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Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro / Linda Reilly

Swansea University Author: Linda Reilly

  • Redacted version - open access under embargo until: 16th October 2026

DOI (Published version): 10.23889/SUthesis.68029

Abstract

The current limitations of in vitro genotoxicity testing, often resulting in misleading predictions of in vivo carcinogenic potential, prompted a project aimed at enhancing predictive accuracy. This study integrated traditional genotoxicity data with a multi-endpoint approach, encompassing various c...

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Published: Swansea, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Jenkins, Gareth J.
URI: https://cronfa.swan.ac.uk/Record/cronfa68029
first_indexed 2024-10-21T09:31:25Z
last_indexed 2024-11-25T14:21:17Z
id cronfa68029
recordtype RisThesis
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spelling 2024-10-21T10:51:25.8443270 v2 68029 2024-10-21 Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro f83ef95a024a00871e695d484f9a977d Linda Reilly Linda Reilly true false 2024-10-21 MEDS The current limitations of in vitro genotoxicity testing, often resulting in misleading predictions of in vivo carcinogenic potential, prompted a project aimed at enhancing predictive accuracy. This study integrated traditional genotoxicity data with a multi-endpoint approach, encompassing various cellular endpoints relevant to carcinogenicity. The developed multi-endpoint testing platform was compared with an innovative Multi-Endpoint Genotoxicity Assessment (MEGA) screen, an automated imaging-based micronucleus assay in A549 cells, providing insights into genotoxic mechanisms. The Swansea-based multi-endpoint platform conducted assays, including cytotoxicity, micronuclei induction (Mn), cell cycle perturbations, and other cancer-related endpoints over time in TK6 and A549 cells. A group of compounds (Cisplatin, Temozolomide, Trichostatin A, Potassium Bromate) underwent assessment across both cell lines. Examining Cisplatin as an example, the multi-endpoint strategy revealed a significant increase in Mn at 4 µM (*P ≤ 0.05), 50% cytotoxicity at 6 µM, early (*P ≤ 0.05) and late-stage (**P ≤ 0.01) apoptosis at 6 µM, and G2/M arrest (****P ≤ 0.0001) at 4 µM after 24 hours with a 24-hour recovery in TK6 cells. In A549 cells, the same time point exhibited a significant Mn increase at 0.5µM (*P ≤ 0.05), 50% cytotoxicity at 3 µM, early-stage apoptosis (*P ≤ 0.05) at 3 µM, and an increase in G1 population (*P ≤ 0.05) starting at 0.5µM. In the MEGA screen, A549 cells demonstrated responses at substantially higher doses (1000 µM), accompanied by significant toxicity. A multiple endpoint approach provided a comprehensive understanding of cisplatin's mechanism of action. Concurrent evaluation of both multi-endpoint systems identified strengths and weaknesses, facilitating the development and refinement of a predictive testing platform for in vitro carcinogenicity assessment. Future exploration of multi-endpoint approaches promises insights into compound mechanisms of action, detection of safety concerns, and contributions to evolving regulatory standards. E-Thesis Swansea, Wales, UK Genetic Toxicology, Carcinogenicity, In Vitro Approaches 16 10 2024 2024-10-16 10.23889/SUthesis.68029 A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Jenkins, Gareth J. Doctoral Ph.D Medical Research Council, Integrative Toxicology Training Partnership Medical Research Council, Integrative Toxicology Training Partnership 2024-10-21T10:51:25.8443270 2024-10-21T10:26:54.6512978 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Linda Reilly 1 Under embargo Under embargo 2024-10-21T10:43:12.5574898 Output 6102141 application/pdf Redacted version - open access true 2026-10-16T00:00:00.0000000 Copyright: The author, Linda Reilly, 2024. true eng
title Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
spellingShingle Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
Linda Reilly
title_short Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
title_full Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
title_fullStr Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
title_full_unstemmed Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
title_sort Novel Multiple Endpoint Approaches for Assessing Genotoxicity and Carcinogenicity Potential In Vitro
author_id_str_mv f83ef95a024a00871e695d484f9a977d
author_id_fullname_str_mv f83ef95a024a00871e695d484f9a977d_***_Linda Reilly
author Linda Reilly
author2 Linda Reilly
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUthesis.68029
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description The current limitations of in vitro genotoxicity testing, often resulting in misleading predictions of in vivo carcinogenic potential, prompted a project aimed at enhancing predictive accuracy. This study integrated traditional genotoxicity data with a multi-endpoint approach, encompassing various cellular endpoints relevant to carcinogenicity. The developed multi-endpoint testing platform was compared with an innovative Multi-Endpoint Genotoxicity Assessment (MEGA) screen, an automated imaging-based micronucleus assay in A549 cells, providing insights into genotoxic mechanisms. The Swansea-based multi-endpoint platform conducted assays, including cytotoxicity, micronuclei induction (Mn), cell cycle perturbations, and other cancer-related endpoints over time in TK6 and A549 cells. A group of compounds (Cisplatin, Temozolomide, Trichostatin A, Potassium Bromate) underwent assessment across both cell lines. Examining Cisplatin as an example, the multi-endpoint strategy revealed a significant increase in Mn at 4 µM (*P ≤ 0.05), 50% cytotoxicity at 6 µM, early (*P ≤ 0.05) and late-stage (**P ≤ 0.01) apoptosis at 6 µM, and G2/M arrest (****P ≤ 0.0001) at 4 µM after 24 hours with a 24-hour recovery in TK6 cells. In A549 cells, the same time point exhibited a significant Mn increase at 0.5µM (*P ≤ 0.05), 50% cytotoxicity at 3 µM, early-stage apoptosis (*P ≤ 0.05) at 3 µM, and an increase in G1 population (*P ≤ 0.05) starting at 0.5µM. In the MEGA screen, A549 cells demonstrated responses at substantially higher doses (1000 µM), accompanied by significant toxicity. A multiple endpoint approach provided a comprehensive understanding of cisplatin's mechanism of action. Concurrent evaluation of both multi-endpoint systems identified strengths and weaknesses, facilitating the development and refinement of a predictive testing platform for in vitro carcinogenicity assessment. Future exploration of multi-endpoint approaches promises insights into compound mechanisms of action, detection of safety concerns, and contributions to evolving regulatory standards.
published_date 2024-10-16T20:48:25Z
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