Limitations of Animal Studies for Predicting Toxicity in Clinical Trials

Norman, Gail A. Van

doi:10.1016/j.jacbts.2019.10.008

Cited by 415 publications

(299 citation statements)

References 58 publications

Supporting

Mentioning

295

Contrasting

Unclassified

Order By: Relevance

“…Although animal models have provided critical insight into how host-microbiota homeostasis is constructed and maintained [33] or influenced by infections or dietary factors [34], they do not faithfully represent the human body and they are not suitable models to assess drug efficacy nor to evaluate complex research questions [35][36][37]. Translating results from murine models to humans remains elusive due to the existence of several key differences between the two systems [38,39], including the anatomy and function of the mouse and human intestinal tract, immune system and interaction with pathogens [40], gut microbiota composition, feeding pattern, genetic background.…”

Section: Limitations Of Traditional In Vivo and In Vitro Modelsmentioning

confidence: 99%

“…The high number of therapeutic compounds that fail to translate in clinical trials [37,77,78], coupled with increasing awareness of the ethical and scientific issues surrounding the use of animal models [38,39,79,80], highlights the need and importance for models that are more physiologically relevant to the human body to personalize treatments and better predict patient outcomes.…”

Section: Limitations Of Traditional In Vivo and In Vitro Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

et al. 2020

View full text Add to dashboard Cite

The interaction between nutrition and human infectious diseases has always been recognized. With the emergence of molecular tools and post-genomics, high-resolution sequencing technologies, the gut microbiota has been emerging as a key moderator in the complex interplay between nutrients, human body, and infections. Much of the host–microbial and nutrition research is currently based on animals or simplistic in vitro models. Although traditional in vivo and in vitro models have helped to develop mechanistic hypotheses and assess the causality of the host–microbiota interactions, they often fail to faithfully recapitulate the complexity of the human nutrient–microbiome axis in gastrointestinal homeostasis and infections. Over the last decade, remarkable progress in tissue engineering, stem cell biology, microfluidics, sequencing technologies, and computing power has taken place, which has produced a new generation of human-focused, relevant, and predictive tools. These tools, which include patient-derived organoids, organs-on-a-chip, computational analyses, and models, together with multi-omics readouts, represent novel and exciting equipment to advance the research into microbiota, infectious diseases, and nutrition from a human-biology-based perspective. After considering some limitations of the conventional in vivo and in vitro approaches, in this review, we present the main novel available and emerging tools that are suitable for designing human-oriented research.

show abstract

Section: Limitations Of Traditional In Vivo and In Vitro Modelsmentioning

confidence: 99%

Section: Limitations Of Traditional In Vivo and In Vitro Modelsmentioning

confidence: 99%

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Although humans and mice share the same genes, their regulation mechanism is different [ 160 ]. Drug testing results vary according to which species is used [ 161 , 162 ]. Therefore, there is a significant demand for models made of human cells as an alternative to animal models.…”

Section: Drug Screening Applicationsmentioning

confidence: 99%

3D Cell Printing of Tissue/Organ-Mimicking Constructs for Therapeutic and Drug Testing Applications

Kim

Kong

Han

et al. 2020

IJMS

View full text Add to dashboard Cite

The development of artificial tissue/organs with the functional maturity of their native equivalents is one of the long-awaited panaceas for the medical and pharmaceutical industries. Advanced 3D cell-printing technology and various functional bioinks are promising technologies in the field of tissue engineering that have enabled the fabrication of complex 3D living tissue/organs. Various requirements for these tissues, including a complex and large-volume structure, tissue-specific microenvironments, and functional vasculatures, have been addressed to develop engineered tissue/organs with native relevance. Functional tissue/organ constructs have been developed that satisfy such criteria and may facilitate both in vivo replenishment of damaged tissue and the development of reliable in vitro testing platforms for drug development. This review describes key developments in technologies and materials for engineering 3D cell-printed constructs for therapeutic and drug testing applications.

show abstract

“…Therefore, there is a growing need for reliable preclinical screening strategies for cardiovascular toxicities associated with emerging cancer therapies prior to human clinical trials. Animal models can fail in predicting drug adverse cardiac effects 10,11 , can be expensive and do not replicate many of the biochemical properties and hemodynamic aspects of the human heart and circulation [12][13][14] . Recently, human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) started being used to assess cardiotoxicity 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

Miller

Meki

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractThe limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity and understanding mechanism. Recently, we developed a functional human and pig heart slice biomimetic culture system that fully preserves the viability and functionality of 300 µm heart slices for 6 days. Here, we tested the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) associated with different mechanisms leading to cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and transcriptome. Slices incubated with any of these drugs for 48 h showed significant loss in viability, cardiomyocyte structure and functionality. Mechanistically, RNA sequencing demonstrated a significant downregulation of cardiac genes and upregulation of oxidative response in doxorubicin-treated tissues. Trastuzumab treatment caused major downregulation in cardiac muscle contraction-related genes, consistent with its clinically known direct effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes in line with its mechanism of action. Heart slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes; they are superior in detecting sunitinib cardiotoxicity phenotypes and mechanism in the clinically relevant concentration range, 100 nM – 1 µM. These results indicate that heart slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanism of action.

show abstract

Limitations of Animal Studies for Predicting Toxicity in Clinical Trials

Cited by 415 publications

References 58 publications

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

3D Cell Printing of Tissue/Organ-Mimicking Constructs for Therapeutic and Drug Testing Applications

Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

Contact Info

Product

Resources

About