Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preliminary clinical studies including interleukin 2 (IL-2) in chemotherapy strategies for treatment of acute myeloblastic leukemia (AML) suggest that IL-2 may improve the disease-free survival of the patients. Because of reports showing interleukin 2 receptor expression on AML blasts, it is important to know whether IL-2 may directly influence these leukemic cells. In initial studies using flow cytometry to analyze surface expression of interleukin 2 receptors (IL-2R), we found expression of the IL-2R alpha chain on blast cells in 26% and of the IL-2R beta-chain in 81% of the patients. To confirm these results at the transcriptional level, we studied the expression of RNA of the IL-2R alpha, beta, and gamma chains by RT-PCR in the bone marrow of 38 newly diagnosed patients with AML and in three AML-derived cell lines. RNA of the alpha chain was detectable in 11/38 patients, the beta chain in 10/38 patients and the gamma chain in 30/38 patients with AML. Blast cells obtained from colonies growing in semisolid media expressed mRNA for IL-2R. RNA for all three IL-2R chains was expressed in lines KG1, HEL 92.1.7 and K562. In comparison with unstimulated cell lines, incubation of the three lines with various amounts of IL-2 over 3 and 14 days did not increase their growth or change message expression of IL-2R, IL-10, and TGF-beta and surface expression of the adhesion molecules CD 11, CD 18, CD 29 and CD 54. In conclusion, despite expression of IL-2 receptors, AML blasts do not respond to IL-2 by proliferation, message expression for various cytokine genes and surface expression of cellular adhesion molecules.
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PMID:AML blasts variably express interleukin 2 receptor alpha, beta or gamma chains without measurable effects on proliferation, cytokine message expression or surface expression of adhesion molecules upon stimulation with interleukin 2. 763 93

Microspectrofluorometry allows the analysis of fluorescent molecules such as anthracyclines in the nucleus of isolated living cells. Using this technique, we confirmed that the amount of doxorubicin or THP-doxorubicin incorporated into the nucleus was related to the resistant or sensitive character of K562 cells. It was then extended to the study of fresh leukemic cells and kinetic studies were performed allowing the calculation of the retention rate (RR) of anthracycline (THP-doxorubicin) into the cell nucleus. A reproducibility study confirmed the accuracy of the method. Blast cells collected in patients with acute myeloid (n = 22) or lymphoid (n = 8) leukemia, at diagnosis (n = 26), or in relapse (n = 4) have been studied. RR varied from 8 to 98% independently of the type of leukemia or the clinical status. RR did not correlate either with P-glycoprotein or with CD34 expression although this latter result should be confirmed on a higher number of subjects. Among 18 patients presenting with AML at diagnosis, 14 have been treated with intensive chemotherapy including anthracyclines; the only one who had resistant disease had the lowest RR value. In conclusion, the results obtained here show that microspectrofluorometry allows the performance of kinetic studies on fresh leukemic cells in order to quantify chemo-resistance phenomena related to drug transport.
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PMID:In vitro study of THP-doxorubicin retention in human leukemic cells using confocal laser microspectrofluorometry. 764 25

This paper reports a relapsed case of acute myeloid leukemia with intracranial, testicular and intestinal tumor formation. A-56-year-old male, diagnosed as M1 on September, 1988, entered complete remission on October 14, 1988, aided by JAL-SG and AML-85 regimen. Blast cells with Auer rods demonstrated 8;21 translocation lacking 11q with 30 of 30 analyzed bone marrow cells, and the following antigen pattern: CD5+, CD19+, CD33+, CD56+, HLA-DR+. After 4 courses of post remission therapy, the maintenance therapy was discontinued because of his liver dysfunction. He was discharged on May, 1989, and was seen as an out patient. He complained of left hemiplegia and was re-admitted on September 30, 1989. Though the bone marrow was in complete remission on September 4th, CT scan and MRI demonstrated intracranial tumor formation. Bone marrow relapse occurred on October 27th, eventually resulting in his death on November 18th. Autopsy showed intracranial, testicular and intestinal tumor formation and blast cell invasion into the liver, spleen and kidneys. We analyzed the characteristics of 14 cases with intracranial tumor formation previously reported. The focal neurological symptoms reflecting the intracranial tumor mass effect were considered to be important initial signs. CT scan was a useful tool for diagnosis. The average age of the 14 cases was 38, 9 and the male/female ratio was 9:5. Six of 9 cases, diagnosed by FAB classification, were M2 and one of the 6 cases in whom chromosomes of blast cells were examined had t(8;21). Though irradiation seemed effective for the reduction of tumor mass, the patients' prognosis was poor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cerebral and testicular myeloblastoma formation in relapsing acute myeloid leukemia (M1) with t(8;21)]. 768 65

