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 growth-inhibitory activity of recombinant human interferon-beta (ReIFN-beta) against cultured human cells was compared with that of natural human fibroblast interferon-beta (IFN-beta), and the influence of deficiency of carbohydrate on the anticellular activity was examined. The IC50 (concentration of drug required for 50% inhibition) of ReIFN-beta against 14 human cell lines was almost equivalent to that of IFN-beta, when the cells were cultured for 7 days and ReIFN-beta or IFN-beta was added on day 0 and exchanged every day from day 1 to day 6. The most sensitive cells (ICE less than 10 units/ml) were Daudi lymphoma cells and 3 melanoma cell lines, and the most insensitive cells (IC50 greater than 10(3) units/ml) were HeLa S3/IS cells (insensitive line) and CCRF-CEM leukemia cells. The other 8 cell lines were moderately sensitive to both interferons. As the intervals of exchange of ReIFN-beta or IFN-beta were extended, the growth-inhibitory activity of both interferons decreased. This phenomenon, which was more significant with ReIFN-beta than IFN-beta, was explicable in terms of the stability of both interferons incubated in the culture medium at 37 degrees. The species specificity of IFN-beta was not mediated by carbohydrate since the growth-inhibitory activity of ReIFN-beta against 2 mouse cell lines was almost equivalent to that of IFN-beta. These results indicate that the anticellular activity of ReIFN-beta was not essentially affected by deficiency of carbohydrate.
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PMID:Growth-inhibitory activity of recombinant human interferon-beta against cultured human cells. 664 44

Ninety-seven patients with refractory or relapsed acute myelogenous leukemia (AML), median age 37 years, received as salvage therapy a single course of idarubicin 6 mg/m2 as an intravenous (i.v.) bolus daily for 5 days, cytarabine (Ara-C) 600 mg/m2 i.v. for a period of 2 hours daily for 5 days and etoposide (VP-16) 150 mg/m2 for a period of 2 hours daily for 3 days (ICE protocol). Thirty-six patients were primarily resistant to standard inductive therapy with daunorubicin and Ara-C; 50 patients were in first relapse, three patients in second or third relapse, and eight patients in relapse after transplants. Forty-two (43%) out of 97 patients achieved complete remission, 11 patients died of infection or hemorrhage during induction, and 44 patients (45%) had resistant disease. Of the various variables examined, only disease status (i.e. refractory versus relapsed AML) was predictive for a significantly lower response rate. The median remission duration was 16 weeks; the overall median survival was 10 weeks. Nausea, vomiting, and oral mucositis were common but were rarely severe. No patient experienced treatment-related cardiac toxicity. In conclusion, the ICE protocol is a tolerable regimen providing effective antileukemic activity in patients with advanced AML. The evolution of this protocol in previously untreated patients with AML appears indicated.
Leukemia 1993 Feb
PMID:Idarubicin in combination with intermediate-dose cytarabine and VP-16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. The GIMEMA Cooperative Group. 842 73

Bcl-2 expression is able to confer drug resistance to chemotherapy-induced programmed cell death. Bax, a partner protein of bcl-2 with extensive aminoacid homology, is a promoter of apoptosis. Apparently the equilibrium of bcl-2 and bax hetero- and homodimers is important for the susceptibility of cells for stimuli inducing apoptosis. In this study we determined the role of bcl-2 to bax expression ratio, bcl-xL and ICE expression level for predicting clinical response to chemotherapy in acute myelold leukemia (AML). Bone marrow samples from 14 patients with AML were examined using an immunophosphatase staining method. Initial bone marrow blast portion was over 80% in all cases. Clinical response was defined by bone marrow aspiration 4 weeks after treatment initiation. There was a significant correlation between bcl-2 to bax expression ratio and clinical response (P < 0.005). No patients with a bcl-2/bax ratio >1.0 achieved complete remission after induction therapy. No significant correlation between bcl-2- and p-glycoprotein-expression was observed in this group. Conversely a high expression of ICE indicated a good clinical response (P < 0.01), whereas expression of bcl-xL had no influence on therapeutic success in this group.
Leukemia 1996 Jul
PMID:Association of bcl-2, bax, bcl-xL and interleukin-1 beta-converting enzyme expression with initial response to chemotherapy in acute myeloid leukemia. 865 95

