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)

The effects of various compounds which modulated the intracellular signal transduction on the induction of class I major histocompatibility complex (MHC) antigens by recombinant human interferon-gamma (rIFN-gamma) were investigated using K562, chronic myelogenous leukemia cells. Class I or class II MHC antigens were not expressed in untreated K562 cells and rIFN-gamma (600 units/ml) weakly induced class I antigens on the cells. Among the compounds tested, verapamil but not the calcium ionophore A23187 enhanced the rIFN-gamma-induced class I antigen expression at both the surface molecule and mRNA levels and enhancement by verapamil occurred in a dose-dependent manner at non-toxic concentrations examined (approximately 50 microM). Verapamil alone had no inducible effect on MHC antigen expression. Deprivation of Ca2+ in culture medium by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) could not cause an enhancement of class I antigen induction by rIFN-gamma. Simultaneous exposure of K562 cells to rIFN-gamma (600 units/ml) and recombinant human tumor necrosis factor (rTNF; 1000 units/ml) in combination with verapamil (50 microM) resulted in a further increase of class I antigens in the cells. The expressions of c-myc oncogene in K562 cells were not changed when the cells were treated with rIFN-gamma (600 units/ml) or verapamil (50 microM), either alone or in combination. These results indicate that verapamil synergistically interacts with rIFN-gamma on the class I antigen induction in K562 cells irrespective of c-myc gene expression and that class I antigen induction in this cell line may not be relevant to calcium influx triggered by IFN-gamma.
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PMID:Effect of verapamil on the class I major histocompatibility complex antigen expression in K562 chronic myelogenous leukemia cells treated with recombinant human interferon-gamma. 151 24

Therapy with interferon-alpha results in complete cytogenetic remission in 15-20% of patients with chronic myelogenous leukemia. Even during prolonged clinical follow-up, most of these patients do not relapse. However, because of the limited sensitivity of cytogenetic techniques (approximately 5%) and Southern blots (approximately 1%), it is uncertain whether the residual malignant clone becomes extinct or persists below the limit of detection in these patients. We used polymerase chain reaction to amplify the chimeric BCR-ABL transcripts in 18 patients with chronic myelogenous leukemia who became Ph1 chromosome negative while receiving treatment with interferon-alpha, either alone or in combination with interferon-gamma. At the time of study, these patients had been Ph1-negative for a median of 22+ months. Fifteen patients were positive for residual BCR-ABL transcripts. No residual BCR-ABL message was detected on analysis of multiple serial samples in three patients. In order to confirm these results, the samples from these three patients, along with positive and negative controls, were analyzed by two independent laboratories in a blinded fashion. In the first laboratory, RNA specimens from all three patients were considered negative using chemiluminescent acidinium-ester-labeled probes. In the second laboratory, samples from all three patients were also negative by conventional polymerase chain reaction (PCR). However, when a second round of amplification was carried out on the amplified samples using a different combination of primers, samples from two of the three patients were positive. The results confirm the presence of a small proportion of BCR-ABL-positive cells in the majority of patients who are in complete remission and highlight some of the potential problems of PCR-based analysis. There is a need to standardize PCR methodology and potential confounding factors need to be addressed before PCR can be generally applied to analysis of minimal residual disease in CML. The implications of BCR-ABL positivity for these patients are discussed.
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PMID:Minimal residual disease in interferon-treated chronic myelogenous leukemia: results and pitfalls of analysis based on polymerase chain reaction. 164 Jul 25

We report herein that defective natural killer (NK) cell cytotoxicity, NK cytotoxic factor (NKCF) production and NK target binding ability of patients with chronic myelogenous leukemia (CML) are functionally restorable after short-term culture (less than 1 week) with recombinant interleukin-2 (rIL-2). We have previously reported that, despite normal to increased numbers of CD16+ large granular lymphocytes, fluorescence-activated-cell-sorted NK cells from CML patients are profoundly defective in NK cell activity and are unable to lyse the CML blast-crisis-derived, NK-sensitive target K562. Since we and others have also previously shown that the defective NK cytotoxicity from CML patients is restorable after 1-4 weeks of incubation with rIL-2, we therefore deemed it important to study the kinetics of IL-2-mediated NK restoration at earlier time intervals (less than 1 week). In the present report, we have demonstrated a significant restoration of NK cell cytotoxicity in CML patients against K562 after 5 days of short-term culture with rIL-2. In addition, recovery of NKCF production and restoration of target-binding capacity to normal levels by NK cells from CML patients were also observed after short-term (less than 1 week) rIL-2 treatment. Finally, we have demonstrated in the present report that adherent cells and peripheral-blood lymphoid cells from CML patients, as compared to normal controls, are unable to produce IL-1 beta and interferon-gamma, respectively, after stimulation with phorbol myristate acetate (IL-1 beta) and phytohemagglutinin-M (interferon-gamma).
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PMID:Natural killer cell immunodeficiency in patients with chronic myelogenous leukemia. IV. Interleukin-1 deficiency, gamma-interferon deficiency and the restorative effects of short-term culture in the presence of interleukin-2 on natural killer cytotoxicity, natural killer-target binding and production of natural killer cytotoxic factor. 188

Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treat 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.
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PMID:Interferon alfa-2c in chronic myelogenous leukemia (CML): hematologic, cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma. 212 Dec 99

We demonstrated the clinical effectiveness of recombinant interferon-gamma (rIFN gamma) (Biogen) in 18 patients with Philadelphia-positive chronic myeloid leukemia. Sequential cytogenetic studies and molecular analyses of the breakpoint cluster region and for immunoglobulin and T cell rearrangements were performed every 3-4 months. In 13 patients who received treatment for a minimum of 3 months, the majority were treated with 1.5 mg/m2, t.i.w., i.v. Nonhematologic effects--particularly chills, rigors, myalgia, fatigue, headaches, and nausea--were significant. Complete or partial hematologic responses were observed in six patients, two of whom had approximately 20% normal metaphases after an average of 74 weeks of treatment. However, reversion to 100% Ph+ cells occurred 30 weeks later. In these two patients, in whom normal metaphases were found, no changes were observed in the presence of rearrangements of the breakpoint cluster region. In addition, the marrows remained hypercellular, and the leukocyte alkaline phosphatase score and B12 levels remained abnormal. No immunoglobulin or T cell beta-chain gene rearrangements were found. These data indicate the clinical effectiveness of rIFN gamma in some patients with chronic myeloid leukemia, although the fundamental nature of the disease is unaltered by this form of treatment.
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PMID:Recombinant gamma-interferon has activity in chronic myeloid leukemia. 215 24

The modulation of growth of normal and leukemic myeloid progenitor cells in soft agar cultures by recombinant human tumor necrosis factor-alpha (TNF alpha) and recombinant human interferon-gamma (IFN gamma) was investigated. TNF alpha inhibited colony formation of all colony types representing different maturational stages of normal progenitor cells committed to the myeloid lineage with different orders of sensitivity. Blast-type colonies derived from patients with acute myelogenous leukemia were more sensitive to TNF alpha inhibition than progenitor cells purified from normal bone marrow or bone marrow from patients with stable-phase chronic myelogenous leukemia. The response of most colony types to IFN gamma was poor. However, when IFN gamma was administered together with TNF alpha, synergistically enhanced antiproliferative effects were detected in all colony types tested. The antiproliferative action of IFN gamma on myelopoiesis was enhanced in culture by the presence of autologous monocytes, presumedly by inducing endogenous production of TNF alpha. However, TNF alpha seemed to act directly on the progenitor cells themselves to suppress their clonal growth, rather than involving accessory marrow elements such as monocytes and/or T lymphocytes.
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PMID:The suppressive effects of recombinant human tumor necrosis factor-alpha on normal and malignant myelopoiesis: synergism with interferon-gamma. 313 11

Relapse is a major concern in autologous bone marrow transplantation (BMT). Therefore, purging of bone marrow to reduce the amount of tumor cells reinfused into the patient is widely used. Immunologic effector cells such as lymphokine activated killer (LAK) cells are attractive for purging of bone marrow since these cells might have an additional in vivo effect on tumor cells in contrast to other purging protocols. In patients with chronic myelogenous leukemia (CML), LAK cells can only be used in some patients for purging bone marrow since LAK cells possess no or only limited cytolytic activity against autologous CML tumor cells in most cases. In this study, we investigated the effect of autologous and allogeneic cytokine-induced killer (CIK) cells on tumor cells from patients with CML. CIK cells have been generated from peripheral blood lymphocytes by incubation with interferon-gamma on day 0, interleukin-1, interleukin-2 and a monoclonal antibody against CD3 on day 1. In contrast to LAK cells, CIK cells were able to lyse both autologous and allogeneic cells from patients with CML as determined by a 51Cr release and a tumor colony assay. The cytotoxicity of CIK cells against CML cells was confined to the CD56+ population. CIK cells showed no major toxic effect on hematopoietic progenitor cells when tested in CFU-GM assays. CIK cells eliminated three orders of magnitude of K562 cells and less than one order of magnitude of progenitor cells (25% reduction). This represents a differential effect of CIK cells on tumor and progenitor cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potential of autologous immunologic effector cells for bone marrow purging in patients with chronic myeloid leukemia. 753 1

