In vivo transgenic mutation assays

Thybaud, Véronique; Dean, S.W.; Nohmi, Takehiko; Boer, J. de; Douglas, George R.; Glickman, Barry W.; Gorelick, Nancy J.; Heddle, John A.; Heflich, Robert H.; Lambert, Iain B.; Martus, Hans‐Jörg; Mirsalis, Jon C.; Suzuki, Takayoshi; Yajima, Nobuhiro

doi:10.1016/j.mrgentox.2003.07.004

Cited by 141 publications

(110 citation statements)

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“…Le séquençage des mutants peut également être envisagé si l'on constate que la fréquence des mutants est en légère augmentation (la fréquence est alors légèrement supérieure aux valeurs des témoins non traités). Des différences en matière de spectre de mutants entre les colonies de mutants des animaux traités et des animaux non traités peuvent appuyer l'hypothèse d'un effet mutagène (29)…”

Section: © Ocde (2013)unclassified

“…Quel que soit le cas de figure, toutes les informations disponibles (par exemple celles sur la toxicité générale ou le métabolisme et la pharmacocinétique) sont exploitées lorsqu'il s'agit de justifier un protocole, en particulier lorsque ce dernier dévie des recommandations standard décrites précédemment. S'ils permettent certes d'accroître la sensibilité, les traitements de plus de 8 semaines sont expliqués clairement et justifiés, car des traitements de longue durée peuvent engendrer une augmentation apparente de la fréquence de mutants par expansion clonale (29). …”

Section: Période D'administrationunclassified

“…Les ateliers internationaux sur les essais de génotoxicité (IWGT) ont approuvé la prise en compte des essais pour la détection in vivo des mutations génétiques chez les RTG et ont recommandé un protocole de mise en application de ces essais (15) (29). La présente LD découle de ces recommandations.…”

Section: Introductionunclassified

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Essai n° 488 : Essais de mutations génétiques des cellules somatiques et germinales de rongeurs transgéniques

2022

Lignes Directrices De l'OCDE Pour Les Essais De Produits Chimiques, Section 4

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Section: © Ocde (2013)unclassified

Section: Période D'administrationunclassified

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Essai n° 488 : Essais de mutations génétiques des cellules somatiques et germinales de rongeurs transgéniques

2022

Lignes Directrices De l'OCDE Pour Les Essais De Produits Chimiques, Section 4

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“…Additionally, sufficient experience with these models is now leading to an international consensus about methodology and interpretation (Heddle et al, 2000;Thybaud et al, 2003). The availability of methods of monitoring specific mutations in vivo, coupled with our increasing knowledge about the role of specific mutations in human carcinogenesis, is opening the door to monitoring those specific mutations known to be intermediate steps on the path to tumor development (McKinzie et al, 2001).…”

Section: Mutation: An "Intermediate" Biomarker Of Carcinogenesismentioning

confidence: 99%

Biomarkers of Cancer Risk and Therapeutic Benefit: New Technologies, New Opportunities, and Some Challenges

MacGregor

2004

Toxicol Pathol

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The biotechnology revolution offers unprecedented opportunities for identification of mechanistically-based biomarkers that report and predict cancer and other pathologies. The combination of genomic technologies with a knowledge of gene sequence and sequence conservation has made available markers that facilitate the correlation of genetic variation with biological outcomes, and "-omic" technologies allow efficient biochemical characterization of functional pathways-providing new markers of the susceptibility of individuals to cancer development, and of tumor susceptibility to specific therapies. New therapeutic agents targeted to individuals with specific genetic or biochemical characteristics already exist. The powerful -omic technologies allow efficient monitoring of gene transcripts, proteins, and intermediary metabolites, making it possible to monitor a large number of key cellular pathways simultaneously. This has enabled the identification of key biomarkers and signaling molecules associated with cell growth, cell death, and cellular metabolism. These new markers are facilitating monitoring of functional disturbance, molecular and cellular damage, and damage-response. Improved imaging technologies have made it feasible to image some of these molecular events noninvasively. To meet the challenge of evaluating and developing consensus criteria for the application of these new technologies and biomarkers, consortium approaches are being increasingly undertaken to share resources and to build a common understanding among the research, industry, and regulatory communities. These developments promise more efficient pharmaceutical product development, safer and more efficacious drugs, and provide clinical practitioners with new and better biomarkers for cancer screening, patient monitoring, and choice of therapy.