Many anticancer agents induce apoptosis in human leukemia cells. Among the various leukemia cells, especially HL-60 cells and U937 cells are very sensitive to apoptosis upon anticancer agents treatment. A serine protease inhibitor TPCK and an ICE-like protease inhibitor VAD-FMK prevented etoposide, camptothecin and ara-C-induced internucleosomal DNA cleavage in human myeloid leukemia HL-60 and U937 cells. Using a cell-free system, we have examined the inhibitory mechanism of these inhibitors on anticancer agent-induced internucleosomal DNA cleavage. Our data indicate that serine and ICE-like proteases may be involved in anticancer agent-induced apoptosis at the different stages, and especially a serine protease may be closely associated with the final step for induction of DNA fragmentation during apoptosis in human myeloid leukemia HL-60 and U937 cells.
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PMID:[The mechanism of apoptosis induced by anticancer agents in human leukemia cells]. 874 73

The present study was designed to investigate the contribution of proteases in anticancer agents-induced apoptosis of human leukemia HL-60 cells. A serine protease inhibitor TPCK and an ICE-like protease inhibitor VAD-FMK prevented etoposide, camptothecin and ara-C-induced internucleosomal DNA cleavage. Using a cell-free system, we have examined the inhibitory mechanism of these inhibitors on etoposide-induced internucleosomal DNA cleavage. We found that cell lysates prepared from etoposide-treated HL-60 cells undergoing apoptosis contain the significant activity to induce internucleosomal DNA fragmentation in isolated nuclei. On the other hand, we could not detect such activity in the cell lysates from untreated HL-60 cells. Treatment of the cell lysates with a serine protease inhibitor TPCK abrogated the DNA fragmenting activity. An ICE-like protease inhibitor VAD-FMK had no effect on this DNA fragmenting activity in vitro. However, the formation of TPCK-sensitive DNA fragmenting activity in etoposide-treated cells was blocked by the VAD-FMK. These data indicate that serine and ICE-like proteases may be involved in etoposide-induced apoptosis at the different stages, and especially a serine protease may be closely associated with the final step for induction of DNA fragmentation during apoptosis in HL-60 cells.
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PMID:[The mechanism of apoptosis induced by anticancer agents in human leukemia HL-60 cells]. 877 71

We have previously reported that mobilization of Philadelphia (Ph) chromosome-negative progenitors is possible in a significant number of Ph1-positive acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML) patients. In this pilot study we employed the same approach for patients with RAEB-t, secondary AML (sAML) and therapy-related AML (t-AML). All patients except one had double or complex cytogenetic abnormalities in marrow cells before mobilization therapy. All patients received an idarubicin-containing regimen (mini-ICE protocol) followed by rh-G-CSF and the first leukapheresis was performed as they were recovering from aplasia. In six out of nine patients the leukapheresis product was entirely karyotypically normal, combined with a significant number of CFU-GM. CD34+ cells and LTC-IC. Recovery time from mobilization therapy was short and no patient died as a result of the procedure. To date, three patients have undergone autografting using their karyotypically normal collections, of which two (sAML) are alive with karyotypically normal marrow a few months after autografting.
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PMID:In vivo mobilization of karyotypically normal peripheral blood progenitor cells in high-risk MDS, secondary or therapy-related acute myelogenous leukaemia. 885 49

The roles of interferons (IFNs) in apoptosis are not fully understood. In this study we show that in the U937 monoblastic leukemia cell line, pretreatment with IFN-gamma enhanced sensitivity to apoptosis triggered by gamma-irradiation or antitumor agents (etoposide or adriamycin), as well as by anti-Fas antibody. In addition, IFN-gamma caused an increased expression of the interleukin-1 beta-converting enzyme (Ice) gene, following strong induction of the interferon regulatory factor-1 (IRF-1) gene, the product of which is a transcriptional activator of the Ice gene. An inhibitor of ICE/Ced-3 family proteases, Z-Asp-CH2-DCB, blocked apoptosis in control cells as well as in IFN-gamma-pretreated cells. These results suggest that enhanced susceptibility of IFN-gamma-pretreated cells to apoptosis is mediated through the induction of Ice by IRF-1. This pathway is not affected by interleukin-1 beta (IL-1 beta) since neutralizing antibody against IL-1 beta failed to suppress the IFN-gamma-mediated enhancement of cell death, and IL-1 beta itself did not mimic the effect of IFN-gamma.
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PMID:Interferon-gamma induces Ice gene expression and enhances cellular susceptibility to apoptosis in the U937 leukemia cell line. 895 78

