Abstract:
:The goal of the present study was to examine the ability of cytochrome P450-2C9 (CYP2C9) to activate cyclophosphamide (CPA) and elicit tumor cell death. A CYP2C9-deficient human lymphoblastoid cell line (AHH-1 cells) and a derivative cell line (H2C9 cells) stably transfected with a cDNA encoding CYP2C9 were used. The catalytic activity present in cell lines was examined by measuring the conversion of diclofenac, a CYP2C9-specific substrate, to its 4'-hydroxy metabolite by high-pressure liquid chromatography. Initial rate plots were constructed and the maximal rate of formation (V(max)) and the Michaelis-Menten constant (K(m)) for diclofenac metabolism were determined. Cytotoxicity was studied by exposing the cells to 0.01 to 4 mM CPA in the presence or absence of sulfaphenazole, a CYP2C9-specific inhibitor. Cell survival was quantitated by determination of the level of tritiated thymidine incorporation. H2C9 cells quickly metabolized diclofenac, indicating the presence of high levels of CYP2C9. Kinetic experiments demonstrated a V(max) and K(m) of 0.62+/-0.012 pmol/min/10(6) cells and 6.16+/-0.62 microM, respectively, for diclofenac metabolism. Diclofenac 4'-hydroxylase activity was undetectable in AHH-1 cells. H2C9 cells were more sensitive to the cytotoxic effects of CPA (50% inhibitory concentration [IC(50)], 0.80+/-0.03 mM) than AHH-1 cells (IC(50), 4.07+/-0.35 mM). The cytotoxicity (IC(50), 1.99+/-0.14 mM) of CPA to H2C9 cells was blocked by sulfaphenazole, demonstrating that the chemosensitivity of these cells is a consequence of intracellular prodrug activation. H2C9 cells mediated a bystander killing effect for CYP2C9-negative PPC-1 cells, reducing the IC(50) of CPA from about 14 to 3.62+/-0.73 mM in PPC-1 cells when they were cocultured with H2C9 cells. These results suggest that the enzyme-prodrug system of CYP2C9 and CPA may be an effective combination for gene-directed enzyme prodrug therapy. Ongoing studies are examining the utility of this system for use in prostate cancer cells.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Zhou D,Lu Y,Steiner MS,Dalton JTdoi
10.1128/aac.44.10.2659-2663.2000subject
Has Abstractpub_date
2000-10-01 00:00:00pages
2659-63issue
10eissn
0066-4804issn
1098-6596journal_volume
44pub_type
杂志文章abstract::One gram of ceftriaxone was given intravenously to 15 patients approximately 2 h before cardiopulmonary bypass surgery. Ceftriaxone levels in plasma (mean +/- standard deviation) were 60.4 +/- 18.8 micrograms/ml (range, 17.0 to 96.0 micrograms/ml) at the beginning of bypass, 44.2 +/- 16.6 micrograms/ml (range, 9.4 to ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.1.37
更新日期:1984-01-01 00:00:00
abstract::The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02067-19
更新日期:2020-04-21 00:00:00
abstract::The present study investigated the effect of a model urease-binding polysaccharide in combination with a histamine H(2) receptor antagonist on Helicobacter pylori colonization in vivo. Euthymic hairless mice were treated daily with dextran sulfate via drinking water and/or famotidine via intragastric gavage starting a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.9.2492-2497.2000
更新日期:2000-09-01 00:00:00
abstract::Spontaneous mutants of susceptible clinical and laboratory isolates of Streptococcus pneumoniae exhibiting reduced susceptibility to evernimicin (SCH27899; MIC, 0.5 to 4.0 mg/liter) were selected on plates containing evernimicin. Four isolates that did not harbor mutations in rplP (which encodes ribosomal protein L16)...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.11.3101-3106.2000
更新日期:2000-11-01 00:00:00
abstract::A-80556 is a novel fluoroquinolone with potent antibacterial activity against gram-positive, gram-negative, and anaerobic organisms. A-80556 was more active than ciprofloxacin, ofloxacin, lomefloxacin, and sparfloxacin against gram-positive bacteria. A-80556 was particularly active against Staphylococcus aureus (MIC f...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.38.5.1071
更新日期:1994-05-01 00:00:00
abstract::An NDM-1 carbapenemase-producing Pseudomonas aeruginosa isolate was recovered from a patient hospitalized in France after a previous hospitalization in Serbia. Genetic studies revealed that the blaNDM-1 gene was surrounded by insertion sequence ISAba125 and a truncated bleomycin resistance gene. This blaNDM-1 region w...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02334-12
