Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current APL chemotherapy protocols usually include high-dose anthracyclines, mitoxantrone, and epipodophillotoxins, which are topoisomerase II inhibitors of high leukemogenic potential. In the last years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL have been made. We report herein a first case of CMML with monosomy 7 occurring after treatment of APL.
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PMID:Secondary chronic myelomonocytic leukemia with monosomy 7 after successful treatment of acute promyelocytic leukemia. 1817 33

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) are malignancies occurring after exposure to chemotherapy and/or radiotherapy. Several studies have addressed cumulative dose, dose intensity and exposure to specific agents of preceding cytotoxic therapy in relation to the risk of developing such leukemia. Since only a small percentage of patients exposed to cytotoxic therapy develop t-MDS/AML, it has been suggested that some genetic predisposition may be involved, specifically associated to polymorphisms in certain genes involved in chemotherapy/radiotherapy response - fundamentally genes intervening in drug detoxification and DNA synthesis and repair. A review is made of the genetic studies related to t-MDS/AML predisposition, focusing on the mechanistic findings of how specific chemotherapeutic drug exposure produces DNA damage and induces the chromosomal abnormalities characteristic of t-MDS/AML, the molecular pathways involved in repairing such drug induced damage, and the way in which they influence t-MDS/AML genesis. Specific issues are (a) the interaction of topoisomerase II inhibitors, alkylators and antimetabolite drugs with DNA repair mechanisms and their impact on t-MDS/AML leukemogenicity and (b) the influence of DNA polymorphisms in genes involved in DNA repair, drug metabolization and nucleotide synthesis, paying special attention to the relevance of folate metabolism. Finally, we discuss some aspects relating to study design that are most suitable for characterizing associations between drug exposure and genotypes related to t-MDS/AML risk - stressing the importance of the inclusion of chemotherapy-exposed control groups.
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PMID:Influence of DNA damage and repair upon the risk of treatment related leukemia. 1823 6

Therapy-related acute myeloid leukemia (t-AML) caused by MLL rearrangements (rMLL) can arise from topoisomerase II agents. However, whether rMLL-related leukemogenesis is inextricably linked to drug cytotoxicity remains controversial. We therefore compared (i) rMLL in children with acute lymphoblastic leukemia (ALL) who developed t-AML and those who did not, (ii) epipodophyllotoxin toxicity in patients with t-AML and in controls, and (iii) rMLL in cells sensitive to etoposide and in those resistant to etoposide. In children with ALL, rMLL appeared to be more frequent in children who developed t-AML than in those who did not (seven pairs, P = 0.04), although independent of the cumulative etoposide dose (P = 0.5). Similarly, the frequency of epipodophyllotoxin-related toxicities did not differ between patients with t-AML and controls (26 pairs, P > 0.17). Moreover, in 25 cell lines, etoposide-induced MLL fusions did not differ in sensitive vs. resistant lines at equitoxic concentrations (P = 0.65). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to drug cytotoxicity.
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PMID:Etoposide sensitivity does not predict MLL rearrangements or risk of therapy-related acute myeloid leukemia. 1850 29

Administration of alkylating agents (Alk), topoisomerase II inhibitors (Topo II) and radiotherapy (RT) can result in therapy-related myelodysplastic syndrome or acute myelogenous leukaemia (t-MDS/t-AML), the optimal treatment for which is allo-SCT. A retrospective review was performed of 24 patients who underwent related- or unrelated-donor SCT for t-MDS/t-AML at our institution. Eight patients remain alive and in continuous remission (median follow-up 54 months (range, 12-161)) with estimated 5-year EFS being 30% (95% confidence intervals 16-58%). Corresponding actuarial risks of relapse and non-relapse mortality (NRM) are 39% (19-60%) and 30% (13-50%), respectively. EFS was 40% in Alk/RT-related t-MDS/t-AML and 11% in Topo II-related t-MDS/t-AML (P=0.05), with an increased risk of relapse in the latter (56 vs 29%, respectively (P=0.05)). In multivariate analysis, development of acute GVHD (P=0.009) and Topo II-related t-MDS/t-AML (P=0.018) were associated with inferior EFS. Patients with acute GVHD had an increased risk of NRM (P=0.03) whereas risk of relapse was higher for patients of advanced age (P=0.046) and for patients who underwent bone marrow (vs blood) SCT (P=0.032). Allo-SCT can result in long-term survival for individuals with t-MDS/t-AML although outcome in Topo II-related t-MDS/t-AML patients remains suboptimal.
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PMID:Predictors of outcome following myeloablative allo-SCT for therapy-related myelodysplastic syndrome and AML. 1867 72