In 1988, a 27-year-old male patient received an allogeneic BMT for leukemic relapse 8 months after ABMT for AML (M2) in first complete remission. Because of chronic GVHD of the liver CsA was administered until 1994. Nine months after discontinuation of CsA, locally advanced gastric granulocytic sarcoma (GS) was diagnosed without evidence of systemic relapse. The patient was treated with two courses of polychemotherapy (ICE, NOVIA). Granulocyte colony-stimulating factor (G-CSF)-mobilized donor buffy coat cells were reinfused after each chemotherapy cycle in an attempt to accelerate hematopoietic regeneration and to induce a graft-versus-leukemia (GVL) effect. Local irradiation and surgical resection of residual leukemic cells resulted in complete remission. Seventeen months from diagnosis of GS the patient relapsed again with multiple lesions and died of generalized bleeding during aplasia after a third course of polychemotherapy (ICE). In our patient donor peripheral blood stem cell support did not accelerate hematopoietic regeneration (time to neutrophil recovery > 0.5 x 10(9) g/l from the start of chemotherapy was 27 days after ICE and 36 days after NOVIA) and did not result in long-term disease-free survival.
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PMID:Polychemotherapy combined with G-CSF-mobilized donor buffy coat transfusion for granulocytic sarcoma after allogeneic BMT for AML. 915 72

The Tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the T-cell immortalizing properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. Tax can upregulate expression of TNF-alpha and TNF-beta, as well as potentiate apoptosis in activated T-cells and in serum starved murine fibroblasts. To examine the role of CD95 (APO-1/Fas) and ICE-proteases in Tax-mediated active T-cell death, Jurkat T cells expressing (APO(S)) or lacking (APO(R)) cell surface expression of CD95 (APO-1/Fas) were genetically modified to express hormone-inducible HTLV-1 Tax constructs. Hormone-inducible action of Tax alone was sufficient to promote programmed cell death in CD95-expressing Jurkat T-cell clones. In contrast, clones lacking CD95 surface expression were resistant to the antiproliferative action of Tax. Both APO(S) and APO(R) clones exhibited Tax-dependent upregulation of CD95 ligand and TNF-alpha. Blocking experiments suggested that while the apoptotic action of Tax critically required ICE-protease function it was largely independent of cell surface interaction of CD95 ligand or TNF-alpha with their corresponding receptors. These observations strongly implicate ICE-proteases in Tax-induced T-cell death, and suggest a possible involvement of CD95 in this process.
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PMID:ICE-proteases mediate HTLV-I Tax-induced apoptotic T-cell death. 917 2

An overwhelming body of evidence has shown that IL-1 beta is a major mediator of inflammatory disease (Tocci and Schmidt, 1996). The discovery of ICE, a unique processing enzyme involved in the production of active IL-1 beta, has provided a new approach to specifically block the production of this potent cytokine. Consequently, the discovery and development of inhibitors against the enzyme could hold great promise therapeutically. Potent inhibitors of the enzyme would be useful in the treatment of a number of important inflammatory diseases and potentially in the management of leukemia (Arend, 1993b; Estrov and Talpaz, 1996). A number of key questions must be answered before the therapeutic potential of such inhibitors can be realized. The development of a pharmaceutically acceptable cysteine proteinase inhibitor will almost certainly involve new chemical strategies gauged at safely inactivating the enzyme. For such inhibitors, it will be necessary to achieve selectivity for ICE from among the growing number of ICE family members while retaining potency. It will also be important to establish the level of inhibition of IL-1 beta required to achieve therapeutic efficacy. The studies comparing IL-1 beta- and ICE-deficient mice suggest that complete abrogation of IL-1 beta is required to achieve efficacy in models of inflammation. It is not known if this is the case in humans. Understanding the source of the residual IL-1 beta produced in ICE-deficient mice will be important in order to ascertain if a similar mechanism could generate active IL-1 beta in patients receiving if a ICE inhibitor. As for ICE itself, a number of formidable questions remain regarding its regulation and mechanism of activation. Answering these questions experimentally will present a major challenge due to the extremely low levels of enzyme present in cells. Studies on other family members may provide easier access to some of these questions and provide clues that can be applied to ICE. The components of the pathway involved in IL-1 trafficking and secretion are unknown, as are the mechanisms of ICE activation and regulation. Clearly other cellular proteins that have yet to be discovered will be involved in each of these processes, opening up new avenues of research in this field.
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PMID:Structure and function of interleukin-1 beta converting enzyme. 919 77


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