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)

Drug resistance in the VP-16 resistant human leukemic cell line (THP-1/E) was studied the possible relevance of topoisomerase II activity. Strand-passing activity in crude nuclear extract from sensitive and resistant cells was comparable and equally sensitive to inhibition by VP-16. However, it was demonstrated that VP-16-mediated pBR322 DNA cleavage in the presence of nuclear extract from resistant cells was reduced to one-tenth of that from sensitive cells. These results suggested that the resistance of THP-1/E cells to VP-16 was due to reduced DNA cleavage activity.
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PMID:Reduced topoisomerase II-mediated DNA cleavage in VP-16 resistant human leukemic cell line. 185 Feb 22

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

Etoposide, a semisynthetic derivative of podophyllotoxin, is increasingly used to treat cancer. Etoposide is a phase-specific, cytotoxic drug acting in the late S and early G2 phases of the cell cycle. It appears to cause breaks in DNA by either an interaction with DNA-topoisomerase II or the formation of free radicals. Most studies show a biexponential decay after the intravenous (IV) administration of etoposide. The peak plasma concentrations of drug and the area under the concentration versus time curve (AUC) are linearly related to the IV dose. Considerable interpatient variability of pharmacokinetic variables exists after IV etoposide. Various metabolites of etoposide have been identified, but their detection and quantitation are disputed. Approximately 30% to 70% of an etoposide dose is excreted. The bioavailability of oral etoposide is approximately 50%, but its absorption is not linear with increasing doses within the range in clinical use. Considerable interpatient and intrapatient variability exists in the pharmacokinetics of oral etoposide. There is no evidence of etoposide accumulation after multiple consecutive doses by either the IV or oral route. The exact roles of the liver and kidney in metabolism and excretion of etoposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This, together with the phase-specific action of etoposide and its increasingly widespread use in treating cancer, makes the clinical pharmacology of this drug of great clinical importance.
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PMID:The clinical pharmacology of etoposide. 198 35

Murine leukemia L1210 cells selected for progressive resistance to doxorubicin (DOX) display both the multidrug resistant (MDR) phenotype and reductions in drug induced topoisomerase II-mediated DNA cleavage in nuclear extracts (Ganapathi, R.; Grabowski, D.; Ford, J.; Heiss, C.; Kerrigan, D.; Pommier, Y., Cancer Commun. 1:217-224; 1989). The present study was performed to characterize the results of exposure of the sensitive (S) and progressively DOX-resistant (10-fold, R1, and 40-fold, R2) L1210 cells to the topoisomerase II inhibitor, etoposide, and to investigate the modulating effects of the calmodulin inhibitor, trifluoperazine (TFP). Immunoblotting experiments indicated no apparent decrease in the p170 or p180 isoforms of topoisomerase II in the resistant sublines versus parental sensitive cells. Cross-resistance to etoposide (VP-16) was similar to that of DOX (10- and 40-fold). A non-cytotoxic concentration of 5 microM TFP enhanced cell kill 1.5- fold in the sensitive and 3- to 5-fold in the progressively DOX-resistant cells. Accumulation of VP-16 was 30% to 50% lower in the resistant sublines versus similarly treated sensitive cells, and a marked enhancement of drug uptake in the presence of TFP was observed in the sensitive but not in the resistant cells exposed to equivalent extracellular levels of VP-16. Although equimolar concentrations of VP-16 produced fewer DNA single strand breaks (SSB) and DNA protein crosslinks (DPC) in the resistant versus sensitive cells, similar DNA damage was apparent when S and R1, but not R2, cells were treated at VP-16 concentrations that produced equivalent cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Trifluoperazine modulation of resistance to the topoisomerase II inhibitor etoposide in doxorubicin resistant L1210 murine leukemia cells. 199 27

