Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), given intravenously 5 micrograms/kg per day, was administered on days 4-8 of timed-sequential chemotherapy (TSC) with mitoxantrone, 12 mg/m2 per day on days 1-3, etoposide, 200 mg/m2 per day on days 8-10 and cytarabine, 500 mg/m2 per day on days 1-3 and 8-10, in 22 patients aged < 60 years with refractory acute myelogenous leukemia in an attempt to increase recruitment of leukemic cells in S phase before the second sequence of TSC. Thirty-eight patients treated with TSC without GM-CSF in a previous trial served as historical controls. In GM-CSF-treated patients, median duration of neutropenia < 0.5 x 10(9)/1 was 33 days and of platelet transfusion requirement 30 days, without any increase by comparison with controls. WHO grade 3 or more extra-hematologic toxicity included sepsis in 60% of patients, vomiting in 30%, diarrhea in 15%, hyper-bilirubinemia in 15%, and mucositis in 10%, without any difference with controls. Among 20 evaluable patients six individuals (30%), with a 95% confidence interval (CI) ranging from 12-54% achieved complete remission, 11 (55%, CI 31-77%) did not respond to therapy and three (15%, CI 3-38%) died from infection. There was no demonstrable in vivo proliferation of leukemic cells during the 5 days of administration of GM-CSF. The average percentage of bone marrow cells in S phase in five patients was 4.0 +/- 2.8 on day 4 and 7.0 +/- 7.2 on day 8 (p = NS). In this cohort of patients refractory to cytarabine, addition of GM-CSF did not increase efficacy of TSC by comparison with historical controls.
Leukemia 1993 Mar
PMID:Granulocyte-macrophage colony-stimulating factor in association to timed-sequential chemotherapy with mitoxantrone, etoposide, and cytarabine for refractory acute myelogenous leukemia. 844 42

We studied the regulatory effects of various cytokines on the susceptibility to lymphocyte-mediated lysis of cell lines established from patients with acute T-lymphoblastic leukemia (T-ALL). None of the cytokines tested affected the sensitivity of these targets to natural killer activity. In contrast, specific cytokines, different for each cell line, enhanced the susceptibility to lymphokine-activated killer (LAK) cells, while interferon gamma (IFN)-gamma always induced resistance. The same cytokines that increased LAK susceptibility also induced proliferative responses. The TALL-101 cell line, which responded to granulocyte-macrophage colony-stimulating factor (GM-CSF) with increased susceptibility to lysis, and to IFN-gamma with resistance, was used as a model to analyze the mechanisms underlying these changes. Cold target inhibition and conjugate formation assays both indicated that the changes in LAK susceptibility were not at the level of effector-target (E/T) binding. Furthermore, no significant changes in surface expression of adhesion molecules involved in E/T binding were induced by either GM-CSF or IFN-gamma on TALL-101 cells. Finally, N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl-esterase assays demonstrated no differences in the ability of these cytokines to trigger the secretion of cytolysins in the bound effectors compared to unstimulated cells. Taken together, these results suggest that the cytokine-modulated susceptibility to lysis of these T-ALL lines might occur at a post-binding stage with mechanisms involving an altered responsiveness to lytic factors.
Leukemia 1993 Mar
PMID:Cytokine modulation of the susceptibility of acute T-lymphoblastic leukemia cell lines to LAK activity. 844 46

Polymerase chain reaction (PCR) was used to identify protein-tyrosine phosphatases (PTPases) in a human leukemic cell line, F-36P. Degenerate primers deduced from the highly conserved amino acid sequences in the catalytic domain of known PTPases were used for amplification. Among 16 clones sequenced, 13 were identical to known PTPases, whereas the other three clones were disclosed to encode novel PTPases. The expression pattern of one of the three newly identified PTPases, designated as F-36-12, was further analysed. In murine tissues, the F-36-12 message was predominantly expressed in brain, kidney, and intestine, and was weakly expressed in heart and thymus. In human hematopoietic cell lines, the F-36-12 message was preferentially expressed in a promyelocytic leukemic cell line, HL60, and two factor-dependent leukemic cell lines, F-36P and F-36E, that are dependent on granulocyte-macrophage colony-stimulating factor or interleukin-3 and erythropoietin, respectively. The transcript was approximately 8 kb long and the message level in HL60 cells was slightly increased at 24 hours and then slowly declined when treated with dimethyl sulfoxide for granulocyte differentiation, while the message level was rapidly decreased when treated with 12-O-tetradecanoylphorbol 13-acetate for monocyte/macrophage differentiation. These results show that several PTPases including three novel ones are expressed in a human leukemic cell line and that the particular PTPase, F-36-12, might be involved in the differentiation process in HL60 cells.
Leukemia 1993 May
PMID:Identification of novel protein-tyrosine phosphatases in a human leukemia cell line, F-36P. 848 28

