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)

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Anthracyclines. 222 2

Over the past ten years several laboratories have explored the use of perfluorochemical emulsions (PFCE) and carbogen (95% O2/5% CO2; C) or oxygen breathing as an adjuvant to radiation therapy and/or chemotherapy in solid tumor model systems. The rationale for the use of PFCE and C or oxygen breathing in this therapeutic setting is that solid tumor masses contain areas of hypoxia which are therapeutically resistant. Since x-rays and many chemotherapeutic agents require oxygen to be maximally cytotoxic and most normal tissues are well-oxygenated, the additional oxygen put in circulation by the PFCE/C should not increase the normal tissue toxicities produced by the various therapies. Several anticancer agents are dependent on oxygen to be cytotoxic, these drugs such as the iron-chelating peptide bleomycin are enhanced in antitumor activity by the co-administration of a PFCE/C. The antitumor alkylating agents especially cyclophosphamide, BCNU and melphalan show increased tumor cell killing without a concomitant increase in bone marrow toxicity when administered with PFCE/C. Enhanced activity was also observed when topoisomerase II inhibitors such as adriamycin and etoposide were co-administered with PFCE/C. Positive effects, although smaller, were observed when antimetabolites such as 5-fluorouracil and methotrexate were co-administered with PFCE/C.
 ...
PMID:Combination of perfluorochemical emulsions and carbogen breathing with cancer chemotherapy. 784 13

Probucol [(4,4'-(-(isopropylidenedithio) bis (2,6-di-t-butylphenol)], a hypolipidemic drug, was evaluated for its effects on the clastogenic activity of ADM in Swiss albino mice. Male mice were treated i.p. with different doses (25, 50 and 100 mg/kg, body weight/day) of probucol for 7 days. Some of the mice in each dose group of probucol and those in the positive control group were injected i.p. with Adriamycin (ADM, 8 mg/kg, body weight) and killed after 24 hr. Femoral cells of mice were collected and studied for the frequency of micronuclei and the ratio of polychromatic erythrocytes to Normochromatic erythrocytes. Furthermore, proteins, DNA, RNA, Malondialdehyde (MDA) and non-protein sulfhydryl (NP-SH) levels were determined in the hepatic cells. Probucol treatment failed to induce any significant clastogenic, cytotoxic and biochemical changes. However, pre-treatment with probucol was found to reduce the ADM-induced micronuclei without any alteration in its cytotoxicity. The DNA, RNA, proteins and NP-SH levels in the hepatic cells of these animals were increased and the MDA concentrations were reduced. The inhibition of ADM-induced clastogenicity by probucol may be attributed to its lipids lowering, iron chelating, free radical scavenging and topoisomerase-II-depleting action.
 ...
PMID:Effect of probucol on the cytological and biochemical changes induced by adriamycin in Swiss albino mice. 902 75

Anthracycline-derivatives are frequently used chemotherapeutics in treatment of numerous human malignancies. Anthracyclines are known for their complex cytotoxic mechanism involving i) inhibition of enzymes such as topoisomerase II, RNA polymerase, cytochrome c oxidase and others; ii) intercalation into DNA; iii) chelation of iron and generation of reactive oxygen species (ROS); iv) induction of apoptosis. Here, mechanistic aspects for successful cytostasis and for side effects, e.g. cardiomyopathy, are discussed. We emphasize recent developments in anthracycline-mediated apoptosis and focus on a well known representative, doxorubicin (adriamycin, adriblastin). We reflect on the role of oxidative stress and interactions with intracellular signaling pathways.
 ...
PMID:Anthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review). 985 55

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

Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 microg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography. Urine collections were performed at baseline and during the infusion to determine the renal clearance of dexrazoxane and the excretion rate of divalent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m(2)/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m(2)/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m(2)/day. Steady-state dexrazoxane levels ranged from 496 microg/l (2.2 microM) to 1639 microg/l (7.4 microM). Dexrazoxane plasma CL(ss) and elimination t(1/2) were 7.2 +/- 1.6 l/h/m(2) and 2.0 +/- 0.8 h, respectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10-66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granulocyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.
 ...
PMID:Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. 1141 Apr 92

