Struggles for equivalence: In vitro developmental toxicity model evolution in pharmaceuticals in 2006

Chapin, Robert E.; Stedman, Donald B.; Paquette, Jennifer; Streck, Randal D.; Kumpf, Steven W.; Deng, Shibing

doi:10.1016/j.tiv.2006.10.006

Cited by 30 publications

(11 citation statements)

References 2 publications

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“…Moreover, mEST employed beating cardiomyocytes as the toxicological endpoint to calculate the ID values which required more realistic endpoints of detection, to utilize the full potential of the test. Towards this goal, several attempts have been made to improve the test (Noaksson et al, 2005;Schmidt et al, 2001;Zur Nieden et al, 2004;Seiler et al, 2004;Chapin et al, 2007;Murabe et al, 2007). These improvements are primarily focused on the rationale of quantitative assessment of the effects of drugs at the cellular level and the possibility that the beating cardiomyocyte approach may fail if tissues other than myocardium are affected (Paparella et al, 2002;Schmidt et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Assessment of drug induced developmental toxicity using human embryonic stem cells

Mehta¹,

Konala²,

Khanna³

et al. 2008

Cell Biology International

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Embryonic stem (ES) cells are unique as they have the potential to be generated in large numbers and the ability to differentiate into the three germ layers via embryoid body (EB) formation. This property could be utilized as an index to study initial mammalian development. We have investigated the utility of a comprehensively characterized human ES (hES) cell line (ReliCellhES1) for testing the embryotoxic effects of compounds using cytotoxicity assays. Further, we performed real time gene expression analysis to check the alterations in germ layer markers expression upon drug treatment. The results show that assays using hES cells could serve as a reliable, sensitive and robust method to assess embryotoxic potential of compounds. They also provide a proof of concept that hES cells can be used as an in vitro model to demonstrate developmental toxicity, and to examine the germ layer-specific effects on differentiating EBs.

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Section: Discussionmentioning

confidence: 99%

Assessment of drug induced developmental toxicity using human embryonic stem cells

Mehta¹,

Konala²,

Khanna³

et al. 2008

Cell Biology International

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“…Acceptance of the mEST along with the WEC and MM test by the regulatory commission was therefore expected 78 ; however, the Scientific Advisory Committee (ESAC) of the ECVAM felt that these in vitro test systems were not adequate 79 . While several strategies have been implemented in attempts to improve mEST [80][81][82][83][84][85][86][87][88][89][90] , a major concern which remains is the species variation as it would be challenging to evaluate or interpret test results in a human context 91,92 .…”

Section: Human Pscs and Embryotoxicitymentioning

confidence: 99%

Human Pluripotent Stem Cells and Drug Discovery: A New Beginning

Verma¹,

Mehta²,

Flora³

2016

Def. Life. Sc. Jl.

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Human pluripotent stem cells (hPSCs) offer unique opportunities to discover and develop a new generation of drugs. Their ability to differentiate into virtually any cell type renders them a cost-effective, renewable source of tissue-specific cell types capable of predicting human responses towards novel chemical entities. Using these improved in vitro models based on physiologically relevant human cell types could result in identifying highly precise and safe compounds, thereby reducing drug attrition rates. Moreover, ability to develop humanised disease models for patient-stratified drug screening makes hPSCs an impeccable tool in translational medicine. In this mini-review we focus on the positives and negatives of utilising hPSC-derived cell types as drug discovery platforms with special emphasis on cardio-, hepato-and embryotoxicity.

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“…Safety issues are an important reason for compound failure during drug development (1)(2)(3). In the case of potential developmental toxicity, safety assessment relies entirely on preclinical data from animal studies.…”

Section: Introductionmentioning

confidence: 99%

“…In terms of the Three Rs (13), the EST could thus replace animal experimentation, whereas the other two tests could only reduce the use of animals. Given that the EST was reported in the ECVAM validation study to perform as well (approximately 80% success rate in correct classification of test substances) as the WEC method and better than the MM assay (4,8,14), it has emerged as an attractive model for use in developmental toxicity screening (1,15).…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets and Early Response Biomarkers for the Prediction of Developmental ToxicityIn Vitro

et al. 2007

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There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers — even a single one — could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.

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Struggles for equivalence: In vitro developmental toxicity model evolution in pharmaceuticals in 2006

Cited by 30 publications

References 2 publications

Assessment of drug induced developmental toxicity using human embryonic stem cells

Assessment of drug induced developmental toxicity using human embryonic stem cells

Human Pluripotent Stem Cells and Drug Discovery: A New Beginning

Molecular Targets and Early Response Biomarkers for the Prediction of Developmental ToxicityIn Vitro

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