更新日期:2013-07-01 00:00:00
abstract::The antimicrobial activities of trovafloxacin, moxifloxacin, sanfetrinem, quinupristin-dalfopristin, and 14 other antimicrobial agents against 218 Bacteroides fragilis group strains were determined. A group of 10 imipenem-resistant strains were also tested. Imipenem, meropenem, and sanfetrinem had the lowest MICs of a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.9.2320
更新日期:1999-09-01 00:00:00
abstract::The effect of monocytopenia and granulocytopenia on the outgrowth of Staphylococcus aureus as well as on antibiotic efficacy was studied in an experimental thigh infection in mice. Pretreatment with etoposide reduced monocyte numbers in blood to 14% and those of granulocytes to 54% at the time of infection. Monocytope...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.6.980
更新日期:1989-06-01 00:00:00
abstract::Macrolide-resistant Mycoplasma pneumoniae (MR M. pneumoniae) has been isolated from clinical specimens in Japan since 2000. A comparative study was carried out to determine whether or not macrolides are effective in treating patients infected with MR M. pneumoniae. The clinical courses of 11 patients with MR M. pneumo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.50.2.709-712.2006
更新日期:2006-02-01 00:00:00
abstract::To date, there is only one drug in use, praziquantel, to treat more than 250 million people afflicted with schistosomiasis, a debilitating parasitic disease. The aryl hydantoin Ro 13-3978 is a promising drug candidate with in vivo activity superior to that of praziquantel against both adult and juvenile Schistosoma ma...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01142-17
更新日期:2017-11-22 00:00:00
abstract::Susceptibilities of 121 clinical Helicobacter pylori strains to metronidazole were determined by both a 5-micrograms metronidazole disk diffusion test and a plate dilution method in duplicate and after different periods of incubation. The distribution of MICs of metronidazole against H. pylori among the strains was fo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.38.10.2357
更新日期:1994-10-01 00:00:00
abstract::Two hundred and fifty-seven ampicillin-resistant clinical isolates of Haemophilus influenzae were tested by disk diffusion and MIC determination for susceptibility to aztreonam, imipenem, and amoxycillin combined with clavulanate. The modal MICs and MICs for 50 and 90% of isolates of all three antimicrobial agents for...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.12.1871
更新日期:1987-12-01 00:00:00
abstract::The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data on strains r...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00559-20
更新日期:2020-08-20 00:00:00
abstract::As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.11.2824
更新日期:1998-11-01 00:00:00
abstract::We compared the inoculum effects for 109 recent clinical isolates of the Bacteroides fragilis group of cefoxitin, cefotetan, ceftizoxime, ceftriaxone, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Bactericidal activity was assayed and morpholo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.9.1868
更新日期:1991-09-01 00:00:00
abstract::Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Theref...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00265-16
更新日期:2016-05-23 00:00:00
abstract::Oxacillin-resistant Staphylococcus aureus is rapidly killed by the endopeptidase lysostaphin, and the addition of beta-lactam antibiotics provides synergistic killing. We investigated the possibility that beta-lactams given in combination with lysostaphin would improve the activity of lysostaphin against oxacillin-res...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.6.2017-2020.2002
更新日期:2002-06-01 00:00:00
abstract::The activity of azlocillin and mezlocillin, new semisynthetic ureido penicillins, was investigated and compared with that of other known beta-lactam antibiotics. At a concentration of 25 mug/ml, azlocillin inhibited 74% of Enterobacter, 97% of Proteus mirabilis, 64% of Citrobacter, 91% of Pseudomonas aeruginosa, and 8...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.6.930
更新日期:1978-06-01 00:00:00