In an effort to improve the additive anti-tumor efficacy of commonly used alkylating agents, the topoisomerase-II inhibitor etoposide was used in combination with either the mitochondrial poison and energy-depleting agent lonidamine or the hemorheologic agent and tumor-blood-flow-increasing agent pentoxifylline. In the FSaIIC murine fibrosarcoma system, these modulators were evaluated for modulation of whole-tumor cell killing vs. bone-marrow CFU-GM toxicity with the alkylating drugs CDDP, CTX, L-PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor-cell and bone-marrow killing, except for BCNU, where a substantial increase in tumor-cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone-marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor-cell vs. bone-marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor-cell killing of 0.5 to 1.0 log were observed. Hoechst-33342-defined tumor-cell sub-population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.
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PMID:Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo. 204 6

Etoposide is known to inhibit the activity of topoisomerase II, and to possess radiosensitizing effects. In this paper we show that pretreatment of mice with etoposide one day before whole-body irradiation had a protective effect against radiation-induced bone marrow death. The LD50/30 of mice given radiation alone was 8.26 Gy while that of mice given etoposide one day before whole-body irradiation was 10.35 Gy. The number of endogenous colony-forming units surviving in whole body-irradiated mice was significantly increased by pretreatment with etoposide.
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PMID:Etoposide protects mice from radiation-induced bone marrow death. 211 Jan 26

The role of topoisomerases in the replication of human adenovirus type 5 was investigated with topoisomerase inhibitors. Both topoisomerase I and topoisomerase II inhibitors blocked adenovirus replication when added at the time of infection. Both types of inhibitors induced strand cleavages at specific sites in the adenovirus early templates. The cleavage sites were mapped near the 5' and 3' ends of the genes transcribed early during infection. At late times after infection, camptothecin, a topoisomerase I inhibitor, inhibited adenovirus DNA replication and induced the formation of single- and double-stranded fragments with breakpoints located at defined regions of the viral genome. The topoisomerase II inhibitors, VP-16 (etoposide) and ellipticine, did not block adenovirus DNA replication and did not induce an appreciable amount of double-strand cleavages in the newly synthesized DNA. On the other hand, VP-16 promoted double-strand cleavages at specific sites of nonreplicating adenovirus DNA. The packaging of adenovirus DNA into virus particles, which contain supercoiled adenovirus DNA (M.-L. Wong and M.-T. Hsu, Nucleic Acids Res. 17:3535-3550, 1989), was inhibited by the topoisomerase II inhibitors. Transcription of adenovirus major late genes was inhibited by both topoisomerase I and topoisomerase II inhibitors. In addition, camptothecin caused a premature termination of major late transcription. Electron microscopic analysis showed that adenovirus templates late after infection were arranged in topologically constrained loop domains. Together, these data provide evidence for the requirement of topoisomerase activities in the replication, transcription, and packaging of the linear adenovirus genome.
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PMID:Involvement of topoisomerases in replication, transcription, and packaging of the linear adenovirus genome. 215 35

Two isoflavones, genistein (4',5,7-trihydroxyisoflavone) (1) and orobol (5,7,3',4'-tetrahydroxyisoflavone) (2) induced mammalian topoisomerase II dependent DNA cleavage in vitro. The cleavage activities of 1 and 2 were comparable to those of known antitumor agents with topoisomerase II dependent DNA cleavage activity such as 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP-16). Two flavones, fisetin (3,7,3',4'-tetrahydroxyflavone) (3) and quercetin (3,5,7,3',4'-pentahydroxyflavone) (4) showed topoisomerase II dependent DNA cleavage activity with similar potentials to that of Adriamycin. Addition of salt (0.5 M NaCl) to the reaction mixture containing genistein and topoisomerase II resulted in a great reduction of DNA cleavage, suggesting that the mechanism of the topoisomerase II dependent DNA cleavage induced by flavonoids is through the cleavable complex formation as seen with m-AMSA and VP-16. DNA unwinding assay using mammalian topoisomerase I showed that both 1 and 2 did not intercalate into DNA but both 3 and 4 intercalated like m-AMSA. Other structurally related flavonoids could not induce topoisomerase II dependent DNA cleavage, indicating that the restricted structures of flavonoids were required for the cleavage activity.
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PMID:Induction of mammalian topoisomerase II dependent DNA cleavage by nonintercalative flavonoids, genistein and orobol. 215 93


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