Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During long-term interferon alpha-2b (IFN) therapy of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) patients, short-term effects of tumor necrosis factor alpha (TNF) on peripheral leukocyte counts, as well as cortisol and corticotropin (ACTH) release were studied. TNF (40-160 micrograms/m2) was given as a 2-h infusion on 5 consecutive days every 3 weeks, in addition to s.c. daily IFN injections (4 mio U/m2), to four (two male/two female) patients, who had been treated for more than 8 months with IFN and additionally for 0-7 months with TNF. Leukocyte counts, cortisol, and ACTH were determined at 30-min intervals between 4 p.m. and midnight. Profiles were determined the day before and on day 1 of TNF therapy. Leukocyte numbers decreased 30 min after start of TNF administration and increased 30-60 min later with a rebound until the next TNF application. The increase of leukocyte counts was due mostly to neutrophil granulocytes. ACTH levels increased 30 min, cortisol 60 min, and leukocyte counts 90 min after start of TNF infusion. Metopirone, an inhibitor of cortisol synthesis given to one patient, suppressed the TNF-induced stimulation of cortisol secretion and subsequent increase of leukocyte counts, while ACTH blood levels were enhanced. It was concluded that leukocyte count increases after TNF/IFN administration might be related to TNF-evoked cortisol secretion.
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PMID:Relation between leukocyte counts and cortisol secretion in CML patients undergoing combined TNF alpha/IFN alpha therapy. 132 78

Normal and leukemic bone marrow cells were studied in the presence of tumor necrosis factor alpha (TNF) together with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in clonogenic assays. Cells of four normal volunteers, three patients with chronic myeloid leukemia, 16 patients with acute non-lymphocytic leukemia (ANLL), and six patients with myelodysplastic disorders were compared. Our results show four patterns of response to TNF in the presence of G-CSF or GM-CSF: (a) increased sensitivity to inhibition by TNF relative to the response of normal bone marrow cells; (b) response indistinguishable from normal bone marrow cells; (c) refractoriness to TNF at all doses; (d) synergistic growth stimulation with both G-CSF and GM-CSF. Leukemic cells of eight additional ANLL patients were incubated in a 3H-thymidine incorporation assay, and three patterns of reactivity to TNF were observed: (a) decreased 3H-thymidine uptake in the presence of TNF; (b) no response to TNF at all doses; and (c) increased 3H-thymidine uptake in response to TNF. Leukemic cells of 26 ANLL patients of various FAB-types were examined for the production of TNF mRNA by Northern blot analysis. TNF mRNA could be detected in cells of eight patients, predominantly in the M5B FAB type. Our data show that the growth response of leukemic cells to TNF is not uniform and was not determined by FAB category.
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PMID:Modulation of leukemic cell growth by tumor necrosis factor: action and expression in myeloid leukemia. 137 61

Patients with Philadelphia-positive chronic-phase chronic myelogenous leukemia (CML) resistant to interferon (IFN) alpha were treated in a phase I/II study with recombinant human tumor necrosis factor alpha to overcome IFN alpha resistance. Doses of 40, 80, 120 or 160 micrograms/m2 TNF alpha were given as 2-h infusions on 5 consecutive days every 3 weeks. IFN alpha (4 x 10(6) IU/m2 s.c., daily) treatment was continued. Six patients were treated, completing 1-24 (median, 12) treatment cycles. Five of the six patients achieved partial hematological remission, while the remaining patient had to stop treatment because of WHO grade 4 thrombocytopenia following the first TNF alpha cycle. No complete hematologic remission or cytogenetic improvement was seen. Side-effects were similar to those described for both substances alone. Maximum tolerable TNF doses usually varied between 80 micrograms/m2 and 160 micrograms/m2. To examine possible pathways of TNF activity in these patients, interferon receptor status and (2'-5')-oligoadenylate synthetase levels were examined in peripheral blood mononuclear cells. Both parameters remained unchanged during TNF alpha treatment. These preliminary data point to significant clinical efficacy of additionally applied TNF alpha in IFN alpha-resistant CML patients.
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PMID:Tumor necrosis factor alpha modifies resistance to interferon alpha in vivo: first clinical data. 139 38

The effect of recombinant human tumor necrosis factor alpha (TNF-alpha) on normal and chronic myeloid leukemia granulocyte-macrophage progenitors (CFU-GM) growing in semisolid agar cultures in the presence of recombinant granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor was studied. Granulocyte-macrophage colony-stimulating factor-dependent growth of normal and chronic myeloid leukemia bone marrow CFU-GM was greatly enhanced by TNF-alpha at doses of 0.1 to 100 units/ml. Growth enhancement included neutrophil, eosinophil, and monocyte-macrophage colonies and clusters at 7 and 14 days of culture. Since similar results were achieved with highly enriched progenitor cell populations, devoid of accessory cells, an indirect effect on CFU-GM growth through the release by accessory cells of other cytokines upon TNF-alpha stimulation was thus ruled out. By contrast, the same doses of TNF-alpha inhibited the growth of normal CFU-GM in granulocyte colony-stimulating factor-dependent cultures. Taken together, our findings indicate that the final effect of TNF-alpha on normal bone marrow granulocyte-macrophage progenitor growth is dependent on the specific growth factor interacting with it, and that both normal and chronic myeloid leukemia CFU-GM are equally responsive to the combined effects of TNF-alpha and a given colony-stimulating factor.
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PMID:Opposite effect of tumor necrosis factor alpha on granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor-dependent growth of normal and leukemic hemopoietic progenitors. 169 65

