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)

Mouse monoclonal antibodies were produced against MT-2 cell line derived from adult T-cell leukemia or human T-cell leukemia virus-rich fraction therefrom. Two IgG1 antibodies, Ta60a and Ta60b, were found to be reactive not only with cell lines derived from adult T-cell leukemia or cutaneous T-cell lymphomas, but also with activated peripheral blood lymphocytes, suggesting the similarity of Ta60 antigen group to Tac antigen which is present on interleukin 2 receptor. Thus, the relationship among these antigens was studied. Two Ta60 antibodies and Tac antibody immunoprecipitated the molecule with almost identical electrophoretic mobility, approximately a Mr 60,000 antigen from [3H]glucosamine-labeled activated peripheral blood lymphocytes or MT-2, MT-1, or ATN-1 cells from adult T-cell leukemia and a Mr 53,000 antigen from HUT-102 cells derived from cutaneous T-cell lymphomas. Further, Tac antibody was found to immunoprecipitate Ta60b molecule on 125I-labeled MT-2 cells by sequential immunoprecipitation, indicating that these two epitopes are on the same molecule. Antibody binding inhibition assays with either 3H-labeled Ta60a or Ta60b antibody demonstrated that Ta60a and Tac are the same epitope, but different from Ta60b. Thus, at least two epitopes were demonstrated to be present on interleukin 2 receptor molecule. However, Ta60b antibody showed almost no blocking effects on proliferation of an interleukin-2-dependent cell line, whereas Ta60a antibody did. Various hematopoietic tumor cells were typed with these two antibodies, but the results with Ta60b antibody were described, because they showed a similar specificity. Ta60b antibody reacted with all adult T-cell leukemia cases, but did not react with T-cell acute lymphoblastic leukemia, lymphoblastic lymphoma, or mature T-cell lymphoma. Interestingly, 3 of 12 acute myeloblastic leukemia and 2 of 5 chronic myelocytic leukemia in blastic crisis showed positive reactions. One-third of B-cell chronic lymphocytic leukemia and B-cell lymphoma as well as a few B-cell lines were also weakly reactive with this antibody. A part of the results with direct tests was confirmed by the absorption tests. The results obtained demonstrated the presence of Ta60b on a certain fraction of malignant hematopoietic cells of other than T-cell origin.
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PMID:Two mouse monoclonal antibodies detecting two different epitopes of an activated lymphocyte antigen on adult T-cell leukemia cells. 257 77

The monoclonal antibody (MoAb) Bsp-1 was used to purify basophilic cells from leukemic blood of five patients with Philadelphia chromosome (Ph') positive chronic myeloid leukemia (CML) and two patients with acute myeloid leukemia (AML) characterized by the chromosomal translocation t(6;9)(p23;q34). When cultured, Bsp-1 positive cells from all CML and AML patients showed the same clonal karyotype changes observed in diagnostic buffy coat preparations, indicating that the basophilic cells were of leukemic origin. In contrast, T lymphocytes from four of five CML patients cultured in the presence of interleukin-2 (IL-2) showed a normal karyotype and were therefore not derived from the leukemic clone. Bsp-1 staining correlated with toluidine blue-positive basophils in chronic phase CML and with toluidine blue-negative blast cells expressing an immature myeloid phenotype in blast crisis CML and AML. Chromosome in situ hybridization showed that the ABL oncogene was translocated from chromosome 9 to chromosome 22 in the CML patients but remained on chromosome 9 in the AML patients. These results indicate that the breakpoint at 9q34 in CML is 5' of ABL, whereas the breakpoint at 9q34 in AML is 3' of ABL. Field inversion gel electrophoresis showed that the 9q34 breakpoint was not within 200 kb 3' of ABL in one of the AML patients, nor was there any rearrangement of the PIM oncogene locus at 6p21.
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PMID:Basophils (Bsp-1+) derive from the leukemic clone in human myeloid leukemias involving the chromosome breakpoint 9q34. 264 88

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.
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PMID:Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer. 266 33

