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)

Therapy-related myelodysplastic syndrome (tMDS) and acute nonlymphocytic leukemia (tANLL) are known late complications of cytotoxic drug therapy for hematologic malignancies, solid tumors, and nonmalignant conditions. The alkylating agents are often the causative agents, but a few reports have implicated cisplatin as an etiologic agent. Cisplatin has a significant impact on the treatment of a number of malignant neoplasms, including testicular and ovarian cancer, and is a part of several clinical trials for squamous cell carcinoma of the head and neck region. Given its increasing use, a complication as significant as tMDS is potentially important. In this article, the authors describe the case of a patient who had myelodysplastic syndrome develop after successful treatment for laryngeal cancer with cisplatin. The treatment included cisplatin in combination with 5-fluorouracil, followed by radiation therapy. The authors also present a review of articles in the literature regarding tMDS and tANLL occurrence after treatment with cisplatin-containing regimens. The authors conclude that cisplatin can be a leukemogenic agent. The drug may potentiate the leukemogenic effects of other alkylating agents and drugs that inhibit topoisomerase II action.
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PMID:Myelodysplastic syndrome after cisplatin therapy. 850 9

Several antineoplastic agents used in the treatment of hematologic malignancies exert their cytotoxic effects by inhibiting the activity of nuclear DNA topoisomerase (topo) I or II. Mechanisms of drug resistance to topoisomerase inhibitors have been defined at the molecular level from in vitro studies using model cell lines, and include quantitative and qualitative changes in topo I and II. The possible roles of these mechanisms in clinical drug resistance and clinical outcomes for patients with hematologic malignancies are now under investigation. Available data indicate that the blast content of topo II does not correlate with clinical outcome in acute myeloid leukemia (AML), and this may also be true in acute lymphocytic leukemia (ALL). Chronic lymphocytic leukemia (CLL) cells are resistant to topo II inhibitors because they express low levels of topo II. Further studies using sequential biopsy samples and assays of topoisomerase activity should establish the role that changes in topo I and II activity play in the development of drug resistance in hematologic malignancies.
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PMID:Drug resistance to DNA topoisomerase I and II inhibitors in human leukemia, lymphoma, and multiple myeloma. 940 61

The anthracyclines are widely used in the treatment of haematological and non-haematological malignancy and there is now more than 30 years' clinical experience with these agents but despite this, their mechanism of action is incompletely understood. The anthracyclines have been shown to intercalate with DNA and indirectly inhibit the activity of the enzyme topoisomerase II, resulting in DNA strand breaks. More recently, workers have focused on induction of apoptosis and have shown that daunorubicin stimulates production of the apoptotic mediator, ceramide and that the activity of doxorubicin can be blocked by inhibitors of CD95 (fas). One of the major problems with anthracycline therapy is the development of resistance which may be mediated by p-glycoprotein or by other mechanisms. Much recent research has concentrated on methods to modulate the drug-resistant phenotype and these include development of new analogues and use of specific reversal agents. The toxicity profile of the anthracyclines includes bone marrow suppression, severe local reaction following extravasation, radiation recall, alopecia, gastrointestinal and hepatic effects, development of secondary malignancies and significant cardiac toxicity. The risk factors for the development of anthracycline-related cardiac toxicity are well documented and several methods have been exploited in attempts at prevention. Finally, a number of drug delivery systems have been developed in order to improve therapeutic response and reduce toxicity to normal tissues, including the use of liposomal preparations.
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PMID:Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. 948 50

First-line chemotherapy and/or radiotherapy can achieve disease-free survival in 30% to 75% of patients with non-Hodgkin's lymphomas (NHL), a diverse group of hematologic malignancies, depending on disease stage. However, as many as 50% of patients with advanced-stage NHL either do not achieve an Initial clinical response or subsequently relapse. Topotecan, a topoisomerase-I inhibitor, is considered a potential treatment for NHL. The efficacy of topotecan, alone and in combination with paclitaxel, in the treatment of patients with relapsed NHL has recently been Investigated. In a clinical study of topotecan as a single agent, patients with aggressive NHL who had received only 1 prior chemotherapy regimen had a 43% response rate, and similar patients with Indolent NHL had a 40% response rate. A combination of paclitaxel and topotecan has been shown to have efficacy in a phase 11 trial, with overall response rates of 27% in patients with primary refractory NHL and 72% in patients with relapsed NHL. Based on these promising early results, further Investigation of topotecan in the treatment of NHL is warranted.
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PMID:The role of topoisomerase-I inhibitors in the treatment of non-Hodgkin's lymphoma. 1062 24

Treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (t-AML) are now well established as complications of cytotoxic chemotherapy. We experienced a 28-yr-old female patient who developed t-MDS/t-AML with characteristic chromosomal abnormalities including 11q23 chromosomal rearrangement following high-dose chemotherapy with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma. The patient was admitted with bulky abdominal masses of B cell lineage non-Hodgkin's lymphoma. After 2 cycles of systemic chemotherapy of the Vanderbilt regimen, the patient underwent ASCT with high dose chemotherapy of the BEAC regimen. She also received radiation of 48 Gy for the residual periportal lymphadenopathy. The initial cytogenetic analysis of the infused mononuclear cells revealed a normal karyotype. Twenty two months after the ASCT, pancytopenia was noted and her bone marrow aspirate showed dysplastic hemopoiesis with myeloblasts up to 12% of nonerythroid nucleated cells. The patient was diagnosed as t-MDS (refractory anemia with an excess of blasts). Cytogenetic analysis showed complex chromosomal abnormalities including 11q23 rearrangement, which is frequently found in topoisomerase II inhibitor-related hematologic malignancies. Four months later, it was noted that the t-MDS had evolved into an overt t-AML. Cytogenetic analysis showed an evolving pattern with more complex abnormalities. The patient was treated with combination chemotherapy, but her leukemic cells were resistant to the therapy.
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PMID:A case of treatment-related myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemotherapy with autologous stem cell transplantation for non-Hodgkin's lymphoma. 1217 56

Therapy-related myelodysplastic syndrome and therapy-related acute myelocytic leukemia (AML) are now recognized as hematologic malignancies that occur a few years after chemotherapy for primary malignancy with alkylating agents or topoisomerase II inhibitors. The secondary leukemia is usually AML and sometimes is preceded by a myelodysplastic syndrome. Acute lymphoblastic leukemia (ALL) as a secondary leukemia is quite rare, and secondary T-cell ALL after AML is even rarer. We report a case of a 56-year-old woman who developed T-cell ALL after a 3-year remission of AML (M2). We thought that this case would be extremely valuable for studying the etiology and biological characteristics of T-cell ALL as a secondary leukemia after AML.
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PMID:T-cell acute lymphoblastic leukemia as a secondary leukemia after a 3-year remission of acute myelocytic leukemia. 1284 92

The RecQ family of DNA helicases consists of specialized DNA unwinding enzymes that promote genomic stability through their participation in a number of cellular processes, including DNA replication, recombination, DNA damage signaling, and DNA repair pathways. Mutations resulting in the inactivation of some but not all members of the RecQ helicase family can lead to human syndromes which are characterized by marked chromosomal instability and an increased predisposition to cancer. An evolutionarily conserved interaction between RecQ helicases and topoisomerase 3s has been established, and this interaction is important in the regulation of recombination and genomic stability. Topoisomerases are critical in the cell because they relieve helical stress that arises when DNA is unwound. Topoisomerases function by breaking and rejoining DNA. By inhibition of the rejoining function, topoisomerase inhibitors are potent chemotherapeutic agents that have been used successfully in the treatment of hematologic malignancies and other cancers. This review discusses the roles of RecQ helicases in genomic stability, the interplay between RecQ helicases and topoisomerase 3s, and current and future prospects for targeting these interactions to develop novel anticancer therapies.
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PMID:The broken genome: genetic and pharmacologic approaches to breaking DNA. 1745 18

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

The topoisomerase-I (topo-I) inhibitor topotecan, derivative of camptothecin, is the only registered drug for relapsed small cell lung cancer (SCLC). The histone deacetylase inhibitor vorinostat has shown preclinical and clinical antitumor activities in hematologic malignancies and solid tumors, including SCLC, and has recently been approved for the treatment of cutaneous T-cell lymphomas. In this study, we analyzed the antitumor effect of vorinostat combined with topotecan or camptothecin in topo-I inhibitor-sensitive H209 and inhibitor-resistant H526 SCLC cells. Simultaneous or sequential exposure (24 h delay) to either agent resulted in strong synergistic cytotoxic effect in both cell lines, as shown by calculating combination index, and confirmed by growth in soft agar. Combination treatments increased S-phase cell cycle arrest paralleled by apoptosis as measured by hypodiploid peak formation, Annexin V binding, DNA fragmentation, and mitochondria destruction. The apoptotic process was triggered by a caspase-dependent mechanism and can be ascribed to the phosphorylation of H2AX, a reporter of DNA double-strand breaks. These effects were paralleled by an increase of topo-I/DNA covalent complexes induced by combination treatment and suggest a potentiation by vorinostat of topotecan-induced DNA damage. Finally, oxidative injury played a significant functional role in the observed enhanced lethality because coadministration of the antioxidant N-acetyl-l-cysteine blocked reactive oxygen species generation, apoptosis, and mitochondria destruction induced by the vorinostat/topotecan combination. To our knowledge, this is the first demonstration of a synergistic antitumor effect between topotecan and vorinostat in SCLC. Because no well-established treatment is available for recurrent SCLC patients, our results indicate that this drug combination should be explored clinically.
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PMID:Synergistic antitumor effect between vorinostat and topotecan in small cell lung cancer cells is mediated by generation of reactive oxygen species and DNA damage-induced apoptosis. 1988 47

Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.
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PMID:Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks. 2131 56


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