Assessment of the performance of the Ames II™ assay: a collaborative study with 19 coded compounds

Flückiger-Isler, Sini; Baumeister, M.; Braun, K.; Gervais, Véronique; Hasler-Nguyen, N; Reimann, Roland; Gompel, Jacky Van; Wunderlich, H. G.; Engelhardt, G.

doi:10.1016/j.mrgentox.2003.12.001

Cited by 143 publications

(64 citation statements)

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“…Ames II assays were performed using Salmonella enterica serovar Typhimurium strains TA98 and TAmix (an equimolar mixture of strains TA7001 and TA7006) (18), with and without metabolic activation by S9 (prepared from livers of phenobarbital-and 5,6-benzoflavone-treated rats). Compounds were dissolved in DMSO and tested over the concentration range of 0.25 to 250 g/ml.…”

mentioning

confidence: 99%

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

Caspers

Bury

Gaucher

et al. 2009

Antimicrob Agents Chemother

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Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (R)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5-and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant Staphylococcus aureus gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.Despite sustained efforts to identify new drugs against antibiotic-resistant bacteria, treatment of infections caused by vancomycin-resistant enterococci and methicillin-resistant staphylococci continues to challenge clinicians (5). Enterococci are often associated with urinary tract infections, intra-abdominal abscesses, endocarditis, and bacteremia, whereas staphylococci are common causes of skin and skin structure infections, endocarditis, osteomyelitis, prosthetic joint infections, catheterrelated bacteremia, and nosocomial pneumonia. Methicillinresistant Staphylococcus aureus (MRSA) accounts for approximately 50% of all S. aureus infections in the United States (24). Once confined to healthcare settings, MRSA has emerged as a serious cause of community-acquired skin and skin structure infections (32), and an increased frequency of skin cultures positive for S. aureus is associated with nasal and intestinal colonization (2).Dihydrofolate reductase (DHFR; EC 1.5.1.3) is an essential enzyme in most pathogenic bacteria, and the clinical success of trimethoprim (28,33,41,43) confirms DHFR as an important chemotherapeutic target. A phenylalanine3tyrosine substitution at position 98 in the wild-type, nontransferable, chromosomally encoded DHFR renders S. aureus resistant to trimethoprim (15); a corresponding tyrosyl residue occurs in transferable plasmid-encoded wild-type staphylococcal DHFR isozymes S1, S2, and S3 (13,14,40) and in the enterococcal DHFRs encoded by dfrE and dfrF. The gene encoding DHFR S1 may also be associated with staphylococcal chromosomal cassette mec N1 (SCCmec-N1) (37).BAL0030543, BAL0030544, and BAL0030545 are novel dihydrophthalazine antifolates with potent activities a...

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mentioning

confidence: 99%

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

Caspers

Bury

Gaucher

et al. 2009

Antimicrob Agents Chemother

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“…Using flow cytometry the frequency of cells without these surface makers is easily performed, requiring only microliter volumes of blood. Other existing and modified in vitro assays like the more high throughput Ames II assay [53], the Vitotox assay [54], can be used for specific purposes, however the discussion of all possible models is beyond the scope of this work.…”

Section: In Silico Assessment Of Mutagenicity Potentialmentioning

confidence: 99%

Testing the Mutagenicity Potential of Chemicals

Verheyen¹

2017

J Genet Genome Res

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All information for the proper development, functioning and reproduction of organisms is coded in the sequence of matched base-pairs of DNA. DNA mutations can result in harmful effects and play a role in genetic disorders and cancer. As mutations can arise through exposure to chemical substances, testing needs to be done on substances that humans and animals can be exposed to. This review focuses on the different testing strategies for risk assessment of chemicals for genotoxicity and carcinogenicity. This review is not meant to cover all testing methodologies, but rather to give an overview of the main methodologies that are used in a regulatory context. In silico and in vitro tools are playing an increasingly important role, in order to reduce in vivo animal testing. Especially in silico tools like (Q)SARs are promising as they are non-testing methods and thereby also reduce the costs and time that are needed to perform in vitro assays. (Q)SARs are not sufficiently reliable to be used as stand-alone tools, and should be associated with expert judgment or used in combination with other Weight of Evidence such as in vitro and in vivo data and data derived from other similar molecules (read-across). For some product (sub) categories, testing (in vitro/in vivo) will be unavoidable; however the future may bring reliable approaches for ensuring human safety.

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“…Sıvı mikroplak versiyonu ile agara uygulama yapılan geleneksel Ames testinin uyumluluğu yapılan birçok çalışma ile gösterilmiştir (11,13,14,18,19).…”

Section: Tartişma Ve Sonuçunclassified