Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of topoisomerase inhibitors on human immunodeficiency virus type 1 (HIV-1) infection of H9 cells in cell culture. Infection is blocked or substantially reduced by the topoisomerase I inhibitor camptothecin (CPT), but not by two topoisomerase II inhibitors. Significant reduction (greater than or equal to 90%) in the amount of virus released, as measured by reverse transcriptase, is obtained if the cells are treated for 1 h with 0.01-0.02 microM CPT at the time of virus infection, and expression of viral proteins is also blocked. CPT is also shown to reduce the level of infection when chronically infected cells are cocultivated with uninfected cells. These results with CPT suggest that this compound may represent a new class of drugs with antiretroviral potential.
 ...
PMID:Inhibition of human immunodeficiency virus (HIV-1) replication in vitro by noncytotoxic doses of camptothecin, a topoisomerase I inhibitor. 170 42

Few agents developed for the treatment of infectious diseases have been heralded to the same extent as the new quinolone derivatives. While these compounds are extremely promising, we still have much to learn about their biologic properties. Detailed analyses of, for example, the mode of action at the target level could have implications for the study and design of both prokaryotic and eukaryotic topoisomerase inhibitors. It is significant that, in spite of the fact that these potent new antimicrobial agents have been in use for only a few years, resistant strains have appeared and have begun to affect the therapeutic potential of the quinolones. Prudent use of these agents will be an important measure of guaranteeing their maximal benefit in future clinical practice.
 ...
PMID:The new quinolones: back to the future. 267 61

Bacteriophage T4 ribonucleoside diphosphate reductase is composed of two proteins, alpha 2 and beta 2, encoded by the nrdA and nrdB genes, respectively. The expression of nrdB is the limiting factor for the assembly of the enzyme. A recently described mutation, nrdB93, may give new insight into the regulation of synthesis of the beta subunit encoded by nrdB. Infection by T4 nrdB93 produced only low concentrations of the beta 2(93) protein. However, a site-specific mutation of phage T4 gene 39, encoding one of the subunits of T4 DNA topoisomerase, phenotypically suppressed the defect. The present work sought to characterize the nature of this defect. The mutation in nrdB93 was a single-base transition (G-->A) resulting in a Gly253-->Asp change. In vivo and in vitro studies provided no evidence of degradation of the beta 2(93) protein. Furthermore, the decrease in beta 2(93) formation was not caused by a delayed onset of transcription, neither by a decreased rate of mRNA formation from the nrdB promoter, nor by a defective intron splicing of the nrdB gene or in the transcription of the terminal segments of the message. These findings are consistent with the concept that the nrdB93 lesion produces a defect at the level of translation.
 ...
PMID:Bacteriophage T4 ribonucleoside diphosphate reductase: on the defect causing decreased formation of the beta 93(2) subunit encoded by the nrdB93 mutant gene. 818 57

Chemical agents able to interfere with DNA topoisomerases are widespread in nature, and some of them have outstanding therapeutic efficacy in human cancer and infectious diseases. DNA topoisomerases are essential enzymes that govern DNA topology during fundamental nuclear metabolic processes. Topoisomerase-interfering compounds can be divided into two general categories based on the mechanism of drug action: poisons and catalytic inhibitors. In past years, investigations of the DNA sequence selectivity of topoisomerase II poisons have identified structural and molecular determinants of drug activity, and indicated that the drug receptor is likely to be at the protein-DNA interface. Moreover, the available results indicate that the biologically relevant DNA-binding activity of topoisomerase poisons is basically protein-mediated and this is discussed in this issue by Giovanni Capranico and colleagues. This suggests that topoisomerase poisons may represent a useful paradigm for small compounds able to bind to protein-DNA interfaces in a site-selective manner, thus increasing the affinity of DNA-binding proteins for specific genomic sites.
 ...
PMID:A protein-mediated mechanism for the DNA sequence-specific action of topoisomerase II poisons. 934 51

1. Dexrazoxane (ICRF-187) is the only clinically approved drug for use in cancer patients to prevent anthracycline mediated cardiotoxicity. 2. The mode of action appears to be mainly due to the potential of the drug to remove iron from iron/anthracycline complexes and thus reduce free radical formation by these complexes. 3. Dexrazoxane also influences cell biology by its ability to inhibit topoisomerase II and its effects on the regulation of cellular iron homeostasis. 4. Although the cardioprotective effect of dexrazoxane in cancer patients undergoing chemotherapy with anthracyclines is well documented, the potential of this drug to modulate topoisomerase II activity and cellular iron metabolism may hold the key for future applications of dexrazoxane in cancer therapy, immunology, or infectious diseases.
 ...
PMID:Dexrazoxane (ICRF-187). 988 68

Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.
 ...
PMID:The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity. 1040 29

