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)

A number of derivatives of camptothecin with a polyamine chain linked to position 7 of camptothecin via an amino, imino, or oxyiminomethyl group were synthesized and tested for their biological activity. All compounds showed marked growth inhibitory activity against the H460 human lung carcinoma cell line. In particular, the iminomethyl derivatives where the amino groups of the chain were protected with Boc groups exhibited a high potency, with IC50 values of approximately 10(-8) M. The pattern of DNA cleavage in vitro and the persistence of the cleavable ternary complex drug-DNA-topoisomerase I observed with polyamine conjugates containing free amino groups support a contribution of specific drug interaction with DNA as a determinant of activity. Modeling of compound 7c in the complex with topoisomerase 1 and DNA is consistent with this hypothesis. The lack of a specific correlation between stabilization of the cleavable complex and growth inhibition likely reflects multiple factors including the cellular pharmacokinetic behavior related to the variable lipophilicity of the conjugate, and the nature and linkage of the polyamine moiety.
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PMID:Synthesis and cytotoxic activity of polyamine analogues of camptothecin. 1691 6

The inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II associated with increased in vitro sensitivity of tumors to etoposide. Maximal synergy has been observed for the sequence of topotecan followed by etoposide. Carboplatin has clinical activity when combined with either of these two agents. These interactions were the pharmacologic rationale for topotecan p.o. days 1-5, carboplatin i.v. day 6, and etoposide p.o. days 6-10. Three successive dose levels were explored: (1) topotecan 2mg/day, carboplatin AUC 5, etoposide 150 mg/day; (2) topotecan 3mg/day, carboplatin AUC 5, etoposide 150 mg/day; and (3) topotecan 3mg/day, carboplatin AUC 5, etoposide 200mg/day. Filgrastim 5 microg/kg/day was injected s.c. days 11-18. Up to 6 cycles were administered every 21 days. Eligible patients had measurable or evaluable, extensive disease, small lung cell lung cancer, no prior chemotherapy, ECOG performance status 0-2, and adequate hematologic, renal, and hepatic function. Follow-up was weekly for CBC. Tumor response was assessed after 2 and 6 cycles. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: grade 3 or 4 non-hematologic toxicity other than nausea and vomiting, grade 4 neutropenia lasting more than 3 days, neutropenic fever or sepsis, grade 4 thrombocytopenia, or failure to recover neutrophils >or=1500/microl or platelets >or=100,000/microl by day 28. Ten patients were enrolled: median age 62 (range, 50-79); female/male 4/6; and performance status 0/1/2 in 2/7/1. Three patients each were treated on dose levels 1 and 2 without DLT. The first 2 patients entered on dose level 3 had no DLT. The third patient on dose level 3 developed grade 4 neutropenia lasting more than 3 days, neutropenic fever, and grade 4 thrombocytopenia on day 15 of cycle 1. The fourth patient on dose level 3 developed grade 4 thrombocytopenia on day 18 of cycle 1. One patient received only 1 cycle and was not evaluable for response. Seven patients completed 6 cycles: 1 had a complete response and 6 achieved a partial response. The third patient on dose level 3 received 2 cycles and had stable disease, but had to be removed from protocol treatment because of grade 4 neutropenia despite dose reduction in cycle 2. The fourth patient on dose level 3 achieved a partial response, but had to be removed from protocol therapy after cycle 5 because of recurrent grade 4 thrombocytopenia. In conclusion, neutropenia and thrombocytopenia were dose-limiting. The maximum tolerated dose (MTD) is topotecan 3mg/day p.o. days 1-5, carboplatin AUC 5i.v. day 6, and etoposide 150 mg/day p.o. days 6-10 with filgrastim.
Lung Cancer 2006 Dec
PMID:Phase I and pharmacologic study of sequential topotecan-carboplatin-etoposide in patients with extensive stage small cell lung cancer. 1704 3

One new pimarane-type diterpenoid (1) and two new taraxerane-based triterpenoids (2 and 3) were isolated from the bark of Macaranga tanarius, along with seven known compounds. Their structures were identified by spectroscopic methods including NMR and MS analyses. Compounds 1-5 were tested for their in vitro inhibition of DNA topoisomerase II, as well as for their cytotoxicities against human lung carcinoma A549 cells (Table 3). The triterpenoids 2-5 showed strong activities in both assays, but the diterpenoid 1 was only moderately active.
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PMID:Isolation, DNA topoisomerase-II inhibition, and cytotoxicity of three new terpenoids from the bark of Macaranga tanarius. 1719 83

Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in DNA damage response and telomere maintenance. Our previous report found that salvicine (SAL), a novel topoisomerase II poison, elicited DNA double-strand breaks and telomere erosion in separate experimental systems. However, it remains to be clarified whether they share a common response to these two events and in particular whether TRF2 is involved in this process. In this study, we found that SAL concurrently induced DNA double-strand breaks, telomeric DNA damage, and telomere erosion in lung carcinoma A549 cells. It was unexpected to find that SAL led to disruption of TRF2, independently of either its transcription or proteasome-mediated degradation. By overexpressing the full-length trf2 gene and transfecting TRF2 small interfering RNAs, we showed that TRF2 protein protected both telomeric and genomic DNA from the SAL-elicited events. It is noteworthy that although both the Ataxia-telangiectasia-mutated (ATM) and the ATM- and Rad3-related (ATR) kinases responded to the SAL-induced DNA damages, only ATR was essential for the telomere erosion. The study also showed that the activated ATR augmented the SAL-triggered TRF2 disruption, whereas TRF2 reduction in turn enhanced ATR function. All of these findings suggest the emerging significance of TRF2 protecting both telomeric DNA and genomic DNA on the one hand and reveal the mutual modulation between ATR and TRF2 in sensing DNA damage signaling during cancer development on the other hand.
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PMID:The telomeric protein TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA double-strand breaks driven by salvicine. 1802 71

Ellipticine and its analogues were reported as topoisomerase II inhibitors and promising antitumor agents. In this work, we showed that the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells A549 can be inhibited by ellipticine. The inhibitory effect was reverted by PI3K inhibitors. The sub-G(1) phase cells after ellipticine treatment appeared at the expense of those that accumulated first at S- and G(2)/M phases during the early stage of treatment. We showed that the progression leading to cell death was impaired by wortmannin, which reverted apoptosis by retaining cells at S- and G(2)/M transition states. The characteristic apoptosis marker p53 activation after treatment appeared first followed by poly(ADP-ribose)polymerase (PARP) fragmentation. They disappeared upon co-treatment with wortmannin and the apoptotic phenotype reversed. Furthermore, ellipticine regulated endogenous survival signaling by up-regulating phosphorylated Akt that returned to its basal level later. Furthermore, ellipticine induced nucleus translocalization of p53 and Akt and recruitment of autophagosomes. The autophagic-related cell death was interfered by wortmannin and the suppressed growth reverted. The Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53. The work showed that ellipticine-induced cytotoxicity in NSCLC cells was achieved through autophagy and apoptotic death as a result of Akt-modulation. Being a topoisomerase II inhibitor, ellipticine proved a regulator in autophagy-related cell death through corporation of p53 and Akt.
Lung Cancer 2009 02
PMID:Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. 2759 91

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound beta-Lapachone.
Lung Cancer 2010 Jan
PMID:Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. 1938 Jan 73

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.
Lung Cancer 2010 Jun
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

A series of novel indolizinophthalazine-5,12-dione derivatives were designed and synthesized by the reaction of 6,7-dichlorophthalazine-5,8-dione with active methylene reagents (AMR) and pyridine derivatives. Some of synthesized compounds exhibited significant in vitro antiproliferative activity at micromolar level toward four human tumor cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell and ardriamycin-resistance breast carcinoma cell. The DNA topoisomerase IB inhibitory assay indicated that DNA topoisomerase IB might be a biological target of the synthesized compounds.
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PMID:Synthesis and antiproliferative activity of indolizinophthalazine-5,12-dione derivatives, DNA topoisomerase IB inhibitors. 2063 58

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 as a second-line therapy in patients with small cell lung cancer (SCLC). Patients who were previously treated for SCLC were entered into the study. Belotecan was given by daily intravenous infusion for five consecutive days, every three weeks. Twenty-five patients were enrolled in this study. On an intention-to-treat basis, belotecan induced an overall response rate of 24%, a median overall survival of 9.9 months, a median time to progression of 2.2 months, and a 1-year survival rate of 38.3%. Grade 3/4 neutropenia developed in 88.0% of patients and grade 3/4 thrombocytopenia in 40.0%. Nonhematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerated as a second-line agent in patients with SCLC.
Lung Cancer 2011 Apr
PMID:A multicenter phase II study of belotecan, a new camptothecin analogue, as a second-line therapy in patients with small cell lung cancer. 2083 94

In small-cell lung cancer (SCLC), resistance to cancer drugs presents a major problem, limiting the effectiveness of chemotherapy. A better understanding of the molecular biology is essential to improve currently available cytotoxic therapy. Herein, a systematic review of studies evaluating the predictive value of multidrug resistance-associated proteins (MDR1, MRP1, MRP2 and MVP), topoisomerase II and ERCC1 for chemotherapy outcomes is presented. The role of MDR1, MRP1 and MRP2 as predictive markers in SCLC has not yet been elucidated. The majority of studies reported an association between protein or gene expression and response to chemotherapy; however, the evidence is limited to univariate analyses performed in the frame of small retrospective trials. In addition, the largest trial did not confirm an independent predictive value for response rates or survival. Genetic variability may be overseen as a more promising marker. Available data on the predictive value of topoisomerase II are scarce and in contrast to the general idea that higher protein or gene expression correlate with greater chemo-sensitivity. The data on a possible predictive value of ERCC1 are also quite limited; in two retrospective studies, ERCC1 turned out to be a significant predictive marker for survival, but only for limited disease patients. In conclusion, a continuous research, with standardized and validated methodology of markers' determination, should be aspired at all times; a better understanding of the biology of SCLC is of utmost importance to enable personalized therapy and to improve survival rates in this, so far, poorly controlled disease.
Lung Cancer 2011 Jun
PMID:Predictive value of multidrug resistance proteins, topoisomerases II and ERCC1 in small cell lung cancer: a systematic review. 2144 Sep 50


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