abstract::Penetration of cefpiramide and cefazolin into a specific extravascular fluid was measured with rabbits bearing capsules in the peritoneal cavity. A general feature of slow accumulation and elimination of drugs from extravascular sites having low surface area/volume ratios has also been observed in this study. The caps...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.32.1.33
更新日期:1988-01-01 00:00:00
abstract::With the emergence of multidrug-resistant mycobacterial strains, better therapeutic strategies are required for the successful treatment of the infection. Although antimicrobial peptides (AMPs) and silver nanoparticles (AgNPs) are becoming one of the popular antibacterial agents, their antimycobacterial potential is n...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02475-12
更新日期:2013-08-01 00:00:00
abstract::The in vitro activity of GR-20263, a new aminothiazolyl cephalosporin, was compared with the activities of other beta-lactam antibiotics by using 800 clinical bacterial isolates. GR-20263 was highly active (inhibition of 90% of the isolates between 0.03 and 1 microgram/ml) against the common Enterobacteriaceae and 5 t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.17.5.807
更新日期:1980-05-01 00:00:00
abstract::The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.2.458
更新日期:1992-02-01 00:00:00
abstract::Actinobacillus actinomycetemcomitans and Capnocytophaga spp. are gram-negative bacteria implicated in the etiology of periodontal disease (particularly in individuals with neutrophil defects) and life-threatening systemic infections. They are resistant to many antibiotics of microbial origin but are sensitive to the n...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.12.2710
更新日期:1993-12-01 00:00:00
abstract::The activities of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators were evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole-genome sequencing analysis. Isolates were collected during 2017 in U.S. hospi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00160-19
更新日期:2019-06-24 00:00:00
abstract::The role of Acinetobacter baumannii ATCC 17978 UmuDC homologs A1S_0636-A1S_0637, A1S_1174-A1S_1173, and A1S_1389 (UmuDAb) in antibiotic resistance acquired through UV-induced mutagenesis was evaluated. Neither the growth rate nor the UV-related survival of any of the three mutants was significantly different from that...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02346-13
更新日期:2014-01-01 00:00:00
abstract::The Burkholderia cepacia complex (BCC) is a group of bacterial pathogens that are highly antibiotic resistant and associated with debilitating respiratory infections. Although bacteriophages of the BCC have been isolated and characterized, no studies have yet examined phage therapy against the BCC in vivo. In a caterp...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01166-08
更新日期:2009-05-01 00:00:00
abstract::The penicillin-binding proteins (PBPs) of a clinical isolate of Staphylococcus aureus specifically resistant to oral cephalosporins were compared with those of a susceptible strain. In the resistant strain, PBP3 (75,000 molecular weight) was missing or had substantially (greater than 100-fold) reduced affinity for pen...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.22.1.172
更新日期:1982-07-01 00:00:00
abstract::Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in Streptococcus pneumoniae. In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.4.988
更新日期:1999-04-01 00:00:00
abstract::Combination therapy using drugs with different mechanisms of action is the current state of the art in antimalarial treatment. However, except for artemisinin-based combination therapies, only a few other combinations are now available. Increasing concern regarding the emergence and spread of artemisinin resistance in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02307-19
更新日期:2020-10-20 00:00:00
abstract::Resistance to antifungal drugs, specifically azoles such as fluconazole, in the opportunistic yeast Candida albicans has become an increasing problem in human immunodeficiency virus (HIV)-infected individuals. The molecular mechanisms responsible for this resistance have only recently become apparent and can include a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.7.1482
更新日期:1997-07-01 00:00:00