Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antileukemic activity of cis-diamminedichloroplatinum (PDD) was studied in rats bearing myelogenous leukemia RBA-Le. Clinical picture, changes in life-span, hematological indices and weight changes were used to assess the effectiveness of the therapy. Maximum effectiveness was noted when PDD was given in combination with Methotrexate (MTX) and Poly I:C, respectively. The mean life-span of the rats treated with PDD and MTX was prolonged to 37 days that is an increase of 147 percent of the control level. Furthermore 20 percent of the treated animals survived symptom-free for more than 60 days. Out of 20 animals receiving PDD in combination with Poly I:C 6 rats survived 60 days symptom-free. In remaining 14 animals who finally died on leukemia an 85 percent increase in life-span was noted. Only slight increase in life-span was recorded in those groups treated with PDD alone and in combination with Cyclophosphamide regardless of dosage schedule. The general toxicity of PDD therapy is discussed.
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PMID:Experimental chemotherapy of rat leukemia RBA-Le with cis-diamminedichloroplatinum. 27 Jun 16

Two congeners of cis-platinum diamminodichloride, 1,2-diamminocyclohexylplatinum malonate (NSC 224964) and 1,2-cyclohexyldiamminoplatinum sulfate (NSC 250427), show approximately equal inhibitory activity in vitro against leukemia L1210 and a line of L1210 (L1210/PDD) that has developed resistance to cis-platinum diamminodichloride. These compounds are also active against L1210/PDD in vivo. These observations suggest that they be tried clinically in patients whose disease has become resistant to cis-platinum diamminodichloride.
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PMID:Lack of cross-resistance between certain platinum coordination compounds in mouse leukemia. 88 87

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.
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PMID:Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells. 138 3

A bone-resorbing product of mouse spleen cells found to have differentiation-inducing activity was most probably leukaemia inhibitory factor (LIF). This revealed that LIF is a cytokine active on bone, in addition to its several other sites of action. In organ culture of newborn mouse bone, recombinant LIF promoted bone resorption by a prostaglandin-dependent process. Resorption by isolated rat osteoclasts was also promoted by LIF through an initial action on osteoblasts which was receptor-mediated. Incorporation of [3H]thymidine into DNA was increased by LIF in cells (most probably osteoblasts) of the newborn mouse bones. Osteoblasts have been shown to produce LIF, and the amount is increased by treatment with retinoic acid or TNF-alpha. LIF also acts directly on osteoblasts to inhibit plasminogen activator activity, by stimulating the synthesis of plasminogen activator inhibitor 1 mRNA and protein. The latter actions are very similar to those of TGF-beta. Again like TGF-beta, LIF was ineffective in promoting bone resorption in vitro in fetal rat long bones. These results, together with the in vivo data showing that high circulating levels of LIF in the mouse are accompanied by a substantial increase in trabecular bone mass, indicate that LIF is another cytokine with potent actions on bone and potentially important interactions with other osteotrophic factors.
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PMID:Leukaemia inhibitory factor and bone cell function. 142 10

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.
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PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

Experiments were undertaken to investigate the molecular basis of primitive hematopoietic progenitor cell regulation in both the long-term culture system and in methylcellulose, particularly with a view to characterizing factors either able or unable to influence the behaviour of primitive leukemic cells from patients with chronic myeloid leukemia (CML). Long-term cultures of CML cells with or without irradiated normal marrow feeder layers were initiated from peripheral blood cells of CML patients with high white blood cell counts. Three weeks later the effect of exogenously added transforming growth factor-beta 1 (TGF-beta 1) on progenitor cycling status was examined. A single addition of 5 ng/ml TGF-beta 1 was able to reversibly arrest the otherwise uninterrupted turnover of primitive leukemic erythroid and granulopoietic progenitors for a period of up to 7 days both in the presence and absence of a normal adherent cell population. When TGF-beta 1 was incorporated into methylcellulose cultures, its ability to inhibit colony formation by CML progenitors showed the same differential activity on primitive cell types exhibited by normal progenitors. Dose-response curves for analogous populations of normal and leukemic cells were indistinguishable. Increasing the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose colony assays decreased the sensitivity displayed by normal clonogenic cells to TGF-beta 1 and no differences were detectable when CML cells were used in such regulator competition experiments. These findings support a general model of primitive hematopoietic cell regulation in which entry into S-phase is determined at the intracellular level by multiple convergent pathways that may deliver either positive or negative signals from activated cell surface receptors for distinct extracellular factors. The present study shows for the first time that primitive CML progenitors exposed to TGF-beta 1 in vitro can be transiently blocked in a noncycling state for several days without loss of viability and that the mechanisms responsible for the emergence and maintenance of a clonal population of CML cells in vivo do not appear to involve changes in their sensitivity to TGF-beta 1. It is thus unlikely that the heightened proliferative activity exhibited by primitive CML progenitors both in vivo and in long-term culture can be explained by an abnormality in the intracellular mechanisms normally activated by TGF-beta 1 receptor-ligand binding. We suggest that primitive CML cells are either defective in their ability to see (or activate) endogenously produced TGF-beta 1, or are defective in their responsiveness to another, undefined, regulator.
Leukemia 1992 Sep
PMID:Granulocyte-macrophage colony-stimulating factor modulation of the inhibitory effect of transforming growth factor-beta on normal and leukemic human hematopoietic progenitor cells. 151 2

