myc increased susceptibility to apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1993

Regulators of normal development and tumor suppression.

Identification of normal growth and differentiation-inducing proteins and how they interact in normal development has made it possible to identify the molecular basis of normal development and the mechanisms that uncouple growth and differentiation so as to produce tumor cells. When normal cells have been changed into tumor cells, the malignant phenotype can again be suppressed. Results on the molecular control of growth and differentiation in normal myeloid hematopoietic cells, changes in the normal developmental program in myeloid leukemia, and the suppression of malignancy in myeloid leukemia and sarcomas, have shown that (A) malignancy can be suppressed either with or without genetic changes in the tumor cells, (B) suppression of malignancy by inducing differentiation does not have to restore all the normal controls, and (C) genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation which stops cells from multiplying.

Cell Differentiation↗
PubMed1992

Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells.

Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.

Animals↗
PubMed1992

Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor.

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.

Animals↗
PubMed1992

The molecular control of hematopoiesis: from clonal development in culture to therapy in the clinic.

The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hematopoietic cell lineages and the molecular basis of normal and abnormal cell development in blood-forming tissues. These regulators include cytokines now called colony stimulating factors and interleukins. Different cytokines can induce cell viability, multiplication and differentiation, and hematopoiesis is controlled by a network of interactions between these cytokines. This network includes positive regulators such as colony stimulating factors and interleukins and negative regulators such as transforming growth factor beta and tumor necrosis factor. Gene cloning has shown that there is a family of different genes for these cytokines. The functioning of the network requires an appropriate balance between positive and negative regulators and the selective regulation of programmed cell death (apoptosis). There are different ways of inducing or inhibiting programmed cell death, and differences in the regulation of this program can result in tumor promotion or tumor suppression. The cytokine network which has arisen during evolution allows considerable flexibility, depending on which part of the network is activated and the ready amplification of response to a particular stimulus. A network may also be necessary to stabilize the whole system. Cytokines that regulate hematopoiesis can induce the expression of genes for transcription factors can thus ensure the autoregulation and transregulation of cytokine genes that occur in the network.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Medicines and culture--a double perspective on drug utilization in a developing country.

A double perspective, one medical-pharmacological and one social-anthropological, is used to understand the logic of drug utilization among practitioners and outpatients at a health unit in Sri Lanka. Both negative and positive aspects of local prescribing practices are highlighted. Western pharmaceuticals are integrated into therapeutic choices for outpatients in Sri Lanka by means of the Ayurvedic theory of balance and practitioners' and patients' behaviour in consultations results in their expectations being met, even if they do not use the same set of health ideas and interpretations of health intervention. The healing power ascribed to Western pharmaceuticals is described and their possible risks discussed from both a biomedical and an anthropological point of view.

Adult↗
PubMed1992

Inhibition of specific pathways of myeloid cell differentiation by an activated Hox-2.4 homeobox gene.

Abnormal expression of homeobox genes is one of the abnormalities associated with the development of murine and human leukemia. Myeloid leukemic cells that can be induced to differentiate to mature cells by interleukin 6 were stably transfected with an activated Hox-2.4 homeobox gene. Expression of the Hox-2.4 gene in the transfected clones inhibited specific pathways of the myeloid differentiation program induced by interleukin 6. The expression of some genes associated with differentiation was almost completely blocked, and the expression of other genes was either partially inhibited or not affected. The results support the hypothesis that abnormal expression of Hox-2.4 may contribute to the development of leukemia by interfering with the differentiation program.

Animals↗
PubMed1992

Selective regulation by hydrocortisone of induction of in vivo differentiation of myeloid leukemic cells with granulocyte-macrophage colony-stimulating factor, interleukin 6 and interleukin 1 alpha.

