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

The adenine nucleoside analogue fludarabine phosphate in combination with cytosine-arabinoside (Ara-C) and granulocyte-colony stimulating factor (G-CSF) has recently proved effective in the treatment of poor-prognosis acute non-lymphoid leukaemia. We used this triple combination in a case of Ph1+ chronic myeloid leukaemia (CML) unresponsive to alpha interferon that had progressed to acute phase after 5 months of treatment with 6-mercaptopurine plus hydroxyurea. The patient was treated with four courses of fludarabine 30 mg/m2 + Ara-C 2 g/m2 (days 1-5) and G-CSF (from day 0 to polymorphonuclear (PMN) recovery). Bone marrow blasts decreased from 80% to less than 5%, and karyotyping showed a progressive clearance of Ph1+ metaphases (from 100% to 9% after the fourth course). The patient is presently receiving autologous bone marrow transplantation (ABMT). This therapeutic success in a patient for whom conventional treatment would usually be ineffective makes this combination worthy of further studies, in view of its wider use as a preparative regimen to ABMT in CML.
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PMID:FLAG (fludarabine+cytosine arabinoside+G-CSF) induces complete remission in acute-phase chronic myeloid leukaemia: a case report. 751 68

The effect of basic and acidic fibroblast growth factors on leukemic blast progenitors was studied in 14 patients with acute myelogenous leukemia and in one patient with chronic myelocytic leukemia in myeloid crisis. bFGF and aFGF stimulated blast-colony formation by leukemic blast progenitors cultured in methylcellulose in two patients. In the other 13 patients, no significant effect of either FGF on blast-colony formation was noted. The combination of bFGF or a FGF and G-CSF, GM-CSF, interleukin-3, or stem cell factor (SCF) had a synergistic effect on blast-colony formation in three patients. In the other patients, however, synergism between FGF and CSF was not detected. In fact, bFGF was found to suppress the stimulation of blast-colony formation due to GM-CSF in one of 10 patients and that due to SCF in four of eight patients. aFGF suppressed the stimulation of blast-colony formation due to GM-CSF in two of 11 patients and that due to SCF in four of eight patients. The results show that bFGF and aFGF do not directly play a major role in leukemic hematopoiesis but that they may modulate the cytokine network affecting leukemic cell growth.
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PMID:The effect of basic and acidic fibroblast growth factors (bFGF and aFGF) on the growth of leukemic blast progenitors in acute myelogenous leukemia. 754 15

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
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PMID:Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation. 754 18

Cytokines are a class of signal peptides which represent a major communication network in living organism. Over the last decade, the discovery, cloning and purification of hematopoietic cytokines (interleukins, hematopoietic growth factors) has increased our understanding of the regulation, proliferation, differentiation and function of hematopoietic cells. More recently, the large scale production of the recombinant forms of these molecules has enabled to treat the patients with pharmacologic doses of cytokines. The therapeutic activity of interferon-alpha (IFN-alpha) has been demonstrated in patients with chronic myeloid leukaemia and other chronic myeloproliferative syndromes. IFN-gamma is useful in the prevention of infections in patients with chronic granulomatous disease. Erythropoietin (EPO) was the first hematopoietic growth factor available for clinical use, initially to treat anaemia in renal failure patients. The next cytokines introduced into the clinic were granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF). They are used successfully in haematological malignant disorders to stimulate granulopoiesis after chemotherapy or bone marrow transplantation and to help mobilise marrow stem cells for peripheral blood stem cell transplantation. Interleukin (IL)-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. However, the value of these agents remains to be established.
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PMID:[Cytokines in the treatment of blood diseases]. 754 26

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

To confirm the reported correlation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) serum concentrations with nonhematologic toxicity after cytotoxic chemotherapy and to examine their possible effects on hematopoiesis, we evaluated serum TNF-alpha and IL-6 concentrations every 3 days during 21 chemotherapy cycles in 11 patients with acute myelogenous leukemia (AML) and one patient with chronic myelogenous leukemia in blast crisis (CML-BC). All patients developed grade IV hematologic toxicity. In 13 patient cycles, grade III-IV nonhematologic toxicity developed: hepatic (nine), pulmonary (six), and stomatitis (five). In these patient cycles, IL-6 concentrations increased from 10.1 pg/mL (4.6-15.6, 95% CI) before nonhematologic toxicity to 64.8 (5.3-124.2, 95% CI) at the onset of toxicity (p = 0.02). TNF-alpha concentrations were not detectable before nonhematologic toxicity but increased to 20.4 pg/mL (not detectable [ND]-45.5, 95% CI) at the onset of grade III-IV toxicity. In six patient cycles, grade II nonhematologic toxicity developed: hepatic (five), pulmonary (one), and stomatitis (two). In these six, IL-6 concentrations increased from 12.1 pg/mL (6.8-17.4, 95% CI) before toxicity to 21.4 (11-31.8, 95% CI) at the onset of toxicity (p = 0.03). TNF-alpha concentrations were detectable in one patient cycle before toxicity and detectable in only two patient cycles at the onset of toxicity. The peak IL-6 and TNF-alpha concentrations did not correlate with the onset of nonhematologic toxicity in 87% of patient cycles. In patient cycles with a cumulative IL-6 area-under-the-serum concentration vs. time curve (AUC) > 1000 pg/mL.d, platelet recovery (> 30 x 10(9)/L and platelet transfusion-independent) occurred earlier at 21.9 days (18.7-25.1, 95% CI) compared to the 30.6 days (23.6-37.5, 95% CI, p = 0.02) in patient cycles with an IL-6 AUC < 1000 pg/mL.d. Patient cycles with a cumulative TNF-alpha AUC > 150 pg/mL.d required a mean of 17.5 units of red blood cells (RBCs) (9.3-25.7, 95% CI) compared to patient cycles with an AUC < 150 pg/mL.d, which required only 8.9 units of RBCs (6.2-11.7, 95% CI, p = 0.03). The peak concentration and AUC for IL-6 and TNF-alpha were not significantly different between those receiving growth factors (G-CSF, six; GM-CSF, one) and those not receiving growth factors (14). Endogenous IL-6 and TNF-alpha serum concentrations increase in patients who experience nonhematologic toxicity and correlate with hematologic recovery after chemotherapy.
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PMID:The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia. 758 79

