Approaches to Induction Therapy with Adult Acute Myeloid Leukaemia

Bishop, James F.

doi:10.1159/000040827

Cited by 12 publications

(7 citation statements)

References 10 publications

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“…25 Therefore, we examined whether THP-1 clones with reduced levels of Metnase For personal use only. on March 28, 2019. by guest www.bloodjournal.org From were more sensitive to the antiproliferative effects of VP-16.…”

Section: Metnase Promotes Thp-1 Cell Proliferation In the Presence Ofmentioning

confidence: 99%

Metnase mediates chromosome decatenation in acute leukemia cells

Wray

Williamson

Sheema

et al. 2009

Blood

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After DNA replication, sister chromatids must be untangled, or decatenated, before mitosis so that chromatids do not tear during anaphase. Topoisomerase II␣ (Topo II␣) is the major decatenating enzyme. Topo II␣ inhibitors prevent decatenation, causing cells to arrest during mitosis. Here we report that acute myeloid leukemia cells fail to arrest at the mitotic decatenation checkpoint, and their progression through this checkpoint is regulated by the DNA repair IntroductionDNA double-strand breaks (DSBs) can result from normal cellular events, such as recombination during immune receptor rearrangement, recovery of stalled replication forks, replication of nicked templates, or failed decatenation. 1 Such DSBs can result in translocations or deletions, and this genomic instability can lead to malignancy. Of the normal cell processes producing DSBs, the least well understood is chromosome decatenation. Sister chromatids become intertwined, or catenated, when chromosomes are replicated during DNA synthesis. When decatenation fails, chromatids can tear during anaphase, producing DSBs. Catenation status is actively monitored at 2 points in the cell cycle. One decatenation checkpoint blocks progression from G 2 to M 2 , and another blocks progression from metaphase to anaphase during mitosis. [2][3][4][5][6] These checkpoints are conserved in most organisms, including yeast. 7,8 Previously, it was reported that bladder and lung cancer cells lack decatenation checkpoints and proceed through mitosis even when decatenation is inhibited. 9,10 It is possible that this failure of arrest at the decatenation checkpoints could be a general feature of malignancy, including acute leukemia. The critical decatenating enzyme is Topoisomerase II␣ (Topo II␣). [2][3][4][5][6]11 Topo II␣ inhibitors can trigger decatenation checkpoint arrest in normal cells at either of the 2 decatenation checkpoints. Recently, we identified and characterized a novel DNA repair protein called Metnase (also SETMAR). Metnase has an amino terminal SET histone methylase domain and a carboxy terminal transposase/nuclease domain. We previously reported that Metnase promotes nonhomologous endjoining of DSBs and methylates histone 3 lysine 36. 12 Metnase appears to be localized to DSBs by interaction with Pso4, a poorly characterized DNA repair component. 13 Metnase may promote DSB repair by interacting with DNA ligase IV, the final component of the nonhomologous end-joining pathway. 14 Metnase is present only in primates and exhibits only partial transposase activity. 12,[14][15][16][17][18][19] We also found that Metnase has endonuclease activity specific for supercoiled DNA and improves Topo II␣-mediated decatenation in vitro and in vivo in noncancerous human cells. 16,20 In this study, we hypothesized that Metnase mediates decatenation in acute leukemia cells. If there is a failure of decatenation arrest in acute leukemia cells when Topo II␣ is inhibited, then perhaps Metnase mediated the continued progression of those cells through the decatenation checkpoi...

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Section: Metnase Promotes Thp-1 Cell Proliferation In the Presence Ofmentioning

confidence: 99%

Metnase mediates chromosome decatenation in acute leukemia cells

Wray

Williamson

Sheema

et al. 2009

Blood

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“…[33][34][35][36] Addition of a third drug has resulted in contradictory effects. However, employment of high-dose cytarabine seems to improve outcome, 7,8,21,24,[37][38][39] without affecting the remission rates. This suggests that high-dose cytarabine provides a better quality of remission.…”

Section: Figurementioning

confidence: 99%

“…However, there is little agreement as to whether intensification of either induction or consolidation treatment can influence the duration of remission and survival. 7,8 This situation may stem from the lack of diversified treatment schemes that take into account the biological heterogeneity of AML. 9 Much effort has been made to identify prognostic factors.…”

Section: Introductionmentioning

confidence: 99%

The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia – analysis of 848 patients

et al. 2001

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We studied the impact of cytogenetics and kind of induction/consolidation therapy on 848 adult acute myeloid leukemia (AML) patients (age 15-83). The patients received three types of induction/consolidation regimen: standard (daunorubicin and cytosine arabinoside (3/7); two cycles); intensive (idarubicin, cytosine arabinoside and etoposide (ICE), plus mitoxantrone and intermediate-dose Ara-C (NOVIA)); and low-dose (low-dose cytosine arabinoside). CR patients under 60 years of age, if an HLA-identical donor was available received allogeneic stem cell transplantation (allo-SCT); otherwise, as part of the program, they underwent autologous (auto)-SCT. CR rates significantly associated with 'favorable' (inv(16), t(8;21)), 'intermediate' ('no abnormality', abn(11q23), +8, del(7q)) and 'unfavorable' (del (5q), −7, abn(3)(q21q26), t(6;9), 'complex' (more than three unrelated cytogenetic abnormalities)) karyotypes (88% vs 65% vs 36%, respectively; P = 0.0001). These trends were confirmed in all age groups. On therapeutic grounds, intensive induction did not determine significant increases of CR rates in any of the considered groups, with respect to standard induction. Low-dose induction was associated with significantly lower CR rates. Considering disease-free survival (DFS), multivariate analysis of the factors examined (including karyotype grouping) showed that only age Ͼ60 years significantly affected outcome. However, in cases where intensive induction was adopted, 'favorable' karyotype was significantly related to longer DFS (P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction. Patients receiving allo-SCT had significantly longer DFS (P = 0.005); in particular, allo-SCT significantly improved DFS in the 'favorable' and 'intermediate' groups (P = 0.04 and P = 0.048, respectively). In conclusion our study could provide some guidelines for AML therapy: (1) patients in the 'favorable' karyotype group seem to have a longer DFS when treated with an intensive induction/consolidation regimen, adopted before auto-SCT instead of standard induction; this underlines the importance of reinforcement of chemotherapy, not necessarily based on repeated high-dose AraC cycles. Allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment; (2) patients in the 'intermediate' karyotype group should receive allo-SCT; (3) patients in the 'unfavorable' karyotype group should be treated using investigational chemotherapy, considering that even allo-SCT cannot provide a significantly longer DFS, but only a trend to a better prognosis. Leukemia (2001) 15, 903-909.

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“…4,5 Ara-C is used in the treatment of leukaemia. 6 All pyrimidine antagonists are prodrugs and intracellular conversion into cytotoxic nucleosides and nucleotides is needed to produce cytotoxic metabolites. Proteins, involved in pyrimidine metabolism, handle these synthetic drugs, as if they were naturally occurring substrates.…”

Section: Introductionmentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Approaches to Induction Therapy with Adult Acute Myeloid Leukaemia

Cited by 12 publications

References 10 publications

Metnase mediates chromosome decatenation in acute leukemia cells

Metnase mediates chromosome decatenation in acute leukemia cells

The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia – analysis of 848 patients

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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