Injection of 10(6) immortalized, but non-leukemic, granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent FDC-P1 cells into GM-CSF transgenic hybrid mice with elevated GM-CSF levels led to death within three months with elevated blast cell numbers in the blood, massive organ infiltration by blast cells, and associated anemia and thrombocytopenia. No disease developed within this period in littermate mice injected with 10(6) FDC-P1 cells. All moribund transgenic recipients contained transformed FDC-P1 cells able to produce rapidly-growing transplanted leukemias in syngeneic normal DBA/2 recipients. The leukemias appeared to arise in the primary recipients by independent transformation events. The transformed cells from different mice differed in their in vitro growth characteristics, their ability to produce GM-CSF or multipotential CSF, and in the nature of the transplanted tumors derived from the primary cells. While all primary recipients at death contained fully transformed leukemic cells, the bulk of the large population of FDC-P1 cells appeared either to be untransformed or to have altered characteristics not yet representing full transformation. If the FDC-P1 engrafted model has some validity for myelodysplasia, the results suggest that sustained CSF administration to myelodysplastic patients possessing abnormal, potentially preleukemic, granulocyte-macrophage populations may increase the risk of death either from accumulated pretransformed or from fully transformed leukemic cells.
Leukemia 1993 Jun
PMID:Leukemic transformation of immortalized FDC-P1 cells engrafted in GM-CSF transgenic mice. 850 82

The use of colony-stimulating factors (CSFs) in acute myeloid leukemia (AML) remains controversial. Potential uses include shortening the period of neutropenia, inducing leukemic cells into the S-phase of the cell cycle, stem cell protection, inducing differentiation of leukemic cells, interrupting autocrine/paracrine loops, direct inhibition of leukemogenesis, and enhancing antimicrobial function. Data from the nine controlled studies of CSFs that have been reported between 1990 and 1995, with varying patient characteristics and other factors, indicate that growth factors have several uses in AML therapy. The published literature now suggests that the safety of CSFs is no longer a major clinical concern, and significant experience has been gained in reducing the period of neutropenia following induction therapy. Yeast-derived granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor appear to be effective and probably have an important role in the management of older adult patients with AML and for those patients with a significant risk for therapy-related morbidity and mortality. The use of CSFs as priming agents remains experimental; results of further prospective placebo-controlled studies, with laboratory correlates, are awaited.
Leukemia 1996 Apr
PMID:Use of growth factors during induction therapy for acute myeloid leukemia. 861 71

We have previously shown that the growth factor FLT3 ligand (FL) is mitogenic for human primary and continuously cultured myeloid leukemia cells. Despite widespread expression of the receptor FLT3 among the leukemia cell lines from certain cell lineages, only two growth factor-dependent myeloid leukemia cell lines showed a significant proliferative response to FL. In the present study, we examined the proliferative effects of FL on a comprehensive set of growth factor-dependent leukemia cell lines. A significant enhancement of cell growth by FL was seen in 10/12 myelomonocytic cell lines, while all cell lines with predominantly megakaryocytic and/or erythroid characteristics did not respond positively, despite the expression of the receptor. The cytokines interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) could independently enhance the FL-stimulated proliferation in a synergistic fashion. Transforming growth factor-(beta)1 (TGF-(beta)1), in a dose-dependent fashion, partially inhibited the FL-promoted proliferation, but basic fibroblast growth factor (bFGF), on its own augmenting the response to FL, significantly abrogated the inhibitory effects of TGF-(beta)1. TGF-(beta)1 down-regulated mRNA and protein expression of the FLT3 receptor. Taken together these data suggest that the effects of FL on the growth of normal and malignant hematopoietic cells can be positively and negatively modulated by other cytokines.
Leukemia 1996 Feb
PMID:Effects of FLT3 ligand on human leukemia cells. II. Agonistic and antagonistic effects of other cytokines. 863 36