Cellular resistance to chemotherapeutic agents is attributable to several mechanisms, including alteration of topoisomerase IIalpha (topo IIalpha) gene expression. Etoposide-resistant MDA-VP human breast cancer cells express lower amounts of enzymatically active and drug-sensitive topo IIalpha than do MDA parent cells, suggesting that the low level of topo IIalpha is the mechanism of resistance. To determine whether transfer of a normal topo IIalpha gene into MDA-VP cells can increase topo IIalpha gene expression, topo IIalpha protein production, and cell sensitivity to etoposide, a recombinant adenovirus, Ad-hTopoIIalpha, containing the human topo IIalpha gene, was constructed. The shuttle vector pAvCvSv-hTopIIalpha was constructed and co-transfected with the pBHG10 packaging vector into 293 cells. Infectious recombinant adenovirus plaques were isolated and purified. Presence of the topo IIalpha gene was confirmed by PCR and restriction enzyme digestion. After infection with Ad-hTopoIIalpha, topo IIalpha mRNA expression in MDA-VP cells increased 7.4-fold, topo IIalpha protein production increased 5.9-fold, and sensitivity to etoposide was enhanced 4.5-fold compared with control transfected cells. Infection of normal human embryonic lung cells and human fibroblast cells with Ad-hTopoIIalpha did not enhance the expression of topo IIalpha or sensitivity to etoposide. Viral uptake was comparable in the MDA-VP and normal cell lines. These data suggest that topo IIalpha gene transfer using an adenoviral vector can selectively increase etoposide sensitivity in drug-resistant tumor cells and may enhance the therapeutic index of etoposide.
 ...
PMID:Adenovirus-mediated human topoisomerase IIalpha gene transfer increases the sensitivity of etoposide-resistant human breast cancer cells. 1049 16

Streptococcus pneumoniae is considered the most frequent bacterial cause of community-acquired pneumonia, and is involved in a significant number of cases of acute exacerbations of chronic bronchitis, acute otitis, sinusitis, meningitis and other infectious diseases. Fluoroquinolones have been extensively investigated in recent years in the search for new agents that has been prompted by the emergence of resistance in this microorganism. Furthermore, the study of resistance from a molecular biology standpoint has helped in elucidating almost all the biochemical mechanisms of resistance and the routes of dissemination of genetic information between bacteria. This short review is focused on the mechanism of action of quinolones and on the mechanisms responsible for resistance of S. pneumoniae to them, given their clinical and epidemiological relevance. S. pneumoniae is a case apart because bactericidal activity against this microorganism can be produced through gyrase, topoisomerase IV or both, depending on the quinolone structure, which shows that structure has an influence on the success of treatment. Knowledge of the resistance prototype is therefore important so that the appropriate antibiotic therapy can be recommended when indicated.
 ...
PMID:[Quinolones and Streptococcus pneumoniae. Mechanisms of action and resistance]. 1258 36

There is considerable interest in the development of sequence-selective DNA drugs. Chemical agents able to interfere with DNA topoisomerases - essential nuclear enzymes- are widespread in nature, and some of them have outstanding therapeutic efficacy in human cancer and infectious diseases. Several classes of antineoplastic drugs, such as amsacrine, daunorubicin, etoposide (acting on type II topoisomerases), camptothecin and indolocarbazole derivatives of the antibiotic rebeccamycin (acting on type IB topoisomerases), have been shown to stimulate DNA cleavage by topoisomerases leading to cell death. However, these molecules exhibit little sequence preference. A convenient strategy to confer sequence specificity consists in the attachment of these topoisomerase poisons to sequence-specific DNA binding elements. Among sequence-specific DNA ligands, oligonucleotides can bind with high specificity of recognition to the major groove of double-helical DNA, resulting in triple helix formation. In this context, derivatives of camptothecin, indolocarbazole, anthracycline and acridine poisons have been covalently tethered to triple helix-forming oligonucleotides. The use of triple-helical DNA structures offers an efficient system to target topoisomerase I and II-mediated DNA cleavage to specific sequences and to increase the drug efficacy at these sites. Chemical optimization of the conjugates is essential to the efficacy of drug targeting. Consequently, the rational design of this new class of anti-cancer agents, conceived from topoisomerase poisons and triplex-forming oligonucleotides, may be exploited to improve the efficacy and selectivity of the DNA damage induced by topoisomerases.
 ...
PMID:Design of new anti-cancer agents based on topoisomerase poisons targeted to specific DNA sequences. 1267 55

Gatifloxacin, a novel 8-methoxyquinolone, was approved in April 2002 and launched in June 2002. Gatifloxacin shows a broad spectrum of antibacterial activity against Gram-negative, Gram-positive, anaerobic, and atypical pathogens. The activity is higher than those of other quinolones against RTI pathogens of S. pneumoniae including the penicillin-resistant strains, H. influenzae, Mycoplasma, and Chlamydia. This drug strongly inhibits the type II topoisomerase, DNA gyrase, and topoisomerase IV of S. pneumoniae and S. aureus to nearly the same extent, leading to the potent activity and low resistance. After an oral administration in humans, gatifloxacin is well absorbed and distributed, and the majority is excreted in the urine as the unchanged form. Its serum half-life is 7-8 h. The clinical effectiveness was observed for various infectious diseases including RTI and UTI. The bacterial eradication rate is 94.1% for Gram-positives, 90.7% for Gram-negatives, and 97.7% for anaerobes. In particular, gatifloxacin showed a high eradication rate of 98.7% for S. pneumoniae. The total cure rate and eradication rate of gatifloxacin in clinical studies are 91.1% and 93.3%, respectively, indicating that the potent activity and good PK profile account for its clinical efficacy.
 ...
PMID:[Antibacterial property and clinical effect of gatifloxacin, a novel quinolone antibacterial agent]. 1283 39


1 2 3 Next >>