Blast cells, obtained from patients with acute myelogenous leukemia (AML), that express surface binding sites for human stem cell factor (SCF) respond proliferatively upon exposure to this molecule. In the presence of human transforming growth factor-beta 1 (TGF-beta 1) the capacity of SCF to augment the proliferative state of AML blasts was, however, almost completely abolished. This inhibitory action of TGF-beta 1 could be reversed by a neutralizing anti-TGF-beta 1 antibody. Studies on the mechanism of TGF-beta 1 inhibition of SCF-induced proliferation of AML blasts revealed that TGF-beta 1 treatment of these cells was associated with down-regulation of SCF receptor surface expression, as detected with a specific monoclonal antibody, which appeared to be preferentially due to an acceleration of decay of mRNA for the c-kit proto-oncogene encoding the SCF receptor, without an effect on the overall transcriptional activity of the c-kit gene. Direct evidence to prove the importance of c-kit down-regulation in the inhibitory effect of TGF-beta 1 on AML growth came also from experiments demonstrating that signal transduction of SCF could be significantly diminished in the presence of TGF-beta 1, as demonstrated by measuring c-kit kinase-associated phosphorylation of target proteins.
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PMID:Transforming growth factor-beta 1 interferes with the proliferation-inducing activity of stem cell factor in myelogenous leukemia blasts through functional down-regulation of the c-kit proto-oncogene product. 768 25

A 71-year-old man was admitted for severe anemia. Bone marrow puncture revealed 48% of blast cells. A diagnosis of acute myelogenous leukemia (AML-M 4) was made. As the patient was old, we administered 300mg of cytarabine ocfosfate (SPAC) for 21 days. Blast cells in bone marrow decreased 5.6%, and SPAC was considered effective. We treated him with the same dose of SPAC for 14 days after a 21-day interval from the end of the first treatment. Although leukemic cells were still seen in bone marrow after two treatments, we considered him in partial remission, and he was discharged. After discharge, the hematological findings remain almost normal with intermittent treatment of 150 mg of SPAC for over one year. Thus, cytarabine ocfosfate might be useful in elderly AML patients.
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PMID:[Low-dose cytarabine ocfosfate therapy in an elderly acute myelogenous leukemia]. 775 92

To establish diagnostic criteria for hypocellular acute leukemia (HL) 32 cases (mean age 67) with 40% or less bone marrow cellularity were analysed and compared with 40 cases of MDS, 27 cases of AML in the elderly (60 > or = ) and 39 cases of AML in the young (60 <). The mean bone marrow cellularity was 30% in HL, 85% in MDS, 87% in elderly AML and 95% in young AML, respectively. Thus hypocellularity was evident in HL. Blast % in bone marrow of HL patients was 17-70% in all nucleated cells including lymphocytes (ANC), 36-93% in non-lymphocytic cells (NLC) and 50% or more in all cases in non-erythroid/non-lymphocytic cells (NENLC). Thus maturation arrest of blast cells was evident in HL, which corresponds to that of overt AML. Out of 20 cases treated with low-dose ara-C 13 cases (65%) achieved complete remission, but most of them relapsed early by manifesting hypocellular bone marrow again. In conclusion HL is a distinct clinical subtype of AML in the elderly, which can be clearly defined by 40% or less cellularity and 30% or more blasts in bone marrow.
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PMID:[Hypocellular acute leukemia]. 778 51