Anthracyclines are a class of antitumor drugs widely used for the treatment of a variety of malignancy, including leukemias, lymphomas, sarcomas, and carcinomas. Different mechanisms have been proposed for anthracycline antitumor effects including free-radical generation, DNA intercalation/binding, activation of signaling pathways, inhibition of topoisomerase II and apoptosis. A life-threatening form of cardiomyopathy hampers the clinical use of anthracyclines. According to the prevailing hypothesis, anthracyclines injure the heart by generating damaging free radicals through iron-catalyzed redox cycling. Although the "iron and free-radical hypothesis" can explain some aspects of anthracycline acute toxicity, it is nonetheless disappointing when referred to chronic cardiomyopathy. An alternative hypothesis implicates C-13 alcohol metabolites of anthracyclines as mediators of myocardial contractile dysfunction ("metabolite hypothesis"). Hydroxy metabolites are formed upon two-electron reduction of the C-13 carbonyl group in the side chain of anthracyclines by cytosolic NADPH-dependent reductases. Anthracycline alcohol metabolites can affect myocardial energy metabolism, ionic gradients, and Ca2+ movements, ultimately impairing cardiac contraction and relaxation. In addition, alcohol metabolites can impair cardiac intracellular iron handling and homeostasis, by delocalizing iron from the [4Fe-4S] cluster of cytoplasmic aconitase. Chronic cardiotoxicity induced by C-13 alcohol metabolite might be primed by oxidative stress generated by anthracycline redox cycling ("unifying hypothesis"). Putative cardioprotective strategies should be aimed at decreasing C-13 alcohol metabolite production by means of efficient inhibitors of anthracycline reductases, as short-chain coenzyme Q analogs and chalcones that compete with anthracyclines for the enzyme active site, or by developing novel anthracyclines less susceptible to reductive metabolism.
 ...
PMID:Human heart cytosolic reductases and anthracycline cardiotoxicity. 1179

Anthracyclines play a major role in the treatment of solid malignancies, but their clinical use is limited by acute or chronic cardiac toxicity. This is not due to the same molecular action involved in the antineoplastic effect, i.e. topoisomerase II inhibition, but can be attributed to different mechanisms: free radical generation, stimulation of sarcoplasmic reticulum calcium release, binding to anionic phospholipids, alteration of sphingolipid metabolism, modulation of gene expression. Anthracycline metabolites, particularly 13-hydroxy derivatives, might contribute to impair iron and calcium homeostasis. Unresolved issues are the relative importance of such injurious mechanisms and the relationship between acute and chronic toxicity. Attempts to reduce anthracycline toxicity have been focused on the development of new derivatives, on the adoption of peculiar delivery systems, and on the association with substances able to interfere with the mechanism responsible for cardiotoxicity. Many anthracyclines have been synthesized and screened, but no major improvement in therapeutic index has been obtained. A possible exception might be represented by the new disaccharidic derivatives, which have provided promising results in preclinical studies. Liposome encapsulation and association with the iron chelator dexrazoxane have also proved to be useful. Novel approaches are targeted at the effects of anthracyclines on nitric monoxide metabolism and on sphingolipid metabolism.
 ...
PMID:Cardiac toxicity of antineoplastic anthracyclines. 1267 9