Thrombopoietin (TPO) is a recently characterized growth and differentiation factor for megakaryocytes and platelets exerting its effects via the receptor MPL. We examined the expression of MPR on the cell surface of a panel of 43 myelomonocytic, erythroid and megakaryocytic leukemia cell lines and 21 primary acute myeloid leukemia (AML) cases by flow cytometry. With few exceptions MPL was found on all 32 erythroid/megakaryocytic cell lines and on all 11 growth factor-dependent myelomonocytic cell lines, albeit at variable percentages and intensities per cell population (with a 10% cut-off level for positivity still 30/43 cell lines scored as MPL positive). The majority of the primary AML samples (including all seven M6/M7 cases) expressed the MPL protein regardless of the morphological and immunological subtype (13/21 cases had >10% MPL-positive cells). Recombinant TPO overexpressed in hamster cells induced a mitogenic response in seven cell lines (one growth factor-independent and six factor-dependent lines) and in 3/21 AML specimens (two AML M2, one AML M7) as measured by 3H-thymidine incorporation. Expression of MPL clearly did not correlate with response to TPO. For further detailed studies of the interaction of TPO with other cytokines we used the AML M7-derived M-07e cells as an informative indicator cell line for which both murine and human TPO acted as a very potent mitogen in a dose-dependent fashion (3- to 11-fold proliferation increase relative to medium alone). This growth factor-dependent cell line which is normally cultured in conditioned medium containing several cytokines could be grown in long-term culture supplemented only with TPO. Co-incubation of M-07e with various cytokines and TPO showed additive proliferative effects for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and synergistic responses for stem cell factor (SCF), interferon (IFN)-alpha, and to a lesser extent for IFN-gamma and tumor necrosis factor (TNF)-alpha. Erythropoietin (EPO), IL-1, IL-6, IL-11 and leukemia inhibitory factor (LIF), know as megakaryocytic maturation-inducing molecules, were not substantially effective, neither singly nor in combination with TPO, with regard to cell growth. Transforming growth factor (TGF)-beta1 antagonized the inductive effect of TPO on M-07e cell growth. Addition of TPO to cultures of megakaryocytic cell lines failed to significantly alter the ploidy distribution and the differentiation marker immunoprofile of the cells indicating a lack of maturation-inducing effects in this model system. In summary, TPO represents an efficient in vitro potentiator of megakaryocytic leukemia proliferation of at least some primary cases or cell lines. While TPO seems to be the major physiological regulator of megakaryocytopoiesis, the present data suggest also some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic leukemia cells as well, thus assigning to TPO a possible pathobiological role in leukemogenesis which would be of clinical relevance. Our data show that the response to TPO is not restricted to cells committed to the megakaryocytic differentiation pathway as we could demonstrate TPO-responsive megakaryocytic and non-megakaryocytic cell lines; thus, these cell lines represent powerful tools in such analyses. Consequently, this new cytokine needs to be properly examined so we can get a clear understanding of the clinical possibilities and dangers.
Leukemia 1996 Feb
PMID:Expression of the receptor MPL and proliferative effects of its ligand thrombopoietin on human leukemia cells. 863 39

Hematopoietic cells require certain cytokines to maintain viability by preventing apoptotic cell death. These cytokines can also protect leukemic cell lines against induction of apoptosis by cytotoxic anticancer compounds. We now show that the cytokines granulocyte-macrophage colony-stimulating factor and interleukin 3 can protect primary human myeloid leukemic cells against doxorubicin-induced apoptosis. Protection was detected in cells from 72% of the myeloid leukemic patients tested. The results indicate that these, and perhaps other, hematopoietic cytokines can decrease the effectiveness of cytotoxic anticancer therapy in some human myeloid leukemias. Leukemic cell sensitization to cytotoxic therapy may, therefore, require decreasing the availability of certain cytokines.
Leukemia 1996 Mar
PMID:Protection of human myeloid leukemic cells against doxorubicin-induced apoptosis by granulocyte-macrophage colony-stimulating factor and interleukin 3. 864 62

Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.
Leukemia 1996 May
PMID:Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors. 865 68

Blast cells derived from patients with acute myelogenous leukemia (AML) were cultured in the presence of interleukin-13 (IL-13). IL-13 did not cause statistically significant alterations of AML blast proliferation when cells were cultured in medium alone or together with IL-4, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. In contrast, IL-13 inhibited constitutive AML blast secretion of IL-1 alpha, IL-1 beta, IL-6, tumor necrosis factor alpha, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. IL-4 caused a similar inhibition of constitutive cytokine secretion as IL-13, but IL-13 caused no additive inhibition in the presence of IL-4. In contrast to IL-4 which increased AML blast release of IL-1 receptor antagonist, IL-13 caused no significant alteration of blast release of the receptor antagonist. IL-13 inhibited cytokine secretion also in the presence of neutralizing IL-4 and IL-10 antibodies and when AML blasts were cultures in serum-free conditions. We conclude that IL-13 has a direct and nontoxic inhibitory effect on constitutive AML blast cytokine secretion.
Leukemia 1996 Sep
PMID:Effects of interleukin-13 on cytokine secretion by human acute myelogenous leukemia blasts. 875 69


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