The experiments reported here continue the study of regulated drug sensitivity by extending the observations to anthracyclines. Previous work has shown that hydrocortisone (HC) protects AML blast stem cells from the lethal effects of cytosine arabinoside (ara-C) while retinoic acid (ATRA) increases ara-C sensitivity; further mechanisms of regulation of ara-C sensitivity might include increase or decrease in repair of sublethal damage. Anthracycline dose-response curves are characterized by an initial shoulder, followed by exponential decrease in survival with increasing dose. The shoulder portion of such curves may indicate the accumulation of sublethal damage. We used two assays to look for evidence of regulation of anthracycline sensitivity by HC or ATRA; the clonogenic assay for blast stem cells detects drug effects on this crucial population, but only after several days on incubation, during which time repair might occur. Measurements of nicks in DNA show damage in the bulk population of cells, but these can be detected very soon after exposure to drug. Both methods showed the HC protected cells in two continuous cell lines (OCI/AML-2 and OCI/AML-5) while ATRA made the cells more sensitive. Blast cells freshly-obtained from six AML patients were also tested. Both assays showed HC protection and ATRA sensitization in three populations. The clonogenic assay detected both effects in cells from a fourth patient; the nicked DNA assay confirmed both effects in a fifth patient, where the results of the clonogenic assay did not reach statistical significance. Neither ATRA nor HC influenced the sensitivity of blasts from a sixth patient; but these cells were highly resistant to drug. Kinetic studies showed that damage persisted longer after treatment with anthracyclines than with ara-C. OCI/AML-2 cells treated with HC before drug accumulated fewer cells with nicked DNA after daunorubicin (DNR). Cells exposed to ATRA after DNR showed increased toxicity in kinetic experiments. We conclude that sensitivity to anthracyclines may be regulated by ligands for steroid receptors. Furthermore, since growth factors do not regulate anthracyclines' sensitivity, different mechanisms may be operative for the action of ligands for cell surface receptors. Finally, we suggest that retinoic acid might be considered for inclusion in standard anthracycline/ara-C regimens for the treatment of AML.
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PMID:Regulation by retinoic acid and hydrocortisone of the anthracycline sensitivity of blast cells of acute myeloblastic leukemia. 780 96

Blast cells from up to 70% of patients with acute myeloblastic leukemia (AML) exhibit a variable degree of autonomous growth in vitro which is related to the production of autocrine growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Approximately 40% of AML blasts with autonomous growth have been reported to exhibit abnormalities of retinoblastoma (Rb) protein expression. As the Rb protein is a known transcriptional repressor of the IL-6 promoter, we have investigated the relationship between absence of Rb protein and cytokine gene expression in AML. Blasts from 28 patients were studied, 19 were Rb protein positive by Western blot and by flow cytometry for nuclear Rb protein; blasts from nine patients were Rb-negative. Of the 28 specimens tested by RT-PCR, 24 were positive for GM-CSF mRNA, 21 for IL-1 beta mRNA, and 14 for IL-6 mRNA. Only the expression of IL-6 was found to be significantly associated with loss of Rb protein expression (p < 0.02). The relationship between Rb protein and IL-6 expression was further studied by suppressing Rb protein expression with antisense oligonucleotides. In three out of seven blasts so treated, IL-6 mRNA was induced following antisense treatment whereas control sense oligonucleotides had no effect. Blasts from four patients which secreted high levels of IL-6 exhibited in vitro autonomous growth which could be partially suppressed by anti-IL-6. These results suggest that deletion of Rb protein expression is a mechanism that can dysregulate IL-6 expression in leukemic blasts and thus potentiate the autonomous growth of these cells.
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PMID:Absence of retinoblastoma protein expression results in autocrine production of interleukin-6 and promotes the autonomous growth of acute myeloid leukemia blast cells. 796 42