The ability to adapt to adverse environmental conditions encountered in food and during host infection is a sine qua non for a successful Listeria monocytogenes infection. This ability is likely to depend on complex regulatory pathways controlled by a number of key regulators. We utilized the pORI19 plasmid integration system to analyze the role of six putative regulatory loci in growth under suboptimal environmental conditions and during murine infection. Disruption of loci encoding a topoisomerase III (lmo2756), a putative methyltransferase (lmo0581), and a regulator of the MarR family (lmo1618) revealed roles for the methyltransferase and the MarR regulator in growth under environmental stress conditions. However, plasmid integration into these loci had no impact on virulence potential in the murine model of infection. Disruption of the alternative sigma factor Sigma-H resulted in a mutant that demonstrated reduced growth potential in minimal medium. Murine studies indicated a minor role for this sigma factor in the infectious process. Strikingly, disruption of both perR and fur loci resulted in mutants that are significantly affected in virulence for mice, with the fur mutant demonstrating the greatest reduction in virulence potential. Both perR and fur mutants demonstrated increased resistance to hydrogen peroxide and the fur mutant was sensitive to low-iron conditions. The virulence defect of both fur and perR mutants could be rescued by iron-overload after esculetin treatment of mice, suggesting that the in vivo role of these gene products is to procure iron for bacterial growth.
 ...
PMID:Disruption of putative regulatory loci in Listeria monocytogenes demonstrates a significant role for Fur and PerR in virulence. 1474 13

Streptococcus pneumoniae has been recognised as a major cause of pneumonia since the time of Sir William Osler. Drug-resistant S. pneumoniae (DRSP), which have gradually become resistant to penicillins as well as more recently developed macrolides and fluoroquinolones, have emerged as a consequence of indiscriminate use of antibacterials coupled with the ability of the pneumococcus to adapt to a changing antibacterial milieu. Pneumococci use cell wall choline components to bind platelet-activating factor receptors, colonise mucosal surfaces and evade innate immune defenses. Numerous virulence factors that include hyaluronidase, neuraminidase, iron-binding proteins, pneumolysin and autolysin then facilitate cytolysis of host cells and allow tissue invasion and bloodstream dissemination. Changes in pneumococcal cell wall penicillin-binding proteins account for resistance to penicillins, mutations in the ermB gene cause high-level macrolide resistance and mutations in topoisomerase IV genes coupled with GyrA gene mutations alter DNA gyrase and lead to high-level fluoroquinolone resistance. Risk factors for lower respiratory tract infections in the elderly include age-associated changes in oral clearance, mucociliary clearance and immune function. Other risks for developing pneumonia include poor nutrition, hypoalbuminaemia, bedridden status, aspiration, recent viral infection, the presence of chronic organ dysfunction syndromes including parenchymal lung disease and recent antibacterial therapy. Although the incidence of infections caused by DRSP is rising, the effect of an increase in the prevalence of resistant pneumococci on mortality is not clear. When respiratory infections occur, rapid diagnosis and prompt, empirical administration of appropriate antibacterial therapy that ensures adequate coverage of DRSP is likely to increase the probability of a successful outcome when treating community-acquired pneumonia in elderly patients, particularly those with multiple risk factors for DRSP. A chest x-ray is recommended for all patients, but other testing such as obtaining a sputum Gram's smear is not necessary and should not prolong the time gap between clinical suspicion of pneumonia and antibacterial administration. The selection of antibacterials should be based upon local resistance patterns of suspected organisms and the bactericidal efficacy of the chosen drugs. If time-dependent agents are chosen and DRSP are possible pathogens, dosing should keep drug concentrations above the minimal inhibitory concentration that is effective for DRSP. Treatment guidelines and recent studies suggest that combination therapy with a beta-lactam and macrolide may be associated with a better outcome in hospitalised patients, and overuse of fluoroquinolones as a single agent may promote quinolone resistance. The ketolides represent a new class of macrolide-like antibacterials that are highly effective in vitro against macrolide- and azalide-resistant pneumococci. Pneumococcal vaccination with the currently available polysaccharide vaccine is thought to confer some preventive benefit (preventing invasive pneumococcal disease), but more effective vaccines, such as nonconjugate protein vaccines, need to be developed that provide broad protection against pneumococcal infection.
 ...
PMID:Drug treatment of pneumococcal pneumonia in the elderly. 1549 50


1 2 3 4 5 Next >>