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)

To ascertain the frequency of treatment-related acute myeloid leukemias and myelodysplastic syndromes (t-AML/t-MDS) in an unselected series, we have identified all adult cases analyzed in our department from 1976 to 1993. Further aims were to compare karyotypic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in 5098 unselected, cyto- genetically abnormal, published cases, and to analyze associations between type of prior therapy and karyotype. Among our 372 AML and 389 MDS, 47 (13%) were t-AML and 62 (16%) were t-MDS. Clonal abnormalities were significantly more common in t-AML and t-MDS than in de novo disease (68% vs 50%, P < 0.05 and 84% vs 45%, P < 0.001, respectively). Among the available 4230 AML and 1629 MDS (the present series and published cases), 14% were t-AML and 15% were t-MDS. In t-AML/t-MDS, the number of anomalies and the ploidy levels differed significantly from de novo cases, with complex and hypodiploid karyotypes being more common in t-AML/t-MDS. In t-AML, unbalanced changes in general, t(1;3), der(1;7), 3p-, -5, 5q-, -7, 7q-, t(9;11), t(11;19), t(11q23), der(12p), -17, der(17p), -18, and -21 were significantly more frequent than in de novo AML. In t-MDS, -5, -7, 7q-, 13q-, der(17p), and -18 were significantly more common. Type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in t-AML/t-MDS. The frequencies of several aberrations varied with type of therapy, eg, 5q- was more frequent in radiotherapy-associated t-MDS, monosomy 7 was more common in t-AML and t-MDS after treatment with alkylators, and t(11q23) in t-AML was associated with topoisomerase II inhibitors. Abnormalities significantly more common in de novo disease were +8 as a sole anomaly, balanced changes in general, t(8;21), t(9;22), t(15;17), inv(16), and t(21q22) in AML, and -Y, 5q-, and 20q- as sole anomalies and +8 in MDS. The results emphasize the strong association between previous genotoxic exposure and karyotypic features.
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PMID:Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. 1245 41

Therapy-related myelodysplasia and myeloid leukemia (t-MDS/t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We report findings on 306 consecutive patients referred to our institution with morphologic review and cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range, 3-83 years) at primary diagnosis and 58 years (range, 6-86 years) at secondary diagnosis were analyzed. Patients had been administered various cytotoxic agents, including alkylating agents (240 patients, 78%) and topoisomerase 2 inhibitors (115 patients, 39%). One hundred twenty-one (40%) had undergone CT alone, 43 (14%) had undergone RT alone, and 139 (45%) had undergone both modalities. At diagnosis of t-MDS/t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n = 63), chromosome 7 (n = 85), chromosomes 5 and 7 (n = 66), recurring balanced rearrangements (n = 31), other clonal abnormalities (n = 39), or normal karyotype (n = 24). Abnormalities of chromosome 5, 7, or both accounted for 76% of all cases with an abnormal karyotype. Seventeen patients acquired t-MDS/t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Shorter latency was observed for patients with balanced rearrangements (median, 28 vs 67 months; P <.0001). Patients with acute leukemia were more likely to have balanced rearrangement than those with myelodysplasia (28% vs 4%; P <.0001). Median survival time after diagnosis of t-MDS/t-AML was 8 months; survival at 5 years was less than 10%. These data confirm and extend previous associations between clinical, morphologic, and cytogenetic findings in t-MDS/t-AML.
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PMID:Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. 1262 43

