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)

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.
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PMID:The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. 2827 43

Amrubicin has been demonstrated to be beneficial in the treatment of patients with relapsed small cell lung cancer (SCLC). The aim of the present study was to evaluate whether there is a significant difference in the efficacy of amrubicin between patients with relapsed SCLC who were previously treated with a platinum agent in combination with a topoisomerase I inhibitor, and those patients previously treated with a platinum agent in combination with a topoisomerase II inhibitor. The medical records of patients with SCLC, who were diagnosed as having relapsed following treatment with a platinum-based regimen and subsequently received amrubicin monotherapy, were retrospectively reviewed. Of a total of 48 patients with SCLC who were treated with amrubicin, the overall response rate, median progression-free survival (PFS) time and median survival time (MST) were determined to be 31.3%, 7.1 and 17.0 months, respectively. The response rate, PFS time and MST did not differ significantly between the patients treated previously with a platinum agent in combination with irinotecan, a topoisomerase I inhibitor, (36.4%, 5.7 and 11.4 months, respectively) and those treated previously with a platinum agent in combination with etoposide, a topoisomerase II inhibitor (30.0%, 4.7 and 14.8 months, respectively). The results indicate that amrubicin may be effective as a second-line chemotherapeutic agent for patients with SCLC, irrespective of which platinum agent and topoisomerase inhibitor-based chemotherapy regimen was previously administered.
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PMID:Correlation between the efficacy of amrubicin and the previous chemotherapy regimen for relapsed small cell lung cancer. 2845 15

Topotecan (TPT), a chemotherapeutic agent, is a topoisomerase-I inhibitor. Topoisomerase-I is a nuclear enzyme that relieves torsion strain in DNA by opening single strand breaks which helps in DNA replication. TPT inhibits this enzyme, thus preventing DNA replication and causes cell death. TPT has demonstrated to have broad spectrum of antitumor activity in tumors like cervical, ovarian, endometrial and small cell lung cancers (SCLCs). The intravenous (IV) formulation of the drug is currently approved by the US Food and Drug Administration for the treatment of patients with SCLC and ovarian cancer at a dose of 1.5 mg/m2 administered daily for five consecutive days, with treatment cycles repeated every 3 weeks. TPT has shown some promising activity in the treatment of non-small cell lung cancer (NSCLC) with favorable side effect profile. Several clinical trials have been conducted with TPT in either IV or oral formulation for the treatment of NSCLC as a first or second-line treatment. Here we reviewed all the clinical trials done with TPT to date in the treatment of NSCLC both as a single-agent and combination therapy.
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PMID:Role of Topotecan in Non-Small Cell Lung Cancer: A Review of Literature. 2898 43

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare yet highly aggressive malignancy with a poor prognosis. Currently, there are no SCCOHT treatment guidelines. After surgery, many patients with SCCOHT receive adjuvant cisplatin and etoposide (CE), based on its efficacy in small cell lung cancer (SCLC). Nonetheless, CE-refractory SCCOHT is still common. Novel therapies (ie, histone deacetylase [HDAC] inhibitors) are being studied as they may target abnormal chromatin remodeling known to be associated with SCCOHT. We present the case of a 21-year-old female with Stage IC SCCOHT status after unilateral oophorectomy. Despite adjuvant CE, the patient developed disease progression. This is the first case report of a patient with CE-refractory SCCOHT treated with second-line topotecan (a topoisomerase-1 inhibitor) and romidepsin (an HDAC inhibitor). Although our patient's SCCOHT further progressed and lead to her death, her story highlights the importance of discovering better therapeutic targets for the treatment of SCCOHT.
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PMID:Refractory Small Cell Carcinoma of the Ovary - Hypercalcemic Type (SCCOHT) Treated with Romidepsin and Topotecan: A Case Report and Review of the Literature. 2977 36

CellMinerCDB provides a web-based resource (https://discover.nci.nih.gov/cellminercdb/) for integrating multiple forms of pharmacological and genomic analyses, and unifying the richest cancer cell line datasets (the NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables data queries for genomics and gene regulatory network analyses, and exploration of pharmacogenomic determinants and drug signatures. It leverages overlaps of cell lines and drugs across databases to examine reproducibility and expand pathway analyses. We illustrate the value of CellMinerCDB for elucidating gene expression determinants, such as DNA methylation and copy number variations, and highlight complexities in assessing mutational burden. We demonstrate the value of CellMinerCDB in selecting drugs with reproducible activity, expand on the dominant role of SLFN11 for drug response, and present novel response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins. We also introduce LIX1L as a gene associated with mesenchymal signature and regulation of cellular migration and invasiveness.
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PMID:CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines. 3055 13

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.
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PMID:Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents. 3224 44

Covering: up to 2020As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could arrest the cell cycle, block the transitorily generated DNA/RNA breaks, and blunt the growth-stimulation by targeting topoisomerase II, tubulin, or insulin-like growth factor 1 receptor. Since 1983, etoposide (VP-16) is being used in frontline cancer therapy against various cancer types, such as small cell lung cancer and testicular cancer. Surprisingly, VP-16 (ClinicalTrials NTC04356690) was also redeveloped to treat the cytokine storm in coronavirus disease 2019 (COVID-19) in phase II in April 2020. The treatment aims at dampening the cytokine storm and is based on etoposide in the case of central nervous system. However, the initial version of PTOX was far from perfect. Almost all podophyllotoxin derivatives, including the FDA-approved drugs VP-16 and teniposide, were seriously limited in clinical therapy due to systemic toxicity, drug resistance, and low bioavailability. To meet this challenge, scientists have devoted continuous efforts to discover new candidate drugs and have developed drug strategies. This review focuses on the current clinical treatment of PTOXs and the prospective analysis for improving druggability in the rational design of new generation PTOX-derived drugs.
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PMID:Challenges and potential for improving the druggability of podophyllotoxin-derived drugs in cancer chemotherapy. 3289 76


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