Projects / Programmes
Unveiling the expansion of the Universe with strongly lensed supernovae
| Code |
Science |
Field |
Subfield |
| 1.02.03 |
Natural sciences and mathematics |
Physics |
Astronomy |
| Code |
Science |
Field |
| 1.03 |
Natural Sciences |
Physical 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. |
51012 |
PhD Tanja Petrushevska |
Physics |
Head |
2020 - 2022 |
142 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
1540 |
University of Nova Gorica |
Nova Gorica |
5920884000 |
14,070 |
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) (?H2Ax 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.