This work was designed to discern the frequency of expression of classical multidrug resistance (MDR) in acute myeloid leukemia (AML) at the time of diagnosis, using Western blotting for P-glycoprotein (Pgp) and functional assays for an MDR phenotype (enhancement of daunorubicin [DNR] accumulation/retention and cytotoxicity by the known MDR modulators verapamil, cyclosporin A, and progesterone). Blast cells were studied from 49 newly diagnosed AML patients who were subsequently treated with the "3 and 7" combination of cytosine arabinoside (ara-C) and DNR. DNR accumulation (1 microgram/mL, 3 hours) and retention (16 hours) were determined by flow cytometry. Cyclosporin A (CsA, 5 mumol/L) or verapamil (6.6 mumol/L) each caused significant enhancement of DNR accumulation and retention in these blast cell samples (P < .001, Wilcoxon's test). Verapamil or CsA caused greater than 20% enhancement of DNR accumulation or retention in over 25% or 50% of these patients, respectively; however, there was no correlation with the presence or degree of enhancement and response to treatment. Progesterone (10 mumol/L) caused no significant enhancement of DNR accumulation or retention. The effects of the MDR modulators on the cytotoxicity of DNR was also determined in blast cells from 40 of the patients, using a flow cytometric assay. CsA alone was cytotoxic (caused an approximate 20% decrease in cell survival compared with control, P < .001); CsA or verapamil caused enhancement of 1 mumol/L DNR cytotoxicity (P < .001). Greater than 40% enhancement of cell kill by CsA or verapamil was observed in over 75% of patients studied. There was no difference in the degree of enhancement of cytotoxicity between patients clinically sensitive or resistant to treatment. Progesterone caused no enhancement in DNR cytotoxicity. In contrast to the functional assays, highly sensitive immunoblots using the C219 antibody to Pgp showed evidence of low level expression of Pgp in blast cells from only 3 of these patients: 1 was chemotherapy resistant, 2 were sensitive. Thus, although the functional assays suggest a high frequency of expression of a classic MDR phenotype in AML patients at the time of diagnosis, with enhancement by CsA obtained at a clinically relevant concentration (5 mumol/L), the frequency of Pgp expression detectable by C219 Western blots was low in these patients. This could be interpreted either that the method used was not sufficiently sensitive to detect Pgp in all of the blast cell specimens that actually overexpressed mdr1, or that the accumulation/efflux-based MDR phenotype observed is not always mediated by Pgp in these previously untreated patients.
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PMID:Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. 810 61

Owing to recent technical developments in automated hematology analyzers, identification of 5-part differential counts in white blood cells and also of abnormal leukocytes has become possible. Blood specimens from 200 patients with leukemic hematologic conditions were processed through a Coulter STKS which gives a favorable white cell differential count utilizing the following parameters: volumetric impedance (V), electric conductivity/cell volume (C), and a monochromatic laser beam which provides collectively white cell scatterplot (S). To analyze the presented figures of a pathologic scatterplot (SP) on the visual display unit, the standard scale derived from 220 normal SP patterns which was composed of four kinds of cell SP scales (neutrophil: N, monocyte: Mo, eosinophil: Eo, lymphocyte: Ly) was applied. Leukemic SP figures were variable depending upon both the type of FAB classification and their therapeutic processes. SP forms of M0-blasts were semi-round and located in the central area surrounded by N-, Mo-, and Ly-SP scale. Blast SP of M1 and M2 was shown as a developing process to the SP field containing immature myeloid cells extending from the central area. It was reasonable that immature neutrophilic SP expression was obtained in M3 and Ph1 positive CML. However, the SP of M3v and Ph1 negative CML showed myelomonocytic features as CMMoL does. Typical myelomonocytic SP patterns were obtained in M4 patients. SP figures of MDS were characterized by deformability, dislocation and another abnormality, and these changes, especially in lymphocytes are very useful for diagnosis of MDS. Therefore, the FAB subtype of AML including MDS and CML could be distinguished from each other on the basis of SP pattern. In lymphoproliferative disorders, limited conductivity in ALL-SP was characteristic, while irregular and deformed SP was peculiar in leukemic malignant lymphoma. It would be a valuable process to analyze the SP pattern obtained from an automated hematology analyzer for identification of leukemic diseases.
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PMID:[Hematological analysis of leukemic diseases using an automated hematology analyzer]. 829 37


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