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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in acute leukemia, and to evaluate the effects of in vivo exposure to topotecan on topoisomerase II levels in leukemic blast cells as measured by image cytometry. Patients who were eligible for this phase I study had relapsed or refractory acute myeloid leukemia (< or = 2 prior regimens) or CML blast crisis (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m2 day), followed by etoposide at two dose levels (100 and 150 mg/m2) i.v. bolus days 6, 7 and 8. Topoisomerase IIalpha levels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting toxicity was seen in two of six patients at the first dose level (topotecan 1.5 mg/m2/day, etoposide 100 mg/m2/day; > or = grade 3 mucositis in both cases). This cohort was expanded to 10 patients; no further non-hematologic dose-limiting toxicity was observed, but given the extent of toxicity seen, further dose escalation was judged not to be feasible. Topo IIalpha levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone marrow blasts by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a patient with CML blast crisis was observed in the 10 patients evaluable for response. The sequential administration of topotecan 1.5 mg/m2/day continuous infusion for 5 days followed by etoposide 100 mg/m2/day x 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIalpha expression in vivo in leukemia cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in acute leukemia.
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PMID:Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. 1008 24

Topotecan- or mitoxantrone-selected cell lines (T8 and MX3, respectively), derived from the human IGROV1 ovarian cancer cell line, were resistant to the topoisomerase I inhibitors topotecan, SN-38 (the active metabolite of irinotecan), and 9-aminocamptothecin, as well as to the topoisomerase II drug mitoxantrone. In both resistant cell lines, decreased accumulation of topotecan and mitoxantrone was observed, caused by enhanced energy-dependent efflux of the drugs involved. In both cell lines, we found that the breast cancer resistance protein/mitoxantrone resistance/placenta-specific ATP binding cassette (BCRP/MXR/ABCP) gene was overexpressed. Furthermore, BCRP/MXR/ABCP expression levels in various partially revertant T8 cells correlated with the levels of resistance to topotecan, SN-38, and mitoxantrone, strongly suggesting BCRP/MXR/ABCP to be the transporter responsible for the enhanced efflux. Pharmacodynamic analysis demonstrated that BCRP/MXR/ABCP is a very efficient transporter of topotecan; in vitro, 70% of the intracellular topotecan pool was transported out of the T8 or MX3 cells within 30 s. In conclusion, we report for the first time that BCRP/MXR/ABCP can also be up-regulated upon exposure of tumor cells to the clinically important drug topotecan, and that BCRP-mediated efflux of topotecan is very efficient. This highly efficient efflux of topotecan by BCRP/MXR/ABCP may have clinical relevance for patients being treated with topotecan.
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PMID:Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. 1049 7

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

Although the prognosis for adults with acute myelogenous leukemia (AML) has improved over the past 10 years, overall results remain modest. Current research areas in the treatment of AML include dose-intensive therapy and stem-cell transplantation (SCT), immunotherapy, modulation of leukemia resistance (eg, multidrug resistance [MDR] Inhibitors), differentiation therapy (eg, retinolds), exploitation of different disease pathophysiology (eg, angiogenesis inhibitors, apoptosis-inducing agents), targeted therapy (eg, monoclonal antibodies, gene therapy), and the development of additional active chemotherapeutic agents with different mechanisms of action. Topotecan, a topoisomerase-I Inhibitor, may potentially enhance the activity of standard induction chemotherapy with cytosine arabinoside (cytarabine) and topoisomerase-II inhibitors. Topotecan is being investigated as salvage and front-line therapy for AML in combination with etoposide, cytarabine, or cyclophosphamide. The role that topotecan will eventually play In the treatment of AML is not yet clear, but encouraging results from triple combination induction therapy In patients with unfavorable prognoses warrant further investigation.
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PMID:New developments in the treatment of acute myeloid leukemia: focus on topotecan. 1062 25

Topotecan is a semi-synthetic, water soluble topoisomerase I inhibitor which has recently been approved for the treatment of ovarian cancers after failure of first-line therapy. A number of different dosing schedules are being investigated in clinical trials including oral administration, a daily infusion on 5- or 3-consecutive days and a continuous infusion for 21 days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks, as standard schedule, produced response rates of 13.8 to 20.5% in the 3 largest phase II/III studies in women with advanced ovarian cancers who had either failed to respond or had relapsed after an initial response to platinum-based chemotherapy (N = 92 to 139), continuous 21-day infusion of topotecan 0.3 to 0.5 mg/m2 has shown efficacy in 2 small phase II studies. There were no statistically significant difference in efficacy between topotecan (1.5 mg/m2/day for 5 consecutive days every 21 days) and paclitaxel (175 mg/m2/day given over 3-h every 21 days) in the randomized phase III study. In 3 large clinical trials, response to topotecan was higher in patients who were platinum sensitive (19.2 to 29%) than in those whose disease was platinum resistant or refractory (11.3 to 13.3%) not statistically significant in 1 study, statistical analysis not reported in the other 2 trials. Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of topotecan. It is reversible, dose-related and non-cumulative. In 2 large studies, topotecan produced grade 4 neutropenia in 78 and 79% of patients and in 40 and 37% of all treatment courses (febrile neutropenia occurred during 3% of 552 courses in 1 study). Grade 4 thrombocytopenia was seen in 18 and 25% of patients and in 6 and 10% of all courses, respectively. Grade 4 neutropenia was significantly more common in patients receiving topotecan than in those receiving paclitaxel (79 vs 23%), as was grade 4 thrombocytopenia (25 vs 2%), in a single randomized clinical trial. Non-hematological adverse events during topotecan therapy were mostly mild. A step beyond is the combination treatment including topotecan as a 3- or 5 days schedule plus a platinum compounds or topoisomerase II inhibitor. These associations of drugs are based on the preclinical data of the in vitro studies showing a synergy of the anti-tumor activity. A novel schedule of topotecan is also the "alternating" chemotherapy consisting of different doublet of drugs given as a sequential way or as a really sequential topotecan therapy. Both methods of combining topotecan as second/salvage treatment or front line therapy are being investigated by numerous authors. Preliminary data suggest interesting results in terms of efficacy, manageable toxicity and new schedules of treatment for topotecan. Low dosages of drug in combination with other agent do not seem to influence the well-known data of efficacy or safety of topotecan literature. Probably the 3-day schedule allows a combination treatment, otherwise not feasible with the standard 5-day administration.
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PMID:[Topotecan: prospects for using it in combination therapy for ovarian carcinoma]. 1078 95

