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

Enteroinvasive Escherichia coli (EIEC) O164 strain RIMD05091045 was isolated from a travelling patient suffering from diarrhoea at the Osaka airport quarantine facility in Japan. The strain showed multidrug resistance against streptomycin, spectinomycin, co-trimoxazole (trimethoprim/sulfamethoxazole) and ampicillin, and reduced susceptibility to ciprofloxacin. Molecular characterization of the multidrug-resistance phenotype revealed the presence of a class 1 integron containing three genes, a dihydrofolate reductase type XII gene, dfrXII, which confers resistance to trimethoprim, an aminoglycoside adenyltransferase gene, aadA2, which confers resistance to streptomycin and spectinomycin, and an ORF of unknown function. Southern blot hybridization and conjugation experiments showed that the class 1 integron was located on a transferable plasmid that was less than 90 kb in size. The resistance of EIEC O164 to ampicillin was found to be due to the presence of TEM-1 beta-lactamase. On the other hand, a single mutation that has not previously been described, P158-to-S, was detected downstream of the quinolone-resistance-determining region of parC of topoisomerase IV and may be responsible for the reduced susceptibility to ciprofloxacin in this strain.
...
PMID:Molecular characterization of a multidrug-resistant strain of enteroinvasive Escherichia coli O164 isolated in Japan. 1571 11

Microsporidia have emerged as causes of infectious diseases in AIDS patients, organ transplant recipients, children, travelers, contact lens wearers, and the elderly. These organisms are small single-celled, obligate intracellular parasites that were considered to be early eukaryotic protozoa but were recently reclassified with the fungi. Of the 14 species of microsporidia currently known to infect humans, Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common causes of human infections and are associated with diarrhea and systemic disease. Species of microsporidia infecting humans have been identified in water sources as well as in wild, domestic, and food-producing farm animals, raising concerns for waterborne, foodborne, and zoonotic transmission. Current therapies for microsporidiosis include albendazole which is a benzimidazole that inhibits microtubule assembly and is effective against several microsporidia, including the Encephalitozoon species, but is less effective against E. bieneusi. Fumagillin, an antibiotic and anti-angiogenic compound produced by Aspergillus fumigatus, is more broadly effective against Encephalitozoon spp. and Enterocytozoon bieneusi but is toxic when administered systemically to mammals. Gene target studies have focused on methionine aminopeptidase 2 (MetAP2) for characterizing the mechanism of action and for identifying more effective, less toxic fumagillin-related drugs. Polyamine analogues have shown promise in demonstrating anti-microsporidial activity in culture and in animal models, and a gene encoding topoisomerase IV was identified in Vittaforma corneae, raising prospects for studies on fluoroquinolone efficacy against microsporidia.
...
PMID:Microsporidiosis: an emerging and opportunistic infection in humans and animals. 1577 37

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most gram-negative and gram-positive organisms, such as the important community-acquired respiratory pathogens Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae), Haemophilus influenzae , and Moraxella catarrhalis . The agent's mechanism of action involves dual targeting of two essential bacterial enzymes: DNA gyrase and topoisomerase IV. Gemifloxacin was approved by the Food and Drug Administration in April 2003 for treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The drug has an oral bioavailability of approximately 71%. Approximately 20-35% of gemifloxacin is excreted unchanged in the urine after 24 hours. The elimination half-life of gemifloxacin is 6-8 hours in patients with normal renal function, supporting once-daily dosing. The 24-hour free-drug area under the plasma concentration-time curve:minimum inhibitory concentration ratio (fAUC(0-24):MIC) associated with efficacy, based on results from in vitro and animal models of infection, is approximately 30. With a mean fAUC(0-24) of approximately 3 microg*hour/ml (35% of total AUC(0-24) of 8.4) and a median S. pneumoniae MIC for 90% of tested strains of 0.03, a fAUC(0-24):MIC ratio of 100 would be expected after standard dosing (320 mg once/day). In clinical studies involving both hospitalized and outpatient populations, gemifloxacin has been highly effective in the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis. Clinical success rates ranged from 93.9-95.9% in patients with community-acquired pneumonia and 96.1-97.5% in those with acute exacerbation of chronic bronchitis. Gemifloxacin is well tolerated; the frequency of adverse events with this agent is low. Most adverse events are mild-to-moderate in severity, with diarrhea (< 4%), nausea and rash (< 3%), and headache (< 2%) most commonly reported. Drug interactions with gemifloxacin are not common, although absorption is greatly reduced when given with divalent and trivalent cation-containing compounds, such as antacids. Due to its potent activity against many common gram-positive and gram-negative respiratory pathogens, its proven clinical efficacy, and its favorable safety profile, gemifloxacin is a highly effective empiric treatment for community-acquired lower respiratory tract infections.
...
PMID:Gemifloxacin for the treatment of respiratory tract infections: in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety. 1589 34