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“…As a result, a signiˆcant increase in the MF was observed at 30 mg/kg in the 2,4-DAT-treated group, but not in the 2,6Introduction Transgenic rodent (TGR) assays have been widely used to study in vivo gene mutations by chemicals or radiation; however, an optimal protocol has not yet been established to assess unknown genotoxic potential. The International Workshop on Genotoxicity Testing (IWGT) strongly recommends a repeated-dose regimen for the TGR assay protocol for regulatory safety assessment as follows: a treatment period of 28 days and a sampling time of 3 days following theˆnal treatment (i.e., IWGT protocol) (1,2). The monograph criteria for TGR mutagenicity assays published by the World Health Organization (WHO) are consistent with the IWGT protocol (3); however, little TGR assay data have been obtained using the IWGT protocol.…”

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confidence: 99%

Evaluation of In Vivo Mutagenicity by 2,4-Diaminotoluene and 2,6-Diaminotoluene in Liver of F344 gpt delta Transgenic Rat Dosed for 28 Days: A Collaborative Study of the gpt delta Transgenic Rat Mutation Assay

Sui

Ohta

Shiragiku

et al. 2012

Genes and Environment

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The transgenic rodent (TGR) assay has been widely used to study in vivo gene mutations by chemicals or radiation; however, an optimal protocol has not yet been established to assess unknown genotoxic potential. The International Workshop on Genotoxicity Testing (IWGT) strongly recommends a repeated-dose regimen for the TGR assay protocol for regulatory safety assessment as follows: a treatment period of 28 days and a sampling time of 3 days following theˆnal treatment. In this study, TGR assays using F344 gpt delta transgenic rats were conducted at three laboratories to evaluate the validity of the IWGT protocol, as part of a collaborative study of the transgenic rat mutation assay. Male F344 gpt delta transgenic rats were orally treated with 2,4-diaminotoluene (2,4-DAT; hepatic carcinogen in rodents; 10 and 30 mg/kg/day) or 2,6-diaminotoluene (2,6-DAT; non-carcinogen in rodents; 60 mg/ kg/day) once daily for 28 days. Rats were euthanized 3 days after the last dosing, and then mutant frequencies (MFs) of the gpt gene in the livers were studied. As a result, a signiˆcant increase in the MF was observed at 30 mg/kg in the 2,4-DAT-treated group, but not in the 2,6-DAT-treated group. These results were commonly observed among the three laboratories. In addition, the overall results from the three laboratories were in general agreement. These results indicate that 2,4-DAT induces gene mutation in the liver of gpt delta rats, but 2,6-DAT does not. These results also indicate that the F344 gpt delta transgenic rat mutation assay can distinguish diŠer-ences in the in vivo mutagenic potential between a hepatic carcinogen and a non-carcinogen. Results from one laboratory showed more variability than those from the other two laboratories, and this appearance was due to the smaller number of colonies scored. Thus, these results demonstrate that the IWGT protocol for the TGR assays is valid, and show that consistent results are obtained among diŠerent laboratories.

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In vivo transgenic mutation assays

Cited by 141 publications

References 54 publications

Essai n° 488 : Essais de mutations génétiques des cellules somatiques et germinales de rongeurs transgéniques

Essai n° 488 : Essais de mutations génétiques des cellules somatiques et germinales de rongeurs transgéniques

Biomarkers of Cancer Risk and Therapeutic Benefit: New Technologies, New Opportunities, and Some Challenges

Evaluation of In Vivo Mutagenicity by 2,4-Diaminotoluene and 2,6-Diaminotoluene in Liver of F344 gpt delta Transgenic Rat Dosed for 28 Days: A Collaborative Study of the gpt delta Transgenic Rat Mutation Assay

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