Topotecan, a topoisomerase-I inhibitor is an active drug in the treatment of AML and MDS. To evaluate its toxicity and efficacy in a combination regimen with cytarabine, we conducted a clinical phase I/II trial in patients with relapsed acute myeloid leukemia (AML) or relapsed or newly diagnosed MDS RAEB, RAEB-t or CMML. Twenty-one patients (11 AML, 10 MDS/CMML) entered the study and were treated with 1.25 mg/m2 topotecan as continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 h daily for 5 days (TA). Cycles were repeated on day 28. The median observation time was 131 weeks (range: 36-196 weeks). A total of 37 cycles of TA were administered. In 1 patient, the dose of TA had to be reduced and in 1 patient, there was a treatment delay for the second cycle, both because of hematologic toxicity. The most frequent non-hematologic side-effect of TA was fever, which occurred in 17 patients (89%) with temperatures over 38 degrees C. None of the patients died due to any treatment-related toxicities, but 2 patients (10%) died within 1 month due to disease progression. A CR was achieved in 7 patients (33%), 3 of whom were MDS and 4 AML. A partial remission was reported in 8 patients (38%), no change of disease in 2 patients (10%) and progressive disease in 4 patients (19%). The median remission duration was 18 weeks (range 2-161 weeks) for MDS patients and 11 weeks (range 2-49 weeks) for AML patients. The time to progression for patients of 60 years and older (n = 10) was 16 weeks (range 2-49 weeks) and the survival was 32 weeks (range 2-119 weeks). TA is a feasible and efficacious chemotherapeutic combination for the treatment of MDS RAEB, RAEB-t, CMML and AML. For patients of 60 years and older, this regimen is also a safe option.
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PMID:Phase I/II clinical study of topotecan and cytarabine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. 1516 Sep 42

Therapy-related leukemia and therapy-related myelodysplasia (t-AML/MDS) are serious and increasingly frequent complications of cytotoxic chemotherapy and/or radiotherapy. Two syndromes can be distinguished, one of which has a long latency (5-7 years or more) and is seen following alkylating agents, frequently with an antecedent dysplastic phase. The other has a short latency period (1-3 years), no antecedent dysplastic phase, and is characteristically seen following topoisomerase II inhibitors. Chromosomal abnormalities can confirm t-leuk/MDS and are predictive of poor prognosis, particularly those involving gains and losses of chromosome 7. There is no standard therapy for t-AML/MDS. This review concentrates on the various treatment approaches for t-AML/MDS. Treatment can be aggressive, with curative intent, particularly for patients who are young with no end-organ damage from the prior malignancy or chemotherapy. Various chemotherapy regimens have been designed to overcome the chemoresistance which is generally characteristic of these syndromes. Bone marrow transplantation offers the best chance for cure, and both myeloablative and nonmyeloablative protocols have been designed. Low dose chemotherapy is an option for patients not able to withstand traditional curative regimens and supportive care is a legitimate option for elderly or infirm patients. Multicenter studies are urgently needed to provide data on which clearcut treatment guidelines can be based, taking into account the patient's age, disease status and risk factors.
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PMID:Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. 1520 99

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.
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PMID:Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML. 1561 58

Treatment-related myelodysplasia (t-MDS) occurs less frequently with the nucleoside analogs than with DNA-damaging agents such as alkylators or topoisomerase II inhibitors. In a chemoimmunotherapy trial conducted between 1997 and 2003 in patients with stage IV indolent lymphoma, 202 patients were treated and 8 have developed MDS between 1 and 5 years after therapy, including 4 who received only fludarabine, mitoxantrone, and dexamethasone (FND) for 6 to 8 courses, with or without rituximab, followed by interferon alpha (IFN-alpha). Complex cytogenetic abnormalities were present in all patients. Abnormalities of chromosome 7 were present in 6 of the 8 patients, 3 of whom received only FND +/- rituximab and IFN-alpha. The abnormalities of chromosome 7 were monosomy 7 in 4 patients (1 of which had add 7p in the remaining chromosome); 1 del 7q; and 1 der 7. MDS with features classically associated with DNA-damaging agents can occur following therapy with FND, with or without rituximab, and IFN-alpha.
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PMID:Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. 1574 Dec 24

