Projects / Programmes
Genotoxic potential of protein tyrosine kinase inhibitors: relevance for human health hazards upon indirect exposure
| Code |
Science |
Field |
Subfield |
| 1.03.00 |
Natural sciences and mathematics |
Biology |
|
| Code |
Science |
Field |
| B220 |
Biomedical sciences |
Genetics, cytogenetics |
| Code |
Science |
Field |
| 1.06 |
Natural Sciences |
Biological sciences |
tyrosine kinase inhibitors, genotoxicity, occupational exposure, in vitro, comet assay, micronucleus assay, gene expression, mixtures
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
34200 |
PhD Matjaž Novak |
Biology |
Head |
2019 - 2022 |
0 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0105 |
National Institute of Biology |
Ljubljana |
5055784 |
0 |
Abstract
The International Agency for Research on Cancer has classified several anticancer drugs in Group 1 (human carcinogens) and group 2B (possible carcinogens). In the last 2 – 3 decades, special guidelines and improved protective measures have been introduced in most countries to protect healthcare workers during the handling of anticancer drugs. Nevertheless it has been found that a significant uptake with elevated biomarkers of effect (related to the genotoxic properties) still occurs worldwide in most workplaces. Therefore, the occupational exposure to the conventional cytotoxic anticancer drugs, mainly because of the inappropriate handling, dispensing, administration to the patients (direct contact) and contact with contaminated patient’s excreta has been identified as a serious health hazard. Tyrosine kinase inhibitors (TKIs) have been introduced in the cancer therapy only 17 years ago and are already among the most popular anticancer drugs with steadily increasing consumption amounts. TKIs function as signal transduction inhibitors with relatively high specificity and do not directly affect DNA structure like conventional cytotoxic anticancer drugs. However, recently it has been demonstrated, that some of them induce DNA damage and genomic instability in nontarget human cells and environmental organisms. Therefore, data that will allow human health risk assessment related to their potential genotoxic activity are needed. The aim of this project is to contribute to the missing information on potential genotoxicity of TKs that is necessary to evaluate the risks for healthy population upon indirect exposure to their residues.
In the first step we will select TKIs that are the most relevant for indirect human exposure. In the next step genotoxic potential of the selected TKIs will be evaluated in vitro in human based cell systems using the classical genotoxicity assays that detect DNA single- (comet assay), double-strand breaks (DSBs) (γH2Ax focci) and genomic instability (micronuclei assay). Both, primary DNA damage and micronuclei formation are also the most widely used genotoxicity biomarkers of occupational exposure to anticancer drugs. In order to obtain in-depth knowledge on the molecular mechanisms of genotoxicity of the studied TKIs the genotoxicity assays will be coupled with the transcriptomic analyses of the responses of genes involved in DNA damage response and repair, metabolism, apoptosis and oncogenes after the exposure to these compounds. Among the differentially expressed genes the most promising biomarker genes or gene signatures will be identified, which will be used for subsequent analysis and prediction of genotoxic potential of other relevant TKIs. Together with genotoxicity data the obtained mechanistic knowledge will provide valuable information on TKIs toxicity which will be relevant for the science based human health risk assessment. As healthcare workers during their everyday work are exposed to a variety of anticancer drugs residues also the combined effects of mixtures composed from selected TKIs and conventional cytotoxic anticancer drugs will be studied.
The multi-level investigation approach proposed in this research project will provide completely new data about the potential genotoxic side effects and the molecular mechanisms responsible for the observed effects. This study is unique as such detailed research has not been performed so far and especially not from the perspective of the undesired effects on indirectly exposed healthy humans. The results of this project will have important implications in the preparation of guidelines, directives and regulations for harmonized risk assessment and management. Overall, the obtained knowledge will bring the answer to the fundamental question whether indirect exposure to TKIs represents the risk to healthy humans related to their potential genotoxicity.