The efficacy of topoisomerase (Topo) I-active drugs may be improved by better understanding the molecular and cellular responses of tumor compared to normal cells after genotoxic insults. Ionizing radiation (IR) + Topo I-active drugs (e.g., Topotecan) caused synergistic cell killing in various human cancer cells, even in cells from highly radioresistant tumors. Topo I poisons had to be added either during or immediately after IR. Synergy was caused by DNA lesion modification mechanisms as well as by concomitant stimulation of two pathways of cell death: necrosis (IR) + apoptosis (Topo I poisons). Cumulative data favor a mechanism of synergistic cell killing caused by altered DNA lesion modification and enhanced apoptosis. However, alterations in cell cycle regulation may also play a role in the synergy between these two agents in certain human cancers. We recently showed that NF-kappa B, a known anti-apoptotic factor, was activated in various cancer cells after poisoning Topo I using clinically active drugs. NF-kappa B activation was dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. Cytoplasmic signaling leading to NF-kappa B activation after Topo I poisons was diminished in cytoplasts (lacking nuclei) and in CEM/C2 cells that expressed a mutant Topo I protein that did not interact with Topo I-active drugs. NF-kappa B activation was intensified in S-phase and blocked by aphidicolin, suggesting that activation was a result of double-strand break formation due to Topo I poisoning and DNA replication. Dominant-negative I kappa B expression augmented Topo I poison-mediated apoptosis. Elucidation of molecular signal transduction pathways after Topo I drug-IR combinations may lead to improved radiotherapy by blocking anti-apoptotic NF-kappa B responses. Recent data also indicate that synergy caused by IR + Topo I poisons is different from radiosensitization by beta-lapachone (beta-lap), a "reported" Topo I and II-alpha poison in vitro. In fact, beta-lap does not kill cells by poisoning either Topo I or II-alpha in vivo. Instead, the compound is "activated" by an IR (damage)-inducible enzyme, NAD(P)H:quinone oxidoreductase (NQO1), a gene cloned as x-ray-inducible transcript #3, xip3. Unlike the lesion modification pathway induced by IR + Topo I drugs, beta-lap kills cells via NQO1 futile cycle metabolism. Downstream apoptosis caused by beta-lap appears to be noncaspase-mediated, involving calpain or a calpain-like protease. Thus, although Topo I poisons or beta-lap in combination with IR both synergistically kill cancer cells, the mechanisms are very different.
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PMID:Cellular and molecular responses to topoisomerase I poisons. Exploiting synergy for improved radiotherapy. 1119 3

Recurrent or metastatic squamous carcinoma of the head and neck (RMSCHN) is a modestly chemoresponsive tumor; however, currently available agents have failed to improve survival. New active agents are needed for the treatment of this disease. Topotecan is a topoisomerase inhibitor that demonstrated initial promising activity in squamous carcinoma of the head and neck. The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan to determine the efficacy and toxicity of a weekly treatment schedule in patients with RMSCHN. Patients with metastatic or locally recurrent squamous carcinoma of the head and neck were treated with topotecan 1.5 mg/m2 x 24 hours by continuous infusion on days 1, 8, 15, and 22 of each 35-day cycle. Patients were stratified in two cohorts: chemonaive and previously treated. Sixteen chemonaive and 16 previously treated patients were registered on study. Grade III/IV neutropenia and anemia occurred in 16% and 18% of patients, respectively. No responses were observed in either cohort. Median survival for previously untreated patients was 4.6 months and 3.2 months for previously treated patients. Topotecan failed to demonstrate efficacy in patients with RMSCHN. Further evaluation of this agent is not planned.
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PMID:Lack of efficacy of topotecan in the treatment of metastatic or recurrent squamous carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (E3393). 1123 52

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice were treated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 10, 20, 40, or 80 daily injections. The toxicity was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the mice cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify parameters related to the efficacy and toxicity of topotecan in our model. The use of a population pharmacokinetic approach allowed us to define a therapeutic window: maintaining plasma concentrations above 0.2 microM for >10 h was necessary for an optimal antitumor effect and avoiding plasma concentrations >0.7 microM allowed a manageable toxicity. Finally, Topo I activity was monitored in ascites from animals treated with different topotecan administration schedules. The optimal schedule defined above allowed for sustained inhibition of Topo I activity associated with a greater antitumor activity. These in vivo data constitute a rationale for clinical studies testing this type of administration.
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PMID:Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation. 1159 18

Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.
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PMID:The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine. 1199 30

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m2 given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m2 given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m2 of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously over 5 days every 28 days is recommended.
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PMID:Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies. 1219 19


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