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)

We have developed an in vitro assay to assess and predict the potential efficacy of in vivo interferon-alpha (IFN-alpha) treatment (5 x 10(6) units/m2 per day) for patients with chronic myelogenous leukemia (CML). Although determining the numbers and affinities of IFN-alpha receptors on CML cells has been developed as a method for predicting treatment response to IFN-alpha, it fails to predict response in CML. Previously, we and others observed that mitogens, toxins and lectins that bind to cell-surface receptors are endocytosed, escaping endosomes in order to act directly on cellular targets. Therefore, we tested the ability of low concentrations of IFN-alpha (5-10 units) to act directly on DNA polymerase (Pol) in purified chromatin nucleoprotein complexes (NPC). NPC were prepared by a methodology that uses direct treatment of leukocyte nuclei with MspI to generate six NPC-containing fractions (S1, M1, S2, M2, 0.1K and R). We found three general categories of in vitro DNA synthesis response for the six different NPC fractions isolated from the white blood cells of patients with CML (n = 19) before their treatment with IFN-alpha. IFN-alpha induced either stimulation, inhibition or had no apparent effect on Pol activity in the six different NPC fractions in a blind assay. In most of the NPC fractions isolated from the leukocytes of patients with progressive CML and in those from CML patients who failed to show a clinical response to IFN-alpha, this cytokine stimulated or had no effect on Pol activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-alpha directly inhibits DNA polymerase activity in isolated chromatin nucleoprotein complexes: correlation with IFN-alpha treatment outcome in patients with chronic myelogenous leukemia. 754 66

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.
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PMID:Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias. 791 48

The purpose of this study was twofold: (1) to develop an optimized, reliable method for the flow cytometric analysis of the intranuclear DNA polymerase, terminal deoxynucleotidyl transferase (TdT) in acute myeloid leukemia, and (2) to establish the usefulness of a novel, fluorescein-isothiocyanate conjugated monoclonal anti-TdT antibody (HT-6) in double-fluorescence staining for surface antigens in the characterization of leukemic cells. Inclusion of an aldehyde blocking buffer in the staining protocol reduced background fluorescence sufficiently to allow for the detection of the low-level fluorescent TdT+ myeloblasts. When admixed to normal peripheral blood mononuclear cells, 0.4-0.5% of HLA-DR+ or myeloid surface antigen+, TdT+ double-stained myeloblasts could be reliably detected above background levels. Flow cytometric TdT measurements using the HT-6 antibody in 55 patients with TdT+ acute lymphocytic or myelocytic leukemia or blast crisis of chronic myelogenous leukemia were equal or superior to the results obtained with a mixture of monoclonal anti-TdT antibodies (anti-HTDT-Mix) and comparable to those obtained by the conventional slide method employing polyclonal rabbit anti-human TdT antiserum. This flow cytometric TdT determination in combination with surface antigen staining using a novel anti-TdT monoclonal antibody (HT-6) allows for the recognition of minimal leukemic blast cells during clinical remission in acute myeloid leukemia.
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PMID:Detection of terminal transferase in acute myeloid leukemia by flow cytometry. 792 95

The bcr-abl fusion gene is the hallmark of chronic myeloid leukaemia (CML) and presumably the cause of its development. Accordingly, long-term disappearance of the bcr-abl gene after intensive therapy suggests that a patient is probably cured of CML. The diagnostic protocol based on coupling of two enzymatic reactions, reverse transcription (RT) and nested polymerase chain reaction (nPCR), for the detection of bcr-abl transcripts in peripheral blood provides a powerful tool for minimal residual CML detection. We have developed a new detection protocol using rTth DNA polymerase as the only enzyme catalysing both reactions for simplifying CML diagnosis. We demonstrate its efficacy investigating residual leukaemic cells in the peripheral blood of 10 patients. This assay offers several advantages over the use of conventional RT-PCR, being more sensitive, faster, less prone to false positives since no opening of the tube is required between the two reactions and requires no special oils or waxes. Our simple assay for bcr-abl chimeric transcripts detection is a practical addition to the diagnostic evaluation of the patient with chronic myeloid leukaemia.
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PMID:Detecting residual bcr-abl transcripts in chronic myeloid leukaemia patients using coupled reverse transcriptase-polymerase chain reaction with rTth DNA polymerase. 977 68

Reactivation of chronic hepatitis B virus (HBV) infection in patients undergoing chemotherapy is well-documented, but reactivation during imatinib mesylate treatment has not been reported. This study reports a 54-year-old man, without prior liver dysfunction but with chronic HBV infection, in whom fatal HBV reactivation occurred during treatment of chronic myeloid leukemia (CML) with imatinib mesylate. He developed fulminant hepatitis followed by marked elevation of HBV DNA polymerase, probably from the lymphocytopenic and immunosuppressive status induced by imatinib mesylate. Imatinib mesylate is widely used to treat CML patients. Although therapy with imatinib mesylate is generally well tolerated, the case presented here suggests that viral reactivation should be considered, even when using imatinib mesylate to treat CML.
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PMID:Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. 1632 42

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol lambda can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol lambda might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.
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PMID:Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy. 1691 60


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