Clones of myeloid leukemic cells can differ in their ability to be induced to differentiate in vitro by different cytokines. Using such leukemic clones, we studied the regulation by hydrocortisone of induction of in vivo differentiation by injection of recombinant interleukin 6 (IL-6), interleukin 1 alpha (IL-1 alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Injection of IL-6 and IL-1 alpha induced in vivo differentiation of leukemic cells that were induced to differentiate by these cytokines in vitro, but not of leukemic cells that were not susceptible to these cytokines in vitro. In contrast, injection of GM-CSF induced in vivo differentiation both in leukemic cells that were susceptible or not susceptible to GM-CSF in vitro. The effect of GM-CSF, but not of IL-6 or IL-1 alpha, on inducing differentiation in vivo was inhibited by pretreatment with hydrocortisone. In leukemic cells that were not induced to differentiate with GM-CSF in vitro, this inhibition of differentiation by pretreatment with hydrocortisone was greater than inhibition of differentiation obtained by pretreatment with cyclophosphamide or irradiation or the use of nude mice. After hydrocortisone pretreatment, the number of peritoneal cells and their ability to produce GM-CSF and IL-6 were suppressed. It is suggested that hydrocortisone can inhibit the effect of an injected cytokine such as GM-CSF on induction of in vivo differentiation of leukemic cells by inhibiting the ability of host cells to produce cytokines to which the leukemic cells are susceptible.

Animals↗
PubMed1991

Rescue from programmed cell death in leukemic and normal myeloid cells.

Growth factor-independent clones of myeloid leukemic cells can regain a growth factor-dependent state during differentiation. Loss of viability in these differentiating leukemic cells in the absence of growth factor was associated with DNA fragmentation and morphologic changes typical of programmed cell death (apoptosis). The differentiating leukemic cells could be rescued from apoptosis by a hematopoietic growth factor such as interleukin-3 (IL-3) and by the tumor-promoting phorbol ester 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), but not by the nonpromoting phorbol ester 4-alpha-TPA. IL-3 and TPA rescued differentiating myeloid leukemic cells by different pathways and also rescued normal myeloid precursor cells from apoptosis. The rescue of differentiating leukemic and normal myeloid cells by IL-3 or TPA was blocked by amiloride inhibitors of the Na+/H+ antiporter. We suggest that TPA may act as a tumor promoter by inhibiting programmed cell death.

Amiloride↗
PubMed1991

Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6.

Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown, it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence, the abrogation of wild-type p53 expression, which is a common feature of many tumours, could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation, the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.

Animals↗
PubMed1991

A deletion and a rearrangement distinguish between the intracisternal A-particle of Hox-2.4 and that of interleukin-3 in the same leukemic cells.

Two intracisternal A-particle (IAP) insertions have been identified in WEHI-3B myeloid leukemic cells, one at the interleukin-3 (IL-3) gene and another at the homeobox gene Hox-2.4. In contrast to the 5-kb IL-3-IAP, the Hox-2.4-IAP is only 2.1 kb in size and contains a rearrangement. The homology throughout the remaining sequences suggests that both IAPs originated from a common progenitor molecule. Both proviral insertions have resulted in transcriptional activation of the adjacent genes, which appears to be a significant step in the leukemogenic process in these leukemic cells.

Amino Acid Sequence↗
PubMed1991

Self-reported symptom distress in cancer patients: reflections of disease, illness or sickness?

This article examines the relationships between symptom distress in a heterogeneous group of cancer patients and a number of possible explanatory variables, categorized as demographic, medical/clinical, individual/psychosocial and variables related to patients' views of care provided by the health care system. A series of explorative multiple regression analyses were undertaken to this end. The data are derived from a cross-sectional study of cancer patients diagnosed in 1987 at one general hospital in the greater Stockholm area, using semi-structured interviews in conjunction with McCorkle and Young's Symptom Distress Scale, Antonovsky's Sense of Coherence Questionnaire, Cutrona and Russell's Social Provisions Scale and Smilkstein's Family APGAR. Symptom distress is studied as a cumulative index, as well as in terms of the sub-indexes of pain, appetite/nausea, functional aspects, psychological aspects and social aspects. When the four categories of explanatory variables are combined, considerably higher levels of variance are explained for all 6 indexes of the Symptom Distress Scale, than when the regression analyses are performed separately with each distinct category of explanatory variables. This provides a statistical illustration of the multifaceted and complex nature of symptom distress. The data are presented in the context of a conceptual discussion about the meaning of symptoms. Symptom distress, in this study, appears to reflect both personal and cultural experiences, that is 'illness' and 'sickness' processes, rather than primarily medical/clinical variables, or 'disease'. Antonovsky's salutogenic model is suggested as a fruitful framework for further analysis.

Aged↗