The translocation t(16;21) involving RUNX1 (AML1) and resulting in the RUNX1-CBFA2T3 fusion is a rare but recurrent abnormality mostly found in therapy-related acute myeloid leukemia (t-AML) associated with agents targeting topoisomerase II (topo II). We characterized, at the genomic level, the t(16;21) translocation in a patient who developed t-AML after treatment of multiple sclerosis with mitoxantrone (MTZ). Long template nested PCR of genomic DNA followed by direct sequencing enabled the localization of RUNX1 and CBFA2T3 (ETO2) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNX1-CBFA2T3 fusion transcript in leukemic cells. The RUNX1 intron 5 breakpoint was located at nucleotide position 24,785. This region contained an ATGCCCCAG nucleotide sequence showing approximately 90% homology to a "hotspot" DNA region ATGCCCTAG present in intron 6 of PML previously identified in therapy-related acute promyelocytic leukemia cases arising following treatment with MTZ. This study suggests a wider distribution in the human genome, and particularly at genes involved in chromosome translocations observed in t-AML, of DNA regions (hotspot) targeted by specific topo II drugs.
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PMID:Identification of a potential "hotspot" DNA region in the RUNX1 gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation. 1902 77

Secondary acute leukemia is a devastating complication in children and adolescents who have been treated for cancer. Secondary acute lymphoblastic leukemia (s-ALL) was rarely reported previously but can be distinguished today from recurrent primary ALL by comparison of immunoglobulin and T-cell receptor rearrangement. Secondary acute myeloid leukemia (s-AML) is much more common, and some cases actually may be second primary cancers. Treatment-related and host-related characteristics and their interactions have been identified as risk factors for s-AML. The most widely recognized treatment-related risk factors are alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The magnitude of the risk associated with these factors depends on several variables, including the administration schedule, concomitant medications, and host factors. A high cumulative dose of alkylating agents is well known to predispose to s-AML. The prevalence of alkylator-associated s-AML has diminished among pediatric oncology patients with the reduction of cumulative alkylator dose and limited use of the more leukemogenic alkylators. The best-documented topoisomerase II inhibitor-associated s-AML is s-AML associated with epipodophyllotoxins. The risk of s-AML in these cases is influenced by the schedule of drug administration and by interaction with other antineoplastic agents but is not consistently found to be related to cumulative dose. The unpredictable risk of s-AML after epipodophyllotoxin therapy may discourage the use of these agents, even in patients at a high risk of disease recurrence, although the benefit of recurrence prevention may outweigh the risk of s-AML. Studies in survivors of adult cancers suggest that, contrary to previous beliefs, the outcome of s-AML is not necessarily worse than that of de novo AML when adjusted for cytogenetic features. More studies are needed to confirm this finding in the pediatric patient population.
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PMID:Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. 1907 83

Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myelogenous leukemia (t-AML) in patients with acute promyelocytic leukemia (APL) are rare events. The cumulative exposure to chemotherapy with alkylating agents and topoisomerase II inhibitors is associated with t-AML that may develop any time after the completion of the treatment. We report the case of an acquired AML who previously received therapy for APL, after two years of being diagnosed. The diagnosis was established by morphologic findings, membrane markers, cytogenetic studies, and fluorescence in situ hybridization (FISH). To our knowledge this is the first documented case in Puerto Rico of a patient with APL that developed a t-AML without the characteristic chromosomal and morphologic findings of APL.
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PMID:Acquired acute myelogenous leukemia after therapy for acute promyelocytic leukemia with t(15;17): a case report and review of the literature. 1953 May 58