Interferon-gamma (IFN-gamma) has been reported to antagonize the stimulatory effect of various conditioned media on the growth of normal hematopoietic progenitor cells and clonogenic blasts from patients with chronic myelogenous leukemia (CML) and acute myeloblastic leukemia (AML). In the present study, using purified recombinant cytokines and homogenous cell populations, we provide evidence for a synergistic or additive effect of IFN-gamma with recombinant human (rhu) hematopoietic growth factors in the stimulation of clonogenic blasts from most AML patients examined. Under conditions of limiting cell concentration, rhuIFN-gamma alone showed little effect on blast proliferation, whereas in conjunction with recombinant human interleukin-3 (rhuIL-3), IFN-gamma significantly enhanced colony formation in 13 of 15 AML cases. Maximal stimulation was obtained at low concentrations of IFN-gamma (2 to 20 pmol/L) in four cases and at higher concentrations (700 to 7,000 pmol/L) in the remainder. IFN-gamma also synergized with recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) in 9 of 13 cases. Within 1 hour of exposure, IFN-gamma induced a twofold to fourfold accumulation of tumor necrosis factor alpha (TNF alpha)-specific transcripts in AML blasts and several AML cell lines that include HL-60 and OCI-AML 1. Further, the synergy between IFN-gamma and IL-3 on AML blasts was partially or completely abrogated by a TNF alpha neutralizing antibody, suggesting that growth enhancement by IFN-gamma may be mediated through TNF alpha production in AML blast culture. Exposure of normal precursors (burst-forming unit-erythroid [BFU-E] and colony-forming unit granulocyte-macrophage [CFU-GM]) to IFN-gamma also resulted in significant growth enhancement, suggesting that the proliferative response elicited by IFN-gamma was not limited to AML blasts. Finally, in M07-E, an IL-3-dependent human "megakaryoblastic" cell line, IFN-gamma also significantly enhanced IL-3-supported colony formation, much in the same way as in primary AML blasts. In contrast, IFN-gamma inhibited growth of all CSF-independent leukemic cell lines tested. This inhibition was partially alleviated by anti-TNF alpha antibody. In summary, our data indicate that IFN-gamma can enhance or antagonize cell proliferation, depending on the cell type. Further, TNF alpha appears to mediate the biologic effect of IFN-gamma either in growth stimulation or growth inhibition.
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PMID:Interferon-gamma enhances growth factor-dependent proliferation of clonogenic cells in acute myeloblastic leukemia. 171 25

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

We investigated the in vitro action of recombinant tumor necrosis factor alpha (TNF) on the clonal growth of normal and malignant myeloid cells. Clonogenic cells from six of nine myeloid leukemia cell lines were very sensitive to the effects of TNF with 50% of the colonies inhibited (ED50) by concentrations of TNF that ranged between 6 and 150 U/mL. A decrease in DNA, RNA, and protein synthesis and in cloning efficiency occurred within three hours of exposure of HL-60 promyelocytes to TNF. The TNF in combination with recombinant interferons produced an additive or synergistic inhibition of colony formation of HL-60 and THP-1 myelomonoblasts. Normal human CFU-GM are sensitive to TNF (ED50 between 100 and 50,000 U/mL), but their sensitivity to TNF depends on the source of colony stimulating factor (CSF) with T lymphocyte derived GM-CSF (recombinant or natural) partially protecting the CFU-GM from the suppression exerted by TNF (and interferons). In eight of 15 cases the clonogenic myeloid leukemia cells from patients with acute or chronic myeloid leukemia were more sensitive than normal CFU-GM using GM-CSF as a source of colony stimulating activity. Further studies showed that the action of TNF on myeloid leukemia cells probably can be only partially explained by differentiation. Our finding of a possible selective cytotoxicity to leukemic clonogenic cells by TNF suggests that TNF may have value in the therapy of some patients with myeloid leukemia.
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PMID:In vitro action of tumor necrosis factor on myeloid leukemia cells. 243 41

