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)

DNA topoisomerases, a class of enzymes that change the topological structure of DNA, have been shown to be the target of many therapeutic agents, including antibacterial agents (quinolones) and anticancer agents. These drugs inhibit the enzyme in a unique way so that the enzyme is converted into a cellular poison. Candida albicans and Aspergillus niger are two major opportunistic fungal pathogens. Our results show that these fungi have high levels of both type I and type II topoisomerases (with a minimum of 5 x 10(5) ATP-independent relaxation units and 2 x 10(5) P-4 unknotting units per liter of wild-type C. albicans). The ATP-dependent type II topoisomerase (termed C. albicans topoisomerase II) was purified by approximately 2,000-fold from C. albicans cells by using a simple isolation scheme that consists of three column procedures: hydroxylapatite, phosphocellulose, and heparin-agarose chromatographies. The responses of the Candida and the calf thymus topoisomerase II to some known topoisomerase II inhibitors were measured. Etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide, compounds known to inhibit catalysis and to enhance DNA breakage by mammalian topoisomerase II, and A-80198, an etoposide derivative, enhanced cleavage by both enzymes at similar concentrations of these compounds, with the response of the calf thymus topoisomerase II from slightly to fourfold higher in magnitude than the response of the Candida enzyme in the same concentration range. In contrast, A-75272 (a cytotoxic tricyclic quinolone) shows a slightly stronger DNA cleavage enhancement effect with the Candida enzyme than with the mammalian counterpart. The abundance of the enzyme in cells and the different drug responses of the host enzyme and the fungal enzyme suggest that the fungal topoisomerase may serve as a target for the discovery of effective and safe antifungal agents.
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PMID:DNA topoisomerases from pathogenic fungi: targets for the discovery of antifungal drugs. 133 49

Etoposide remains an integral component of therapy for non-small cell lung cancer. Its single-agent activity, and, hence, its activity in combination therapy, need to be reassessed in light of several reports of increased activity at higher doses. Although no effective means of overcoming resistance to etoposide appear to exist, topoisomerase II levels may predict sensitivity to treatment. Biologic response modifiers appear to add little or nothing to standard etoposide chemotherapy for non-small cell lung cancer. Continuous low-dose etoposide infusions do not appear to exhibit the same degree of activity as has been observed with prolonged oral dosing. The availability of effective means of reducing hematologic and emetic side effects of chemotherapy may permit rational trials of more intensive therapy.
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PMID:The role of standard-dose etoposide in the management of non-small cell lung cancer. 133 19

Etoposide, a podophyllotoxin derivative, has demonstrated antitumor efficacy in a number of human malignancies, including lymphomas, germinal tumors, and lung cancer (especially small cell). Etoposide's antineoplastic activity is achieved through DNA strand breakage, which likely results from the formation of a complex involving drug, DNA, and the DNA unwinding enzyme, topoisomerase II. The drug's steady state volume of distribution ranges from 5 to 17 L/m2, and it is highly bound to plasma protein with an average free plasma fraction of 6%. A number of etoposide metabolites have been confirmed or postulated. Several cell lines have been shown to acquire resistance to etoposide through membrane transport changes. Considerable intrapatient variability exists in pharmacokinetic parameters following intravenous (IV) and oral dosing. Approximately 30% to 40% of unchanged IV drug is excreted in the urine, whereas biliary excretion appears a minor route of drug elimination. The bioavailability of oral etoposide averages 50%, although wide variability exists both among and within different patients. Bioavailability decreases as the dose of oral etoposide is increased. Several recent studies have attempted to correlate etoposide plasma concentrations with toxicity (primarily myelosuppression) in hopes of using this information to optimize drug dosing.
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PMID:Etoposide pharmacology. 149 25

Etoposide (VP16-213), a topoisomerase II inhibitor, has produced complete responses in 17% of previously treated patients with acute nonlymphocytic leukemia (ANLL) but has little activity in acute lymphoblastic leukemia. As salvage therapy for relapsed ANLL etoposide produces 28% complete responses in combination with amsacrine, 49% with 5-azacytidine, and 51% with anthracycline. It has been successfully combined with high-dose cytarabine as a salvage treatment. In a randomized trial in previously untreated patients with ANLL, etoposide significantly prolonged remission duration. Etoposide has been used to intensify postinduction therapy with or without bone marrow rescue, but its exact role in that setting has not been clarified. Because of its schedule dependency in other tumors, etoposide should be investigated using different schedules in ANLL.
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PMID:Etoposide in the treatment of leukemias. 149 26

DNA topoisomerase II was isolated from mouse leukemia L1210 cells and the activity was determined by using P4 phage knotted DNA and pBR 322 DNA as the substrates. Based on these results, a method for screening antitumor agents by using DNA topoisomerase II as a target was established. The experiments showed that DNA topoisomerase II catalyzed pBR 322 DNA breaking and relaxing which were reversible and dependent on ATP. The activity was increased 2-4 times in the presence of ATP 1 mmol.L-1. In contrast with type II enzyme, the activity of DNA topoisomerase I was completely inhibited in the presence of ATP 1 mmol.L-1 and had full activity in the absence of ATP. Type II enzyme also showed the unknotting activity by using p4 phage knotted DNA as a substrate. DNA cleavage and relaxing reaction induced by type II enzyme increased 5-fold in the presence of Doxorubicin (Dox) 1 microgram.ml-1 or daunorubicin (Dau). Etoposide (Eto) and aclarubicin B (Acl B) also stimulated the reaction at 100 micrograms.ml-1. The cleavage reaction resulted from topoisomerase II was inhibited by other agents, such as frankincense extracts, terpenic compounds (BC series).
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PMID:Determination of DNA topoisomerase II activity from L1210 cells--a target for screening antitumor agents. 166 90