Clonogenic cell culture assay was used to evaluate the effect of mast cell growth factor (MGF) on peripheral blood granulocyte-macrophage (GM) progenitors in 26 patients with myeloproliferative disorders (MPDs). MGF alone had a statistically significant stimulatory effect on GM colony formation, as also did interleukin-3 (IL-3) and GM colony-stimulating factor (GM-CSF), although the progenitors could form colonies spontaneously as well. When MGF was combined with either IL-3 or GM-CSF the effect was additive and was as great as that achieved with a mixture of IL-3, GM-CSF, G-CSF and IL-6. The highest colony-forming capacity of all was seen when MGF was added to the above mixture. Within the subgroups of MPDs, the stimulatory effect of MGF was significant in polycythemia vera (PV), essential thrombocythosis (ET) and chronic myelogenous leukemia (CML). MGF was the most potent single factor in PV, while GM-CSF was most effective in idiopathic myelofibrosis and both IL-3 and GM-CSF in CML. The fact that the ability of MGF to induce colony growth varied between the subgroups of MPDs may mean that the target progenitors in these diseases are biologically different. In conclusion, MGF, either alone or with others, was a potent growth factor for GM progenitors in MPDs.
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PMID:The effect of mast cell growth factor on peripheral blood granulocyte-macrophage colony-forming cells in methylcellulose in myeloproliferative disorders. 758 39

The expression of the ectoenzyme gamma-glutamyl transpeptidase (EC2.3.2.2., gamma GT) was investigated by flow cytometry on populations of peripheral blood mononuclear cells (PBMC) from healthy subjects and patients suffering from several types of leukemia before and under chemotherapy. In unstimulated PBMC, 28% of these cells were found to be gamma GT positive. The highest expression was measured on monocytes (CD14/gamma GT+ cells: 60%). Within the subsets of T lymphocytes (CD3/gamma GT+ cells: 18%) we saw no clear differences between CD4+ and CD8+ cells. B lymphocytes, NK cells, and activated cells showed low expressions (up to 10%). Treatment of PBMC with mitogens, alpha-IFN, IL-2, and GM-CSF did not affect the enzyme expression on normal mononuclear cells (MNC). However, a rapid increase of gamma GT+ cells was found in the presence of glutathione (GSH) and n-acetyl cysteine (nAC), particularly on monocytes, B cells, and NK cells. Comparing 40 healthy subjects and untreated patients suffering from leukemias, a significantly higher expression of gamma GT+ cells in the total MNC populations (B-CLL: 57%, CML: 62% gamma GT+ cells) was observed in B-chronic lymphocytic leukemia (B-CLL) and chronic myelogenous leukemia (CML), whereas other leukemias did not show clear differences. Most interestingly, the gamma GT expression was diminished in all populations of CML cells after 5 h of incubation in the presence of 10 units/ml IFN-alpha. These data suggest a possible protective role of gamma GT in MNC and a regulatory function of this enzyme in the development of CML.
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PMID:gamma-Glutamyl transpeptidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias. 759 85

A significant fraction of patients with chronic myelogenous leukemia (CML) in the chronic phase have durable hematologic remissions following treatment with interferon-alpha. Some clinical trials are beginning to show a modest overall survival advantage with interferon compared to hydroxyurea. The only curative therapy for CML is allogeneic bone marrow transplantation. In chronic lymphocytic leukemia (CLL), stable early stage disease requires no treatment. Recent trials have confirmed that several new purine analogues are effective in CLL. In acute myeloid leukemias there appears to be a dose-dependent effect on remission and intensified treatment may increase the percentage of disease free survivors. Hemopoietic growth factors may reduce treatment-related morbidity and mortality. Enhancement of cytotoxicity by prestimulation with GM-CSF is still controversial. All-trans retinoic acid induces remissions in 80% of patients with acute promyelocytic leukemia by forcing the leukemic promyelocytes to maturation. Allogeneic bone marrow transplantation is effective in high risk patients with Philadelphia chromosome positive acute lymphocytic leukemia (ALL), in patients with relapse or resistant acute myelogenous leukemia (AML) or ALL. In patients with ALL a risk-adapted therapy including allogeneic and autologous bone marrow transplantation and the use of hemopoietic growth factors to improve supportive therapy may result in more cures.
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PMID:[Current aspects of therapy in chronic and acute leukemias]. 762 46

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.
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PMID:Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. 767 Jan 18


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