The MLL gene, located within band 11q23, has been shown to be involved in translocations with a large variety of reciprocal sites in both lymphoid and myeloid leukemia and has also been shown to undergo submicroscopic self-fusion/partial duplication. We report 29 patients with cytogenetic evidence of 11q23 alteration, all of which demonstrate molecular cytogenetic evidence of amplification of the MLL gene by fluorescence in situ hybridization (FISH). In all MLL cases, the patients were clinically classified as having transforming myelodysplasia (RAEB/RAEBT) or AML. An additional patient with AML was found by 24-color and gene-specific FISH to have AML1 oncogene amplification. Four patients had been previously diagnosed with cancer and had received topoisomerase II targeted drug therapy which is known to be associated with fusion transcripts involving the MLL and AML1 genes. MLL amplification appeared in various forms: an atypical banded region that bridges from 11q23 into a dicentric chromosome, expanded regions emanating from band 11q23, chromosome 11 paint-positive rings with "spoke-like" MLL amplification, and expansion at sites other than chromosome 11 (including extra markers) in the absence of one of the 11 homologues. The fluorescence pattern in most cases suggests palindromic duplication with neighboring sequences in the long arm of chromosome 11. As opposed to MYCN amplification in hsrs (homogeneously staining regions) and double minutes in neuroblastoma, amplification of MLL in most cases occurred at the site of the gene. All of our patients rapidly developed refractory AML. The frequency and clinical correlations of MLL gene amplification in leukemia will need careful follow-up, since the frequently cryptic amplification described in these cases may not generally provoke confirmatory FISH studies. The reported MLL cases represented about 1% of the total abnormal MDS/AML cases over 8 years. A common cytogenetic profile of 5 q-, -17/17 p-, -18/18 q-, and a missing or abnormal chromosome 11, may help direct appropriate follow-up studies. The MLL and the AML1 oncogenes appear to be the only oncogenes amplified at the natural site of the gene. Both genes also show a high degree of diversity of pathogenic mechanisms of leukemia evolution, including numerous reciprocal fusion genes in transformation to either AML or ALL and gain of function amplification.
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PMID:Oncogene amplification in transforming myelodysplasia. 1602 82

Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, antimetabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.
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PMID:Therapy-related leukemia and myelodysplasia: susceptibility and incidence. 1776 13

In therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), at least eight alternative genetic pathways have been defined based on characteristic recurrent chromosome abnormalities. Patients presenting as t-MDS and patients presenting as overt t-AML cluster differently in these pathways. The cytogenetic pattern depends on the type of leukemogenic therapy received: alkylating agents, topoisomerase II inhibitors, or radiotherapy. Three types of gene mutations are observed in MDS and AML: (1) Activating mutations of genes in the tyrosine kinase-RAS/BRAF signal transduction pathway, leading to increased cell proliferation (Class I mutations); (2) Inactivating mutations of genes encoding hematopoietic transcription factors, resulting in disturbed cell differentiation (Class II mutations); and (3) Inactivating mutations of the tumor suppressor gene p53. At least 14 different genes have been identified as mutated in t-MDS and t-AML, clustering differently and characteristically in the eight genetic pathways. Class I and Class II mutations are significantly associated, indicating their cooperation in leukemogenesis The chromosome aberrations and gene mutations detected in the therapy-related and in the de novo subsets of MDS and AML are identical, although the frequencies with which they are observed may differ. Hence, therapy-related and de novo MDS and AML are identical diseases and should be subclassified and treated similarly.
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PMID:Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. 1802 56

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) have been reported only rarely following treatment of AML. We report five patients treated for de novo AML who developed t-MDS/t-AML, all with chromosome 7 abnormalities, including -7, del(7)(q22q36) and del(7)(p11.22p22). All had been treated with cytarabine, topoisomerase 2 inhibitors and granulocyte or granulocyte-monocyte colony-stimulating factor and three with alkylating agents as part of autologous transplant regimens. These cases further document t-MDS/t-AML as a complication of therapy for AML. Presence of chromosome 7 abnormalities in patients with and without prior alkylating agent therapy suggests possible association with the antimetabolite cytarabine.
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PMID:Therapy-related myelodysplastic syndrome and acute myeloid leukemia following treatment of acute myeloid leukemia: possible role of cytarabine. 1809 51


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