Significance for science
Tyrosine kinase inhibitors (TKIs) are used for targeted cancer therapy and are due to their specific mechanism of therapeutic action considered as safer for patients as well as healthcare personnel that can be exposed indirectly, compared to classical cytotoxic anticancer drugs. However, recently it has been demonstrated that some of them exert genotoxic effects in non-target human cells and environmental organisms. As the use of TKIs in cancer therapy is rapidly increasing and it has already been stressed out that knowledge gaps exist regarding the potential hazard they represent upon indirect exposure (Cass et al., 2017).
The proposed postdoctoral research project will fill the knowledge gap and provide completely new data about the potential genotoxic side effects of TKIs and the related hazard relevant for the risk assessment for healthy humans that are indirectly exposed to the residues of these compounds. A multi-level investigation approach proposed in this research project will allow us to be the first to answer how TKIs affect non-target human cells. Moreover, this will be the first study in which the effects of TKIs in combination with conventional chemotherapeutics will be explored in normal, non-target human cells. This study is unique as such detailed research has not been performed so far and especially not from the perspective of the undesired effects on indirectly exposed healthy humans.
The obtained knowledge will be of great importance as indirect exposure to TKIs can potentially affect relatively large populations. Due to predominant outpatient application of these drugs in addition to healthcare staff in hospitals also family members including children that may be more vulnerable than adults can potentially be exposed and at risk. Furthermore, the consumption of TKIs is constantly increasing, also due to the use in the treatment of other diseases. Recently, TKIs are also used for the treatment of certain cancers in pets.
The results of this project will have important implications in the preparation of guidelines, directives and regulations for harmonized risk assessment and management (i.e. basic education and related precautions should be introduced to protect family members and caregivers from indirect or direct exposure to these drugs), which is very important for public health protection and sustainable development. In this context, the project will also contribute to national and EU policies and strategies related to human health and environment protection, i.e. to EU Occupational Safety and Health (OSH) Strategic Framework. Moreover, the newly obtained knowledge will also be useful in the future drug development.
Altogether, the obtained new knowledge will bring the answer to the fundamental question whether indirect exposure to residues of TKIs represents the risk to healthy humans related to their potential genotoxicity.
Significance for the country
Tyrosine kinase inhibitors (TKIs) are used for targeted cancer therapy and are due to their specific mechanism of therapeutic action considered as safer for patients as well as healthcare personnel that can be exposed indirectly, compared to classical cytotoxic anticancer drugs. However, recently it has been demonstrated that some of them exert genotoxic effects in non-target human cells and environmental organisms. As the use of TKIs in cancer therapy is rapidly increasing and it has already been stressed out that knowledge gaps exist regarding the potential hazard they represent upon indirect exposure (Cass et al., 2017).
The proposed postdoctoral research project will fill the knowledge gap and provide completely new data about the potential genotoxic side effects of TKIs and the related hazard relevant for the risk assessment for healthy humans that are indirectly exposed to the residues of these compounds. A multi-level investigation approach proposed in this research project will allow us to be the first to answer how TKIs affect non-target human cells. Moreover, this will be the first study in which the effects of TKIs in combination with conventional chemotherapeutics will be explored in normal, non-target human cells. This study is unique as such detailed research has not been performed so far and especially not from the perspective of the undesired effects on indirectly exposed healthy humans.
The obtained knowledge will be of great importance as indirect exposure to TKIs can potentially affect relatively large populations. Due to predominant outpatient application of these drugs in addition to healthcare staff in hospitals also family members including children that may be more vulnerable than adults can potentially be exposed and at risk. Furthermore, the consumption of TKIs is constantly increasing, also due to the use in the treatment of other diseases. Recently, TKIs are also used for the treatment of certain cancers in pets.
The results of this project will have important implications in the preparation of guidelines, directives and regulations for harmonized risk assessment and management (i.e. basic education and related precautions should be introduced to protect family members and caregivers from indirect or direct exposure to these drugs), which is very important for public health protection and sustainable development. In this context, the project will also contribute to national and EU policies and strategies related to human health and environment protection, i.e. to EU Occupational Safety and Health (OSH) Strategic Framework. Moreover, the newly obtained knowledge will also be useful in the future drug development.
Altogether, the obtained new knowledge will bring the answer to the fundamental question whether indirect exposure to residues of TKIs represents the risk to healthy humans related to their potential genotoxicity.