In vivo administration of an anti-interleukin-2 (anti-IL-2) receptor monoclonal antibody is a potential new therapy for prevention of allograft rejection of a freshly transplanted organ. Such an approach is more selective than targeting all T cells, or even the CD4 or CD8 major subsets, because only the very recently activated cells should be affected. A clinical trial of anti-Tac monoclonal antibody is in progress in which 20 mg of the immunoglobulin G 2a (lgG2a) antibody is administered intravenously daily for 10 days after cadaveric renal transplantation. Combinations with and without azathioprine, and with varying doses of cyclosporine with prednisone, are being evaluated in a randomized trial. Results to date show a significant immunosuppressive effect of anti-Tac, as measured by a reduced incidence and later onset of acute rejection episodes compared with cyclosporine plus prednisone or cyclosporine plus azathioprine plus prednisone. Removal or cytodestruction of IL-2-receptor positive cells from the peripheral blood does not occur to any major degree, even though serum levels of the antibody are always detectable. In addition, functional studies of MLR, CML, and suppressor cell generation 4 days after cessation of anti-Tac administration show no significant difference between treated and control groups The effect of anti-Tac seems, therefore, to be limited to inhibition of IL-2-mediated T-cell growth during the period of administration, with recovery after a few days' lag period.
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PMID:Prophylactic use of monoclonal anti-IL-2 receptor antibody in cadaveric renal transplantation. 268 58

Our earlier studies demonstrated that about 55% of chronic myeloid leukemia (CML) patients in remission exhibited impaired natural killer (NK) cytotoxicity (low NK responders) while antibody-dependent cellular cytotoxicity (ADCC) of these patients, on chicken red blood cells as targets, was within normal range. In this paper, we have attempted to modulate the NK cytotoxicity of CML patients in remission with interferon (IFN) and interleukin-2 (IL-2) singly or together. ADCC using K562 target-directed monoclonal antibody (MAb) 4.6E10 was also modulated by treating the effectors with IFN or IL-2. Pretreatment of nonadherent mononuclear cells from peripheral blood (NAPBMNC) with IFN or IL-2 was found to result in 20 and 21% increase in target cell lysis in case of healthy donors, 79 and 98% increase in case of CML normal NK responders, and 164 and 159% increase in case of CML low NK responders. Combined use of IFN and IL-2 potentiated further the lymphocytotoxicity to 25% in healthy donors, 135% in normal NK responder CML patients and 283% in low NK responder CML patients. This treatment resulted in restoration of cytotoxicity of the latter group of patients to a normal level. The augmentation was seen in 80-100% CML patients. Although ADCC with chicken red blood cells as targets was within normal range, ADCC mediated with MAb to K562 cells was significantly lower in CML low NK responders (24.5%) than CML normal NK responders (42.4%) and healthy donors (65.9%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of natural killer and antibody-dependent cellular cytotoxicity by interferon and interleukin-2 in chronic myeloid leukemia patients in remission. 278 54

We examined the expression of cell-surface interleukin-2 (IL-2) receptor (Tac antigen) on peripheral blood leukemic cells and measured soluble IL-2 receptor p55(alpha) chain (sIL-2R) levels in sera from chronic myelogenous leukemia (CML) patients with blastic crisis. Flow cytofluorometric analysis performed by dual immunofluorescence in three cases demonstrated coexpression of Tac antigen with myeloid (CD13, CD14, or CD33) or lymphoid (CD10) antigen on significant proportions of peripheral blood leukemic cells. Radiolabeled IL-2-binding assay demonstrated the specific IL-2 binding sites in three cases examined. The exogenous IL-2, however, failed to induce proliferative response. A myeloid cell line, Yut-K3, established from peripheral blood leukemic cells from a CML patient with blastic crisis, also expressed cell-surface Tac antigen and CD13 concurrently. SIL-2R assay showed that Yut-K3 released a detectable amount of sIL-2R in its culture supernatant. The serum sIL-2R levels were significantly elevated (range: 2,580 to 172,000 U/mL) in 12 CML patients with blastic crisis and were slightly elevated in ten patients in chronic phase (range: 250 to 820 U/mL) and in three in accelerated phase (range: 790 to 1,305 U/mL) compared with those in 24 normal controls (range: 70 to 695 U/mL, P less than .01). These results indicated that the leukemic cells from CML patients with blastic crisis expressed and released IL-2 receptor (Tac antigen). Longitudinal studies performed in three cases of CML with blastic crisis showed that the change of serum sIL-2R level was closely associated with that of the number of peripheral blood leukocytes and blasts, the percentage of blasts and serum LDH levels, also suggesting that the serum sIL-2R level is a useful clinical indicator of the leukemic cell burden in vivo.
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PMID:Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis. 278 81