Etoposide is a phase-specific, schedule-dependent derivative of podophyllotoxin that appears to act by inhibiting DNA-topoisomerase II. Early preclinical work demonstrated sharp activity in mouse leukemias and possible synergy with cisplatin. As a single agent (either orally or intravenously), it demonstrated limited benefit in non-small cell lung cancer (NSCLC), with response rates around 10%. In combination with cisplatin, it has become a mainstay of chemotherapeutic efforts, either as primary therapy or in conjunction with radiation. Response rates in advanced disease average around 30%, climbing to more than 50% in patients with Stage IIIA or IIIB disease. More recent work suggests that the issue of the true synergy of etoposide with cisplatin in NSCLC needs reassessment. The relative roles of etoposide and cisplatin in the combination are unclear, as several studies conflict. Pharmacokinetic data suggest that multiple daily fractions of etoposide are superior to prolonged infusions, warranting several future trials. The current major role for etoposide plus cisplatin would appear to be in multimodality therapy where the combination can be readily combined with radiation and/or surgery. Several other agents have been studied with etoposide or etoposide plus cisplatin (mitomycin, vindesine, doxorubicin, cyclophosphamide, ifosfamide, and carboplatin), but it is unclear whether the addition of any of them offers any response or survival advantage.
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PMID:Etoposide in the management of non-small cell lung cancer. 184 48

Etoposide (VP-16) resistance is expressed following in vitro exposure of HN-1 and MCF-7 human tumor cells to the drug itself or to fractionated X irradiation. VP-16-selected sublines prove cross-resistant to Adriamycin, amsacrine and actinomycin D, whilst X-ray-pretreated sublines show cross-resistance to only actinomycin D. These differential responses, in the HN-1 series, are not associated with significant differences in amounts of immunoreactive topoisomerase (topo) II, altered topo-II catalytic activity of nuclear extracts or changes in susceptibility of the topo II to VP-16- or amsacrine-induced DNA-protein cross-link formation. Therefore significant modifications in topo II appear not to be implicated in VP-16 resistance in these HN-1 sublines.
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PMID:A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance. 184 24

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the Mr 170,000 P-glycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed cross-resistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR. Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and m-AMSA-induced DNA cleavage was 5-fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. Therefore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage complex.
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PMID:Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin-resistant human small cell lung carcinoma cell line. 196 22

Etoposide, a derivative of epipodophyllotoxin, is one of the most important new drugs that was introduced into the management of the malignant lymphomas during the past decade. A growing number of specific protocols include this useful agent in the management of malignant lymphoma, both at the time of primary treatment and at relapse. The broad activity of etoposide across several histologic subtypes of malignant lymphoma and Hodgkin's disease indicates a potential that is only now being fully exploited. Used according to optimal doses and schedules, etoposide has single-agent activity that rivals earlier drugs such as the alkylating agents and doxorubicin. Functioning as a protein synthesis and topoisomerase II inhibitor, it offers the potential for non-cross-resistant cytotoxicity. After a brief comment on the single-agent activity of etoposide, this report will focus on the integration of etoposide into multiagent protocols used in the primary treatment of malignant lymphoma and Hodgkin's disease. The specific findings from protocols such as prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide-cytarabine, bleomycin, vincristine, and methotrexate (Pro-MACE-CytaBOM) (US National Cancer Institute [NCI]) and etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) (Vancouver) for the primary treatment of malignant lymphoma, and vinblastine, etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, and prednisone (VECABOP) (Vancouver) for the treatment of previously untreated patients with advanced Hodgkin's disease will be discussed.
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PMID:The evolving role of etoposide in the management of lymphomas and Hodgkin's disease. 198 27

The epipodophyllotoxin derivative etoposide (VP-16) has been in widespread use both alone and in combination chemotherapy for the past decade. It has phase-specific cytotoxicity that acts in the last S and G2 phases of the cell cycle. Although its mode of action is not certain, it appears to act by causing breaks in DNA by interaction with DNA-topoisomerase II or by the formation of free radicals. Most studies show biexponential decay after the intravenous (IV) administration of etoposide. Approximately 30% to 70% of administered etoposide is excreted, with approximately 45% present in the urine. Etoposide is available in oral and IV preparations. It is highly schedule-dependent, with once-daily doses (e.g., for 5 to 8 days every 21 days) giving results superior to intermittent administration. The bioavailability of oral etoposide is approximately 50%, but its absorption is not linear with increasing dose (e.g., greater than 200 mg/d, bioavailability decreases). Factors influencing the bioavailability of oral etoposide include patient status, concurrent medications, hepatic and renal function, and nausea and vomiting. In numerous clinical trials, etoposide has demonstrated excellent activity against a range of tumors, including small cell lung cancer (SCLC), malignant lymphomas, gestational trophoblastic tumors, Ewing's and soft tissue sarcomas, and germ cell tumors, with more modest activity in other tumors (e.g., non-SCLC). Although few comparative studies have been carried out, available data suggest that oral etoposide administered daily during 5 to 8 days is similar to the IV preparation in range of activity. In a study of 53 elderly patients with SCLC treated with etoposide (200 mg/d for five times), there was a response rate of 79% and a median survival of 9.5 months. These results were similar to those achieved with more intensive IV regimens. Several studies of chronic oral etoposide (50 mg/m2/d for 21 times) have been reported recently. Responses were observed in SCLC and germ cell tumors among patients who had relapsed after standard etoposide-containing regimens. These data suggest that etoposide may be a "new" drug when given in this schedule. The high response rates with oral etoposide suggest that oral administration may be substituted for IV administration. This substitution may allow for greater flexibility in chemotherapeutic administration, less hospitalization, and more acceptable toxicity.
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PMID:The pharmacology of intravenous and oral etoposide. 198 31


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