Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan is a topoisomerase I inhibitor that is highly active against small cell lung cancer (SCLC). Etoposide is another drug that is effective for SCLC. Since combination of these two topoisomerase inhibitors revealed a synergistic effect in vitro and showed a safety in phase I study, we conducted a phase II study in patients with previously un-treated extensive disease (ED) SCLC to evaluate the efficacy and toxicity of this combination. Fifty patients with previously untreated ED-SCLC were enrolled. Irinotecan was administered intravenously at 60mg/m(2) on days 1, 8, and 15, while etoposide was given at 80mg/m(2) on days 2-4. Treatment was repeated every 4 weeks for four cycles. The overall response rate was 66.0%, with a complete response rate of 10.0%. The median survival time was 11.5 months and the 1- and 2-year survival rates were 43.2 and 14.4%, respectively. The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (62.9%), leukopenia (28.0%), and anemia (14%). The other grade 3 toxicity was diarrhea (2%). This irinotecan and etoposide regimen is active against ED-SCLC with relatively mild toxicity.
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PMID:Irinotecan and etoposide for previously untreated extensive-disease small cell lung cancer: a phase II trial of West Japan Thoracic Oncology Group. 1602 21

A 50-year-old man was referred to our department with esophageal cancer. He had past history of small cell lung cancer treated with chemoradiation therapy 10 years prior. The disease was evaluated as complete remission after chemoradiation therapy and no recurrence had been observed. Esophagectomy accompanying postoperative chemotherapy was applied, but he died of secondary myelodysplastic syndrome with its acute myeloblastic transformation. Risk evaluation revealed a high incidence of esophageal cancer after radiation therapy and hematological malignancies after chemoradiation therapy in usual regimen with topoisomerase inhibitor or alkylating agents. Chemoradiation therapy is thought to be one of a few highly effective therapeutic alternatives and many complete remission cases have been reported in small cell lung cancer or esophageal cancer. In post-therapeutic follow up of patients with such past therapeutic histories, we should be cautious about secondary malignancies even if primary malignant disease was evaluated as complete remission in long past history.
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PMID:Secondary myelodysplastic syndrome after small cell lung cancer and esophageal cancer. 1610 15

Based on the topoisomerase IIalpha catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase IIalpha. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase IIalpha correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIalpha-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase IIalpha-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase IIalpha expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIalpha is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
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PMID:A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs. 1688 Feb 87

Lung cancer is the leading cause of cancer deaths among both males and females. Although there have been several advances in the treatment armamentarium, both small cell and nonsmall cell lung cancer continue to be prognostically poor diseases that are refractory to therapy. Several of the regimens involved in treating the disease include drugs that inhibit the topoisomerase enzymes, whose specific role in relieving torsional strain on DNA to facilitate replication and transcription has long been known. Topoisomerase inhibition, however, has increasingly gained attention because of its efficacy in disease stabilization in lung cancer, with continued elaboration of its exact mechanism in lung cancer therapy. This review presents the biology and molecular mechanics of the topoisomerase enzymes, as well as the effect of their inhibition in SCLC and NSCLC, with discussion of specific drugs and the data to support and explain its use as a chemotherapeutic target in lung cancer.
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PMID:A review of topoisomerase inhibition in lung cancer. 1722 34

Amrubicin is a totally synthetic anthracycline anticancer drug and a potent topoisomerase II inhibitor. Recently, amrubicin was approved in Japan for the treatment of small- and non-small-cell lung cancers (SCLC and NSCLC). Here, we review the efficacy and toxicities of amrubicin monotherapy and amrubicin in combination with cisplatin for extensive-disease SCLC (ED-SCLC), and of amrubicin monotherapy for advanced NSCLC, as observed in the clinical trials. Recommended dosage for previously untreated advanced NCSLC was 45 mg/m2/day by intravenous administration for 3 days. Dose-limiting toxicities were leucopenia, thrombocytopenia, and gastrointestinal disturbance. Response rate was 27.9% for advanced NSCLC, and 75.8% for ED-SCLC with a median survival time (MST) of 11.7 months. Recommended dosage of amrubicin was 40 mg/m2/day in combination with cisplatin at 60 mg/m2/day, with MST of 13.6 months and 1-year survival rate of 56.1%. In sensitive or refractory relapsed SCLC, response rate was 52 and 50%, progression-free survival was 4.2 and 2.6 months, overall survival was 11.6 and 10.3 months, and 1-year survival rate was 46 and 40%, respectively. These results are promising for the treatment of both NSCLC and SCLC. Further clinical trials will clarify the status of amrubicin in the treatment of lung cancer.
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PMID:Amrubicin for non-small-cell lung cancer and small-cell lung cancer. 1762 45

