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

---

Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
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.
...
PMID:Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies. 1219 19

DNA topoisomerase II targeting agents such as etoposide and doxorubicin are well-established cancer chemotherapeutic agents. Topotecan (Hycamtin) and irinotecan (Camptosar) are launched drugs that target topoisomerase I and have significant activity against many solid malignancies. These agents have important mechanistic similarities, converting their target enzyme(s) to generate DNA damage. Recent structural and biochemical studies on targeting of topoisomerases by antitumor agents are providing a framework for understanding drug action at the enzyme level, and at the level of cellular pathways important for responses to this unique type of DNA damage. These investigations into the mechanisms of action of topoisomerase-targeting agents should aid in the design of dinical protocols that optimize the activity of these agents.
...
PMID:DNA topoisomerases in cancer chemotherapy: using enzymes to generate selective DNA damage. 1243 Oct 29

Small-cell lung cancer (SCLC) is highly chemosensitive but up to 70% of patients with limited disease and more than 90% of patients with extensive disease will relapse after first-line treatment. There are several standard chemotherapy regimens used for second-line treatment yet the prognosis for patients requiring this treatment remains poor. The topoisomerase-I inhibitor, topotecan, has achieved response rates of up to 22% in previously treated patients with SCLC and survival almost double that achieved with other single agents. Compared with cyclophosphamide/doxorubicin/vincristine (CAV), single-agent topotecan achieved a higher response rate, longer survival and statistically significant improvements in dyspnea, hoarseness, fatigue, anorexia and interference with daily activities. Brain metastases are common in SCLC. Topotecan crosses the blood-brain barrier and shows promise for the management of brain metastases.
...
PMID:The role of topotecan in treating small cell lung cancer: second-line treatment. 1456 8

Patients with non-small cell lung cancer (NSCLC) typically receive platinum-based combination chemotherapy. In spite of improvements in symptoms and survival, response rates remain low and newer agents are being investigated. The newer agents may offer increased efficacy and reduced toxicity compared with established agents and regimens. The topoisomerase-I inhibitor, topotecan, achieves single-agent response rates of 4-25% in NSCLC. Topotecan has also been studied in combinations: a combination of topotecan, administered using the standard 5-day schedule, with cisplatin was effective but was associated with myelosuppression. The combination of topotecan plus carboplatin may be better tolerated and warrants further investigation. Topotecan was also combined with newer agents (gemcitabine, vinorelbine, docetaxel, paclitaxel) using a range of different administration schedules of topotecan. Response rates of up to 30% were achieved. A weekly schedule of topotecan was effective and well tolerated and was also convenient for healthcare professionals and patients.
...
PMID:Combination chemotherapy with topotecan for non-small cell lung cancer. 1456 11

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.
...
PMID:Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430). 1466 44

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.
...
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

Locally advanced non-small-cell lung cancer represents 30% to 40% of all pulmonary malignancies. Most patients will die of the disease after aggressive contemporary treatments. Therefore, significant improvement in therapeutic methods must be implemented to improve overall survival rates. The arrival of a new generation of chemotherapeutic agents--including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar) and topotecan (Hycamtin)--offers the hope of significant advances in the treatment of lung cancer. Irinotecan and topotecan are camptothecin derivatives that inhibit topoisomerase I enzyme. It is believed that topoisomerase I inhibitors stabilize a DNA/topoisomerase I complex and interact with replication machinery to cause cell death. A significant amount of data demonstrates that these topoisomerase I inhibitors also act as radiosensitizers. With the increasing data that support concurrent chemoradiation treatment for malignancies, including lung cancer and head and neck cancers, there is an impetus to pursue the additional drugs that may potentially improve local control and survival. Irinotecan is undergoing early clinical trials in the combined-modality setting in several different disease sites. This paper will review the data on the role of camptothecin derivatives as a radiosensitizer and as a component of combined-modality therapy for lung cancer. It is hoped that newer treatment strategies, like the combination of radiation and topoisomerase I inhibitors, will have a significant impact on cure rates in the future.
...
PMID:Topoisomerase I inhibitors in the combined-modality therapy of lung cancer. 1525 65

Topotecan HCl is an antitumor drug exhibiting topoisomerase 1-inhibitory activity. Topotecan is used in the treatment of metastatic carcinoma of the ovary and as second-line treatment of small-cell lung cancer. Reported dose-limiting adverse reactions to topotecan are primarily hematologic in nature. To date, only one other case of lung toxicity in a patient taking topotecan has been reported. The authors describe the development of obliterative bronchiolitis, as evidenced by radiographic and pulmonary function testing abnormalities, in a 61-year-old woman who presented with dyspnea, and who was receiving topotecan for peritoneal carcinomatosis.
...
PMID:Topotecan-induced bronchiolitis. 1530 Nov 30

The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m(-2) b.i.d. days (D)1-5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m(-2) day(-1) with a dose escalation of 0.1, then at 0.05 mg m(-2) day(-1). Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22-78) years, received a median 8 (2-19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m(-2) b.i.d. D1-5 and 1.8 mg m(-2) 96 h (total dose) infusional topotecan D8-11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.
...
PMID:A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours. 1598 34


<< Previous 1 2 3 4 5 6 Next >>

---