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

It has been known that thymidylate synthetase (TS) and thymidine kinase (TK) are DNA-synthesizing enzymes via the de novo and salvage pathways, respectively, in pyrimidine metabolism, and an immunological method using a monoclonal antibody to bromodeoxyuridine (BrdU) is useful for the detection of S-phase cells. We investigated the effects of hyperthermia on DNA synthesis in bone marrow cells obtained from patients with acute myeloblastic leukemia. TK isozymes in bone marrow cells of patients with acute myeloblastic leukemia were separated into two types, i.e., fetal type isozyme in cytosolic cell fraction and adult type isozyme in mitochondrial cell fraction. Heating at over 43 degrees C as a hyperthermia markedly suppressed enzyme activity of fetal type TK isozyme and number of S-phase cells labelled with BrdU, but not activities of adult type TK isozyme and TS. These results indicate that hyperthermia may regulate the proliferation of S-phase cells by the suppression of salvage synthesis of DNA.
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PMID:Thermal effects on DNA synthesis in bone marrow cells of patients with acute myeloblastic leukemia. 144 19

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.
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PMID:Retinoids in cancer treatment. 144 94

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.
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PMID:Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2. 145 74

DNA methylation plays an important role in gene regulation. We have analyzed the methylation status of CCGG sites in and around the human proto-oncogene c-myc in blood cells from patients with acute and chronic leukemias and with myelodysplastic syndromes using restriction endonucleases. The 5' region of c-myc was unequivocally hypomethylated in all the 58 specimens studied, including 10 from normal bone marrow and 1 from human placenta. In contrast, the 3' region was hypermethylated in a great majority of cases. However, this region was hypomethylated in 1 of 12 patients with de novo acute myeloid leukemia, 1 of 6 patients with chronic myeloid leukemia, and 4 of 5 patients with acute myeloid leukemia preceded by a documented stage of myelodysplastic syndromes. One possible mechanism for the 3' region of c-myc to have remained hypomethylated may be a "delayed methylation" during transforming events toward a more aggressive stage of the disease, but the precise mechanism is unknown.
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PMID:Methylation status of c-myc oncogene in leukemic cells: hypomethylation in acute leukemia derived from myelodysplastic syndromes. 146 40

In this study, we further established the role of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta, tumor necrosis factor-alpha (TNF-alpha), and interferon-alpha (IFN-alpha) as regulators of proliferation of acute myeloid leukemia (AML) cells. AML cells from 8 of 15 patients incorporated high levels of 3H-thymidine (3H-TdR) in the absence of exogenous growth factors. The spontaneous DNA synthesis could be abrogated with monospecific antibodies directed toward IL-1 alpha, IL-1 beta, or TNF-alpha, as well as with antigranulocyte-macrophage colony-stimulating factor (GM-CSF). Human recombinant GM-CSF reversed the inhibitory action of each of these antibodies and reinduced DNA synthesis in AML cells. Thus, in these cases, constitutively produced IL-1 or TNF-alpha had stimulated the synthesis of GM-CSF, which resulted in GM-CSF-dependent proliferation of AML blasts. Exogenous IL-1 up-regulated the endogenous production of GM-CSF, suggesting a positive regulation of autocrine growth factor production. We also present evidence that TNF-alpha may exert both stimulative as well as inhibitory effects on DNA synthesis in AML cells. The enhancing effect of TNF-alpha was mediated through the induction of GM-CSF production, as stimulation of DNA synthesis in AML blasts could be abrogated with anti-GM-CSF antibody. A concentration-dependent inhibitory effect of TNF-alpha on 3H-TdR incorporation into AML blasts was observed only when these cells were grown in the absence of GM-CSF. Finally, we show that human recombinant IFN-alpha is a potent inhibitor of AML cell proliferation in vitro.
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PMID:Effect of interleukin-1, tumor necrosis factor-alpha, and interferon-alpha on the blast cells of acute myeloblastic leukemia. 150 80

By using monoclonal antibodies against lymphoid and myeloid differentiation antigens, surface marker analysis was performed on the tumor cells from 42 patients with acute leukemia and lymphoblastic lymphoma. Nine (21%) of 42 cases were diagnosed biphenotypic leukemia. Two (17%) of the 12 patients with acute myeloid leukemia, four (18%) of 22 with acute lymphocytic leukemia and three (38%) of 8 with lymphoblastic lymphoma expressed both lymphoid and myeloid antigens. Tumor cells from six patients expressed both T-cell and myeloid antigens, and those from three other expressed both B-cell and myeloid antigens. Southern blot analysis was performed on the DNA from four patients with biphenotypic leukemia cells expressing T-cell and myeloid antigens. DNA from one patient showed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene, and that from one other showed clonal rearrangement of both IgH gene and T-cell receptor beta-chain gene. DNA from two other patients showed a germline configuration of both genes. These results indicate that biphenotypic leukemia, especially T-cell and myeloid phenotype, is not so rare in acute leukemia and lymphoblastic lymphoma. The results of immunogenotypic analysis were not consistent with those of immunophenotypic analysis in biphenotypic leukemia.
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PMID:[Immunophenotypic and immunogenotypic analyses of acute leukemia and lymphoblastic lymphoma expressing myeloid and lymphoid antigens]. 150 95

