Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukaemia (AML) is characterized by a block in differentiation and an unregulated proliferation of myeloid progenitor cells. While the cause of AML in children is unknown, risk factors that have been identified include exposure to toxins such as ethanol, pesticides and dietary topoisomerase II inhibitors, prior chemotherapy with alkylating agents or topoisomerase II inhibitors, constitutional disorders such as Down's syndrome and type I neurofibromatosis, and haematopoietic failure syndromes such as Fanconi anaemia and severe congenital neutropenia. With intensified chemotherapy including high-dose Ara-C, followed in many cases by bone marrow transplantation, and with improvements in supportive care, current survival rates approach 50%. Future advances in paediatric AML will include better risk stratification to determine optimal treatment and targeted cytotoxic therapy.
Best Pract Res Clin Haematol 2001 Mar
PMID:Acute myeloid leukaemia in children. 1135 25

Secondary leukaemias are common, accounting for more than 40% of all patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). A clinical history of exposure to haematotoxins or radiation is helpful; however, many older patients are diagnosed with leukaemia with no antecedent history of exposure. These patients' disease show a remarkably similar phenotype to classic therapy-related leukaemia. The specific cytogenetic abnormalities common to MDS, alkylating-agent-related AML and poor-prognosis AML (3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19,20q-, +21, t(1;7), t(2;11)), probably reflect a common pathogenesis distinct from that of other de novo AMLs, although the pathogenetic pathway has yet to be elucidated. Possibly, tumour suppressor genes are implicated and genomic instability may be a cause of multiple unbalanced chromosomal translocations or deletions. Typically, these patients are either elderly or have a history of exposure to alkylating agents or environmental exposure 5-7 years prior to diagnosis. Another distinct entity affects the mixed lineage leukaemia (MLL) gene located on 11q23. These account for about 3% of patients with therapy-related leukaemia and have a short latency period from exposure, usually to an inhibitor of topoisomerase II. Other therapy-related patients with t(8:21), inv16 or t(15;17) translocations should be treated as any other de novo AML with similar cytogenetics. In summary, the major prognostic factor is related to the pathogenetic mechanisms of the leukaemia. Cytogenetics and molecular features are a better predictor of outcome than patient history. Patients should receive standard induction therapy. However, the long-term outcome is relatively poor; the best results being obtained among patients undergoing allogeneic transplantation.
Best Pract Res Clin Haematol 2001 Mar
PMID:Biology and therapy of secondary leukaemias. 1135 27

Childhood myeloid leukaemias are a diverse collection of conditions. Although many are also seen in adults, some are peculiar to childhood. In childhood AML, as in adults, cytogenetic abnormalities are associated with specific clinical features and define prognostic groups. In infants under 1 year with AML, the incidence of 11q23 abnormalities is particularly high. The finding of identical 11q23 breakpoints in infant leukaemia as in therapy-related leukaemias suggests a role for in utero exposure to topoisomerase II inhibitors. There are a number of constitutional disorders that predispose children to develop AML, usually with a preceding myelodysplastic phase. Monosomy (or deletion of the long arm) of chromosome 7 is the most frequent chromosome abnormality in the bone marrow of such patients. Abnormalities of chromosome 7 are also common cytogenetic findings in all morphological subgroups of childhood myelodysplasia, either as a primary abnormality or associated with disease progression.
Best Pract Res Clin Haematol 2001 Sep
PMID:Childhood myeloid leukaemias. 1164 Aug 70

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. Therapeutic interventions for MDS other than allogeneic bone marrow transplantation have been palliative. Because most of the patients are elderly and may not be candidates for ablative transplant conditioning regimens, treatment has focused on supportive care. Recently, several novel biological and chemotherapeutic agents have demonstrated activity in MDS and are being incorporated into the treatment paradigm. These agents are based on specific mechanisms aimed at angiogenesis in the bone marrow, secretion of growth factors and/or their receptors, and modulators in their intracellular pathways. Several agents are in the initial stages of clinical trial, including anti-vascular endothelial growth factor, bevacizumab, receptor tyrosine kinase inhibitors, farnesyl transferase inhibitors, protein kinase C inhibitors, matrix metalloproteinase inhibitors and other agents such as thalidomide and arsenic trioxide. Novel chemotherapeutic agents include topoisomerase inhibitors such as topotecan and rubitecan, and deoxyadenosine analogues such as troxacitabine, tezacitabine, and clofarabine. Prognostic factors predicting response in MDS patients treated with intensive chemotherapy have been identified and include younger age and favorable cytogenetics.
Best Pract Res Clin Haematol 2004 Dec
PMID:Nucleoside analogs and antimetabolite therapies for myelodysplastic syndrome. 1549 95

Secondary leukemia is a poorly defined term that often refers to the development of acute myeloid leukemia (AML) following the history of a previous disease, such as a myelodysplastic syndrome or a chronic myeloproliferative disorder. Secondary leukemia can also be a consequence of treatment with chemotherapy, including alkylating agents and topoisomerase II inhibitors, and/or radiotherapy, or due to exposure to environmental carcinogens. Outcomes for this large and variable group of patients with secondary AML have been poor compared to people who develop AML de novo. The question arises whether a diagnosis of secondary leukemia per se indicates a poor prognosis or whether their bad outcomes result from an association with certain morphologic and biologic characteristics. Morphologic dysplasia in de novo AML is related to unfavorable cytogenetics, but has no independent prognostic relevance under the conditions of intensive chemotherapy. While there is no significant correlation between cytogenetic risk groups and dysplasia, cytogenetic features do have an impact on outcome among both de novo and secondary AML patients. In various subgroups of secondary AML, the spectrum of cytogenetic abnormalities is similar to de novo AML, but the frequency of abnormalities associated with unfavorable and intermediate risk cytogenetics, such as a complex karyotype, trisomy 8, monosomy 7, and others, is higher in secondary AML. The survival of patients with therapy-related myeloid leukemia (t-AML) is generally shorter than for those with de novo AML within the same cytogenetic risk group. Across the population of t-AML, however, survival varies according to cytogenetic risk group, with longer survival in patients with favorable-risk karyotypes. The term secondary AML is too broad and imprecise to be of importance and should not be used. These AML patients should be enrolled on front-line chemotherapy trials and should be stratified by pretreatment disease status and exposure history, if necessary. Most importantly, the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.
Best Pract Res Clin Haematol 2007 Mar
PMID:Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia? 1733 52

The cure rate for several solid tumour malignancies including breast cancers, head and neck cancers, bone cancers, and sarcoma has improved remarkably with the advent of neoadjuvant and adjuvant therapies. Unfortunately, exposure to chemotherapy or radiation as a part of these treatments exposes patients to the risk of subsequent myeloid malignancies. Therapy related myeloid malignancies have certain characteristic findings. They typically arise within 10 years of treatment exposure, they are seen in younger patients, and the greatest risk is in patients who receive therapy with alkylating agents or topoisomerase II inhibitors. Solid tumours whose therapies utilize these agents at higher doses, namely bone/soft tissue cancers, testicular cancer, anal cancer, and brain tumours, appear to be the groups at highest risk for T-MN. Beyond these patients, emerging populations diagnosed with T-MN include prior platinum exposure, and patients requiring G-CSF support with chemotherapy.
Best Pract Res Clin Haematol 2019 03
PMID:Myeloid malignancies after treatment for solid tumours. 3092 74