We have previously demonstrated that solamargine (SM), the major steroidal glycoalkaloid extracted from Chinese herb Solanum plants, reveals down-regulation of HER2 and up-regulation of Fas and tumor necrosis factor receptor (TNFR) expressions, triggers the mitochondria-mediated cell apoptosis pathway, and sensitizes human nonsmall cell lung cancer (NSCLC) H441 and A549 adenocarcinoma cells to chemotherapy. The present study shows that SM enhances HER2 expression in NSCLC large cell carcinoma H661 and small cell lung cancer (SCLC) H69 cells and may increase the susceptibility of the cells to trastuzumab, the humanized anti-HER2 antibody. The combinational treatment of SM and trastuzumab synergistically augments and inhibits H661 and H69 cell proliferation. After treatment with SM, coexpression of HER2 and topoisomerase IIalpha (TOP2A) H661 and H69 cells is more sensitive to the TOP2 inhibitor, epirubicin. The combinatory use of low concentrations of SM with the low-toxic epirubicin accelerated greater apoptotic cell death than each drug did alone in H661 and H69 cells. Relevant studies have shown that HER2 overexpressing cancer cells are more resistant than HER2 low-expressing cells to the chemotherapeutic agent and tumor necrosis factor-induced apoptosis. These investigations have indicated that HER2 overexpression does not suffice to induce intrinsic and pleomorphic drug resistance. The data presented herein suggest that the expression of HER2 did not influence the SM-induced apoptosis of different types of lung cancer cells and that the SM up-regulation of HER2 and TOP2A expressions simultaneously augmented trastuzumab and epirubicin-induced deaths of lung cancer H661 and H69 cells.
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PMID:Solamargine enhances HER2 expression and increases the susceptibility of human lung cancer H661 and H69 cells to trastuzumab and epirubicin. 1807 28

Although the advancement of the chemotherapy of non-small cell lung cancer and small cell lung cancer is remarkable in recent years, it is still unsatisfactory. Therefore, some new agents or a new treatment strategy for lung cancer is required. Amrubicin is a totally synthetic anthracycline anticancer drug that acts as a potent topoisomerase II inhibitor. Recently, amrubicin has been approved in Japan for the treatment of small- and non-small cell lung cancers and some clinical trials about amrubicin were conducted in Japan, and promising results have been reported for the treatment of small cell lung cancer in particular. The preclinical, pharmacology and clinical data of amrubicin for the treatment of advanced lung cancer are reviewed.
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PMID:Amrubicin for the treatment of advanced lung cancer. 1923 96

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan in patients with small cell lung cancer (SCLC). Patients with previously untreated extensive stage disease (ED) SCLC were entered into the study. Belotecan was given by daily intravenous infusion at 0.5mg/m(2)/day for 5 consecutive days, every 3 weeks. 62 patients were enrolled in this study. The overall response rate to chemotherapy on an intention-to-treat basis was 53.2%. The median overall survival was 10.4 months, the median time to progression 4.6 months, and the 1-year survival rate 49.9%. The most common toxicity was hematologic. Grade 3/4 neutropenia occurred in 71.0% of patients and grade 3/4 thrombocytopenia 12.9%. Non-hematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerable as single agent in patients with ED SCLC. Further investigations with platinum or other active agents are needed.
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PMID:A multicenter phase II study of belotecan, new camptothecin analogue, in patients with previously untreated extensive stage disease small cell lung cancer. 1968 59

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

Amrubicin is a totally synthetic anthracycline anticancer agent that acts as a potent topoisomerase II inhibitor. Amrubicin has been approved in Japan for the treatment of lung cancer, and the results from clinical studies of amrubicin as a single agent or as part of combination regimens for lung cancer, particularly for small cell lung cancer, conducted in Japan and overseas have been promising. Amrubicin should be included among new treatment strategies especially for chemoresistant patients. Here, preclinical, pharmacological, and clinical data on the use of amrubicin for the treatment of small cell lung cancer are reviewed.
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PMID:Next-generation anthracycline for the management of small cell lung cancer: focus on amrubicin. 1992 Sep 5


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