Basophils were isolated from the peripheral blood of two patients with Philadelphia positive-chronic myeloid leukemia using monoclonal antibody Bsp-1 and fluorescence activated cell sorting. DNA blot analyses demonstrated rearrangement of the breakpoint cluster region gene in the isolated basophils, which suggests their leukemic origin. Isolated T cells from these patients that were cultured for 14 days in the presence of interleukin-2 lacked rearrangement of the breakpoint cluster region gene and are therefore unlikely to be derived from the chronic myeloid leukemia clone.
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PMID:Basophils exhibit rearrangement of the bcr gene in Philadelphia chromosome-positive chronic myeloid leukemia. 325 49

Cytotoxic cells (CTCs) generated from peripheral blood lymphocytes of 5 chronic myeloid leukemia (CML) patients in remission on stimulation with autologous leukemic cells and allogeneic lymphocytes (3-cell assay), were propagated in vitro in interleukin-2 (IL-2)-containing medium and periodic stimulation with autologous leukemic cells, for a period of 4 to 6 months. During this period, the cells were assessed for phenotype and for cytotoxic responses in a 4-h 51Cr release microcytotoxicity assay. The CTCs continued to show specific lysis of autologous leukemic cells and bone marrow (BM) cells. However, the nonspecific lysis of natural killer (NK) targets and the proportion of cells showing NK phenotype (HNK-1 antigen) increased progressively on cultivation in IL-2-containing medium. Therefore cells showing CD8 phenotype and specific cytotoxic function were segregated by cloning CTCs under the condition of limiting dilution in the presence of allogeneic feeder cells and IL-2-containing medium. Three cytotoxic T cell (CTL) clones expressing CD3+, CD8+, and HLA DR+ phenotypes were obtained from CTCs of 2 CML patients. These clonoid populations, maintained in IL-2-containing medium and periodic antigenic stimulation with autologous leukemic cells, showed specific lysis of autologous leukemic cells and BM cells even at lower (10:1) effector:target ratios. They did not kill K562 (erythroblastoid leukemic NK target cell line) cells and autologous phytohemagglutinin-induced blasts. These clones apparently functioned in an MHC-restricted manner as they did not lyse allogeneic CML cells which would also express a similar set of maturation antigens if sensitization was, as it appeared, against these antigens. Finally, interaction of autologous BM cells with CTL clones reduced the colony forming potential of BM cells only to the extent of 18%-30%. The results therefore indicate that such CTL clones can possibly be used in adoptive immunotherapy as they showed minimal BM toxicity.
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PMID:Propagation of cytotoxic effectors from chronic myeloid leukemia patients and cloning of cytotoxic T cells. 326 15

We have shown that short-term incubation (45 min) of peripheral blood lymphocytes of normal donors with OKT3 monoclonal antibody (MoAb), directed against T-cell-associated antigen CD3, resulted in an acquisition of lytic activity against fresh leukemic cells. Induction of such antileukemia activity was specific for OKT3, since Leu-1 MoAb (directed against another T cell surface molecule, CD5) did not induce a lytic effect. The OKT3-generated antileukemia effect was displayed against various types of leukemia including chronic myelogenous leukemia and acute myelogenous leukemia of various histological subtypes (M1, M2, M5). We furthermore demonstrated that OKT3 MoAb substantially enhanced leukemia killing by interleukin-2 (IL-2)-activated killer cells obtained from peripheral blood of patients with leukemia. Of most importance was the observation that the combined treatment of effector cells with IL-2 and OKT3 MoAb resulted in the highest levels of lysis of both autologous and allogeneic fresh leukemic cells that have been observed in leukemic patients to date. Of importance was to note that OKT3 treatment was effective in induction of cytotoxic activity also in patients whose effector cells were unresponsive to stimulation with IL-2 alone. All of these observations suggest that IL-2-activated and OKT3-MoAb-treated effector cells may represent the most aggressive population of antileukemia-directed killer cells and may play a significant role in the treatment of human leukemia.
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PMID:Augmentation of antileukemia lytic activity by OKT3 monoclonal antibody: synergism of OKT3 and interleukin-2. 350 69

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


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