Previously, a subset of T cells co-expressing the myeloid antigen CD33 has been described in patients with acute myelogenous leukaemia. However, normal lymphocytes have been viewed as not expressing the CD33 antigen. We have developed culture conditions which allow for the rapid expansion of CD3+CD33+ cells from patients with myeloid leukaemia as well as normal individuals. The protocol for cellular expansion includes the addition of interferon-gamma on day 0, interleukin-1, interleukin-2 and a monoclonal antibody against CD3 on day 1 to peripheral blood lymphocytes. Using this protocol, total cell number increased more than 600-fold within 16 d of culture. Cells could be kept in culture for more than 6 months. Cells of the CD3+CD33+ phenotype increased to 15.2 +/- 4.6% using this protocol after 16 d in culture. These cells have been characterized by flow cytometry and have been found to express the alpha, beta T-cell receptor, co-express the CD2, CD5, CD7 and HLA-DR antigens and did not express CD14 or CD15 antigens. Cells of the CD3+CD33+ phenotype were unable to lyse tumour cells as determined in a 51Cr release assay. In patients with chronic myeloid leukaemia. CD3+CD33+ cells seem to be negative for expression of bcr/abl transcript in contrast to CD33- cells. Our data suggest that CD3+CD33+ cells do exist in peripheral blood from normal individuals.
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PMID:Propagation of large numbers of cells of a human mixed-lineage T-lymphoid/myeloid. 764 87

The effects of interferon-gamma (IFN-gamma) and/or tumor necrosis factor-alpha (TNF-alpha) on the growth of leukemic blast progenitors in 6 acute myeloblastic leukemia (AML) patients, 1 chronic myelocytic leukemia (CML) patient in blast crisis and a granulocyte colony-stimulating factor-(G-CSF-) dependent OCI/AML1a cell line established from an AML patient, were studied. Cells of fresh blood samples and the OCI-AML1a cell line were cultured in methylcellulose media and suspension culture in the presence of G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) supplemented as a growth stimulatory factor. Both cytokines suppressed the primary and secondary colony formation in methylcellulose culture of leukemic blast progenitors. The recovery of clonogenic cells in suspension culture was also suppressed by IFN-gamma and TNF-alpha. The primary colony formation in methylcellulose reflects the terminal divisions of leukemic blast progenitors, while the secondary colony formation in methylcellulose and the clonogenic cell recovery in suspension have been considered to reflect their self-renewal capacity. Therefore, IFN-gamma and TNF-alpha are considered to be effective in suppressing not only the terminal divisions but also self-renewal of leukemic blast progenitors. When both cytokines were added simultaneously to cultures, the suppressive effect of each cytokine was enhanced. The results may suggest the effectiveness of IFN-gamma and TNF-alpha in the treatment of leukemia.
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PMID:Combined effect of interferon-gamma and tumor necrosis factor-alpha causing suppression of leukemic blast progenitors in acute myeloblastic leukemia. 769 1

Cytokines have been widely tested in clinical trials during recent years and beneficial responses have been observed in a variety of malignant, infectious and autoimmune diseases. Interferon-alpha induces remissions in patients with certain hematological malignancies such as hairy cell leukemia and chronic myelogenous leukemia. A proportion of patients with chronic viral hepatitis is cured upon application of interferon-alpha. Treatment with interferon-gamma reduces the number of infections in patients with chronic granulomatous disease. In addition, several chronic infections with intracellular pathogens also respond to treatment with this cytokine. With the exception of some patients with renal cell carcinoma and malignant melanoma, solid tumors are largely resistant to administration of these cytokines. Cytokine treatment has changed the outlook for a small group of patients with selected chronic diseases. However, clinical experience with cytokines is still limited and only interferons have been tested for treatment of a variety of diseases. Thus, it seems reasonable to expect that more cytokine-responsive diseases might be identified by continued research efforts.
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PMID:Cytokine therapy of neoplastic and inflammatory disease. 832 83


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