Alkylating agents, topoisomerase II inhibitors, ionizing radiation, and other hematotoxins induce DNA damage in hematopoietic stem cells that results in lesions such as balanced and unbalanced chromosome rearrangements, -5/del(5q) and/or -7/del(7q), as well as other submicroscopic genetic lesions. Together with epigenetic alterations, these result in dysplasia, clonal expansion, and ultimately myeloid leukemia. Combinations of lesions are required to induce overt leukemia. Altering a small subset of signaling pathways leads to disruption of normal self-renewal, proliferation, differentiation, and apoptotic mechanisms that control the development of hematopoietic stem cells and their differentiation into mature effector cells. Recent studies have shown that cytogenetically normal (CN-) AML is quite heterogeneous at the molecular level. Patients with CN-AML harboring mutations in NPM1, FLT3, CEBPA, WT1 or expressing high levels of BAALC, ERG, or MN1 have distinctly different clinical outcomes. NPM1 mutations are independently associated with higher remission rates and longer disease-free and overall survival in AML. Copy number alterations (CNAs) are deletions or amplifications of single genes. CNAs have been found at the breakpoints of known chromosomal translocations. Fewer CNAs have been detected in AML than in pediatric ALL. Micro-RNAs (miRs) are non-coding small RNA molecules containing about 22 nucleotides that are typically encoded within introns. They hybridize to complementary mRNA targets and modulate protein expression by inhibiting translation and/or inducing degradation of target messenger RNAs. This new class of genes has recently been shown to play a pivotal role in malignant transformation. miRs are down-regulated in many tumors and thus appear to function as tumor suppressor genes. Distinctive genome-wide miR expression profiles have been associated with different subsets of AML. A miR signature that is associated with clinical outcome in patients with high-risk molecular features of AML (those who have FLT3-ITD or wild-type NPM1) has been reported. This subgroup constitutes approximately 65% of patients with CN-AML and one-third of all patients with AML <60 years old. Down-regulation of the miR-181 family contributes to an aggressive leukemia phenotype through mechanisms associated with the activation of pathways of innate immunity mediated by toll-like receptors and interleukin-1beta.
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PMID:Micro-RNAs and copy number changes: new levels of gene regulation in acute myeloid leukemia. 1982 34

Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.
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PMID:Incidence and susceptibility to therapy-related myeloid neoplasms. 2002 17

The acute leukaemias account for about 30% of all malignancy seen in childhood across the Western world. A peak incidence of precursor B cell ALL has emerged as socio-economic conditions have improved in countries worldwide. From twin studies and the use of neonatal blood spots it has been possible to back track the first initiating genetic events within critical haemopoietic cells to foetal development in utero for most precursor B cell ALL and some cases of AML. These events may occur as part of normal foetal development. Whether other factors (environmental or constitutional) are involved to increase the chance of these first genetic changes happening is unclear. For some leukaemias (e.g. infant MLL positive ALL) the first event appears adequate to create a malignant clone but for the majority of ALL and AML further 'genetic' changes are required, probably postnatal. Many environmental factors have been proposed as causative for leukaemia but only ionising irradiation and certain chemicals, e.g. benzene and cytotoxics (alkylators and topoisomerase II inhibitors) have been confirmed and then principally for acute myeloid leukaemia. It appears increasingly likely that delayed, dysregulated responses to 'common' infectious agents play a major part in the conversion of pre-leukaemic clones into overt precursor B cell ALL, the most common form of childhood leukaemia. Constitutional polymorphic alleleic variants in immune response genes (especially the HLA Class II proteins) and cytokines may play a role in determining the type of immune response. High penetrance germ-line mutations are involved in only about 5% of childhood leukaemias (more in AML than ALL). There is little evidence to support any role of viral transformation in causation, unlike in animals. Other environmental factors for which some evidence exists include non-ionising electromagnetic radiation and electric fields, although their mode of action in leukaemogenesis remains unclear. There is no single cause for childhood leukaemia and for most individuals a combination of factors appears to be necessary; all involving gene-environment interactions. To date few clear preventative measures have emerged, except the complete avoidance of first trimester X-rays in pregnancy; a healthy diet with adequate oral folic acid intake both preconception and early in pregnancy; and the early exposure of children to other children outside the home to facilitate stimulation and maturation of the natural immune system. Here then are clear echoes of the "hygiene hypothesis" regarding the initiation of allergies, autoimmune disease and type I diabetes mellitus in children and young people.
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PMID:Aetiology of childhood leukaemia. 2022 94


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