In this study, we evaluated the individual in vitro sensitivity of fresh acute myeloid leukemia (AML) cells to VP-16, and attempted to correlate VP-16 cytotoxicity with AML cell growth characteristics and drug-induced DNA single-strand breaks (SSB). Primary (PE1) colony inhibition assays allowed us to characterize two distinct groups of AML: group I (patients 1 through 6), which displayed sensitivity to VP-16 similar to that of normal CFU-GM (IC90 of 20.52 +/- 2.44 micrograms/mL v 20.48 +/- 2.23 micrograms/mL after 1 hour drug exposure, respectively); and group II (patients 7 through 11), which was more sensitive to VP-16 (IC90 of 7.26 +/- 2.93 micrograms/mL, P = .004). Subsequently, groups I and II were termed normosensitive and hypersensitive, respectively. This objective VP-16 sensitivity classification, as determined by PE1, remained unaltered when assessed by secondary (PE2) colony inhibition assay (evaluating the self-renewal fraction of AML progenitors), or by cytofluorometric viability assay (evaluating the ultimately differentiated blast cell population). These findings would suggest that individual sensitivity to VP-16 of a particular cell population is maintained throughout CFU-AML differentiation. Finally, we report that sensitivity of AML cells to VP-16 did not correlate either with cell growth characteristics or with SSB generation. Indeed, AML cell sensitivity to VP-16 appeared more closely related to DNA repair kinetics after drug removal, ie, hypersensitivity being essentially characterized by a prolonged retention of SSB during the posttreatment period. Interestingly, the established HL-60 cell line, which presented greater sensitivity to VP-16 cytotoxicity than KG1, HEL, and K562, was also found to exhibit delayed DNA SSB repair kinetics, as compared with the other AML cell lines. These results suggest that hypersensitivity to VP-16 of some AML cells may be related to a deficient DNA-repair mechanism.
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PMID:Sensitivity of fresh acute myeloid leukemia cells to etoposide: relationship with cell growth characteristics and DNA single-strand breaks. 151 45

The retinoblastoma susceptibility gene (RB) is expressed in all lineages of normal hematopoietic cells and plays an important role in controlling cell cycle progression at G1/S. Abnormalities of the RB gene may, therefore, predispose to the development of hematologic malignancies. DNA rearrangement was reported to be present in 1.5-12.1% of cases with primary leukemias and the absence of the RB gene product was also observed in 6.3-23.2%. The abnormalities were frequently observed in blastic crisis of CML, especially of the megakaryoblastic phenotype, AML with monocytic differentiation and Ph1-positive leukemias. These results indicate that abnormalities of RB are relatively common in hematologic malignancies and loss of RB function may contribute to the altered growth of these cells.
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PMID:[Abnormalities of the retinoblastoma susceptibility gene (RB) in hematologic malignancies]. 151 56

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) inhibits the entry into DNA synthesis of murine spleen colony-forming units (CFU-S) and protects these cells during chemotherapy. This synthetic peptide also inhibits the growth of normal human marrow progenitors granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) and decreases their percentage in DNA synthesis at nanomolar concentration. In view of its clinical application as a marrow protector, we have investigated its effects on malignant cells. Studies were carried out on HL-60 cells and on fresh leukemic cells from patients with either chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Results showed that AcSDKP, whatever the doses used, did not modify the proliferation of both HL-60 cells and AML cells even when enhanced by stimulating factors such as interleukin 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, no change in the number and the percentage in S-phase of both HL-60 clonogenic cells and CML progenitors was observed. Our data clearly demonstrate that the tetrapeptide AcSDKP was ineffective on leukemic cells and therefore by acting selectively on normal progenitors represents a potent therapeutical agent for the protection of normal bone marrow progenitors during chemotherapy.
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PMID:The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells. 154 96

Mutations in the N-ras gene are found in one-third of patients with acute myeloid leukemia. The N-ras mutations could serve as markers for residual cells, if a highly sensitive method for detecting the mutations was available. We applied a new method, solid-phase minisequencing, to analyze bone-marrow cells from 16 patients with acute myeloid leukemia for mutations in codon 12, 13 and 61 of the N-ras gene. In the solid-phase minisequencing technique the mutations are identified by a primer extension reaction, in which a single labelled nucleoside triphosphate is incorporated into an immobilized DNA fragment previously amplified by the polymerase chain reaction. We identified N-ras mutations in 5 of the patients (30%). In one patient, we observed 2 mutations that were shown to be located in different alleles. With the solid-phase minisequencing method, we were able to determine the proportion of mutated cells in the samples. We found that in 4 of the samples only a fraction (7-64%) of the blasts carried an N-ras mutation, and in one sample practically all blast cells were mutated. The method was highly sensitive, allowing us to identify N-ras mutations even when the sample consisted of 99.7% normal cells and only 0.3% mutated blasts.
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PMID:N-ras gene mutations in acute myeloid leukemia: accurate detection by solid-phase minisequencing. 154 4


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