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in a variety of responses associated with wound healing and inflammation. Thus, TGF-beta 1 enhances production of several extracellular matrix proteins both in vitro and in vivo, is chemotactic for monocytes, and alters the functioning of lymphocytes. We have examined the ability of TGF-beta 1 to affect the behavior of human THP-1 promonocytic leukemia cells, a cell line with the capacity to differentiate into macrophage-like cells. TGF-beta 1 reduces the growth rate of these cells, induces morphologic changes, and promotes adherence to culture surfaces. In addition, the adherent cell population expresses high levels of esterase activity, acquires the ability to ingest latex beads, and releases elevated levels of interleukin 1. TGF-beta 1-treated cells also express elevated levels of the beta 2 family of integrins. Taken together, these results suggest that TGF-beta 1 is capable of promoting the maturation of promonocytic cells into macrophages. This outcome has implications at wound sites where TGF-beta 1 and a myriad of other factors interact with many cell types to facilitate healing.
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PMID:TGF-beta inhibits proliferation of and promotes differentiation of human promonocytic leukemia cells. 152 33

A large number of reports have described the potential of transforming growth factor beta 1 (TGF-beta 1) as an antitumor agent on the basis of its antiproliferative action on a wide variety of tumor types in culture. In this report we now extend the assessment of TGF-beta 1's antitumor potential by evaluation in vivo versus the mouse monomyelocytic leukemia, Wehi 3BD+, and the human lung adenocarcinoma, A549. In culture both Wehi 3BD+ and A549 cells, sampled from in vivo, were sensitive to inhibition (greater than or equal to 50%) by TGF-beta 1 (greater than or equal to 1 ng/ml) in a 6 day proliferation assay. Despite their sensitivity to TGF-beta 1 in culture, in vivo the growth of neither tumor was reproducibly altered following treatment with various doses, routes and schedules of TGF-beta 1. For example, the median lifespan of mice inoculated with Wehi 3BD+ cells (10(3) or 10(5) cells, ip) was not increased by TGF-beta 1, given as 9 daily ip injections or 7 days of continuous ip infusion. Dose levels in these studies ranged over greater than 2 logs and were escalated to include those frankly lethal (28 micrograms/mouse by injection or 7 micrograms/mouse/day by infusion). Furthermore, the growth of A549 tumors implanted sc in athymic mice was not inhibited by iv injection (every 3 days for 5 injections or 6 consecutive daily injections), sc treatment distal to the tumor (every 3 days for 5 injections or continuously infused for 14 days), or even sc injection adjacent to the tumor (every 3 days for 5 injections), although dose levels of TGF-beta 1 covered a wide range including those which produced lethalities. On the basis of cumulative dose, continuous infusion of TGF-beta 1 by both ip and sc routes was more toxic than frequent injections given by the same routes. These studies indicate lethality is reached without a meaningful tumor inhibition being produced following ip, sc, or iv injections, and sc or ip infusions of TGF-beta 1.
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PMID:Transforming growth factor beta 1: lack of in vivo antitumor activity on A549 and Wehi 3BD+ tumors. 156 84

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.
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PMID:Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. 175 74

Murine myelomonocytic leukemia M1 cells have been used to examine the effects of type-beta 1 transforming growth factor (TGF-beta 1) on cellular proliferation and differentiation in monocyte-macrophage lineage. TGF-beta 1 inhibited immature M1 cell growth due to a general slowdown of the cell cycle, without arrest at any specific point. Ten nanograms per milliliter TGF-beta 1 completely suppressed phagocytic activity and adhesion to the dish surface and partially inhibited the expression of Fc receptors and vimentin during the differentiation of M1 cells induced by IL-6. IL-6-induced declines in the expression of c-myc mRNA and in the accumulation of G0/G1 cells were also partially blocked by TGF-beta 1. When treated concurrently with IL-6 and TGF-beta 1, approximately 50% of M1 cells were morphologically converted to promonocyte or monocyte-like cells, which did not exhibit the characteristics of mature macrophages. Although pretreatment with TGF-beta 1 also inhibited the IL-6-induced phagocytic activity, this inhibition was reversible. Once TGF-beta 1 was removed from the culture medium after 72 h of incubation with IL-6, the kinetics of differentiation induced by IL-6 were faster in pretreated cells than in nonpretreated cells. TGF-beta 1 appears to inhibit the IL-6 induced conversion of M1 cells at the intermediate stage of monocytic differentiation.
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PMID:Effects of type-beta 1 transforming growth factor on the proliferation and differentiation of mouse myelomonocytic leukemia cells (M1). 187 63


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