Previous studies using unseparated normal human bone marrow cells have indicated that recombinant tumor necrosis factor alpha (rTNF-alpha) can inhibit the in vitro colony growth by normal granulocyte/macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells in a dose-dependent manner. In the present studies, by using very low numbers of highly enriched normal bone marrow progenitor cell populations as target cells, we have extended these previous findings to provide convincing evidence that erythroid and myeloid colony growth suppression by rTNF-alpha is manifested by a direct interaction between rTNF-alpha and CFU-GM and BFU-E progenitor cells. In addition, the sensitivity of normal peripheral blood and chronic myeloid leukemia bone marrow CFU-GM and BFU-E colony growth to inhibition by rTNF-alpha was examined and found to be comparable with that of normal bone marrow CFU-GM and BFU-E. Although the continuous presence of high doses of rTNF-alpha (5000 units/ml) was required in methylcellulose cultures for maximal CFU-GM (90%) and BFU-E (70%) colony suppression, short-term exposure (24 to 72 hr) of normal bone marrow-enriched progenitor cells to rTNF-alpha, in the absence of hematopoietic growth factors, was sufficient to irreversibly suppress up to 50 to 65% of CFU-GM colony growth. In contrast, the number of BFU-E colonies was increased under these conditions. If, however, hematopoietic growth factors (Mo-T-cell-conditioned medium and erythropoietin) were present during preincubation of the cells with rTNF-alpha, BFU-E were then slightly suppressed while the extent of CFU-GM inhibition remained essentially the same. The suppressive effect of rTNF-alpha on erythroid and myeloid progenitor cell growth appears to be most pronounced on the more primative stages of committed progenitor cell development, since inhibition of CFU-GM- and BFU-E-derived colony growth progressively decreased with the delayed addition of rTNF-alpha to methylcellulose cultures. [3H]Thymidine incorporation was also inhibited by rTNF-alpha in normal bone marrow-enriched progenitor cell populations stimulated to proliferate in liquid culture by colony-stimulating factors. This effect was transient, however, since the activity of rTNF-alpha declined after the first 24 h of culture at 37 degrees C, particularly at low doses of rTNF-alpha where the activity was completely lost after 48 h of culture. This loss of activity appeared to be due to a decreased sensitivity of progenitor cells to the antiproliferative effects of tumor necrosis factor (TNF) after an initial exposure rather than a lack of available TNF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of recombinant human tumor necrosis factor on highly enriched hematopoietic progenitor cell populations from normal human bone marrow and peripheral blood and bone marrow from patients with chronic myeloid leukemia. 304 Feb 31

Recombinant technology-produced tumor necrosis factor alpha (rTNF-alpha) inhibits clonogenic growth of normal granulocyte-macrophage colony-forming cells (GM-CFC) when it is continuously present in the culture medium. In our studies, day 7 and day 14 GM-CFC were inhibited and showed similar response. A decrease in the number of large colonies accounted for most of the inhibition, whereas growth of small clusters was inhibited to a lesser extent. Comparable inhibition was observed when bone marrow cells were cloned at low (2.5 x 10(4)/ml) or high (10 x 10(4)/ml) cell densities. A similar degree of inhibition by rTNF-alpha was found when conditioned medium from the human placenta or a bladder carcinoma cell line was used as the source of the colony-stimulating factors (CSF). The dose-response curve of GM-CFC to rTNF-alpha was sigmoidal, the maximum inhibition (90%) occurring at approximately 100 ng/ml of rTNF-alpha. Short-term treatment of bone marrow in suspension culture for 2 hr did not affect the subsequent colony formation, suggesting that TNF had an antiproliferative rather than a direct toxic effect on normal GM-CFC. GM-CFC derived from previously untreated patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) showed an in vitro dose response to rTNF-alpha similar to that of normal GM-CFC. Inhibition of colony formation by CML-derived GM-CFC was more pronounced than GM-CFC from normal marrows, especially at low concentrations of rTNF-alpha. An increase in the concentration of rTNF-alpha above 250 ng/ml had no further effect on colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor and human hematopoiesis: II. Inhibition and mode of action on normal and chronic myelogenous leukemia-derived granulocyte-macrophage progenitor cells. 314 10

Leukemia cells from a patient with chronic myelogenous leukemia (CML) in accelerated phase were used to generate CD4+, CD8- T lymphocyte lines from an unrelated normal subject sharing HLA-A2 and DR4 with the patient. In chromium release cytotoxicity assays, lines showed specificity for patient cells and were unreactive against third-party CML and K562 cells. Cytotoxicity was blocked by anti HLA-DR on target cells. Some lines showed preferential cytotoxicity to PHA-induced lymphoblasts and some to CML cells. There was a broad correlation between cytotoxicity to CML cells by 51Cr release and CFU-CM inhibition. However, even weakly cytotoxic lines were inhibitory to CML CFU-GM. This effect was partly mediated by the T cell line supernatant: four of five supernatants tested inhibited the growth of CFU-GM. Antibody neutralization studies demonstrated the presence of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in these supernatants. There was a greater suppression of CML CFU-GM when compared with CFU-GM from normal individuals. One supernatant from a noncytotoxic T cell line stimulated CFU-GM and was demonstrated by antibody neutralization studies to contain interleukin-3 (IL-3) and GM-CSF. These data indicate that alloreacting CD4 cells exert both cytotoxic and cytokine-mediated antileukemia effects which may relate to the graft-vs.-leukemia (GVL) effect in CML following bone marrow transplantation.
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PMID:Cellular and cytokine-mediated effects of CD4-positive lymphocyte lines generated in vitro against chronic myelogenous leukemia. 755 22


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