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.
...
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

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.
...
PMID:SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer. 1640 60

Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-soluble salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivatives irinotecan and topotecan did not cause haemorrhagic cystitis because of their higher physicochemical stability and solubility at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhoea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitising solubilisers. Leukopenia and thrombocytopenia occur in 65% and 80%, respectively, of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhoea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clinical pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concentration-time curve values and steady-state concentrations for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metabolism may be associated with a higher risk for secondary malignancies.
...
PMID:Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. 1652 21

Currently, approximately 40 drugs are registered for the chemotherapeutic treatment of cancer, the vast majority of which either interact directly with DNA (eg, alkylating, methylating, platinating agents, topoisomerase inhibitors), or affect DNA synthesis (antimetabolites). Whilst such agents remain of great importance in combination chemotherapy regimens, many cancer drug discovery groups have questioned whether any further significant gains may be made through the development of novel DNA-interactive drugs. Such agents tend to be associated with dose-limiting antiproliferative tissue toxicities (eg, myelo-suppression, nausea and vomiting, diarrhea or mucositis) which is indicative of their general lack of selectivity in targeting tumor versus normal tissue DNA. Perhaps surprisingly to some, Dr D Von Hoff (University of Texas Health Science Center, San Antonio, Texas, USA) proposed that the investigation of DNA-interactive agents is still yielding some promising agents. He illustrated this with the following new agents.
...
PMID:DNA-interactive agents. 1846 68

The phylum Apicomplexa includes a large group of protozoan parasites responsible for a wide range of animal and human diseases. Destructive pathogens, such as Plasmodium falciparum and Plasmodium vivax, causative agents of human malaria, Cryptosporidium parvum, responsible of childhood diarrhoea, and Toxoplasma gondii, responsible for miscarriages and abortions in humans, are frequently associated with HIV immunosuppression in AIDS patients. The lack of effective vaccines, along with years of increasing pressure to eradicate outbreaks with the use of drugs, has favoured the formation of multi-drug resistant strains in endemic areas. Almost all apicomplexan of medical interest contain two endosymbiotic organelles that contain their own mitochondrial and apicoplast DNA. Apicoplast is an attractive target for drug testing because in addition to harbouring singular metabolic pathways absent in the host, it also has its own transcription and translation machinery of bacterial origin. Accordingly, apicomplexan protozoa contain an interesting mixture of enzymes to unwind DNA from eukaryotic and prokaryotic origins. On the one hand, the main mechanism of DNA unwinding includes the scission of one-type I-or both DNA strands-type II eukaryotic topoisomerases, establishing transient covalent bonds with the scissile end. These enzymes are targeted by camptothecin and etoposide, respectively, two natural drugs whose semisynthetic derivatives are currently used in cancer chemotherapy. On the other hand, DNA gyrase is a bacterial-borne type II DNA topoisomerase that operates within the apicoplast and is effectively targeted by bacterial antibiotics like fluoroquinolones and aminocoumarins. The present review is an update on the new findings concerning topoisomerases in apicomplexan parasites and the role of these enzymes as targets for therapeutic agents.
...
PMID:DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery. 2020 34

Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2.5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting.
...
PMID:A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. 2045 55

Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.
...
PMID:MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile. 2273 75


<< Previous 1 2 3 4 5 Next >>

---