Quinazolines are anticancer agents that are clinically used for the targeted treatment of tumors where the ErbB receptors are overexpressed or bear specific mutations. These agents can also act as radiosensitizers. The purpose of this Ph.D. project is the evaluation of new anticancer quinazolines derivatives as radiosensitizers. These will belong to the following categories:

1. Derivatives that inhibit the tyrosine kinase domain and have inhibitory action in specific mutations of EGFR: deletions of exon 19 (del 746-750) or/and the exon 21 (L858R) (1^st generation)
2. Derivatives that have broader activity to overcome EGFR resistant mutations to the 1^st generation and inhibit all ErbB family signaling (2^nd generation).
3. Derivatives that have high specificity for the T790 mutation of EGFR, which is the most common mechanism of resistance to the therapy using the first two generation quinazolines (3^rd generation).

For the purpose of this study, the new produced quinazolines derivatives are evaluated for their anti-cancer activity and for their ability of radiosensitizing. The most promising radiosensitizers of this study will be compared with the current quinazolines that are used nowadays in clinical routine. The ultimate goal is to propose new promising anticancer agents that can also act as radiosensitizers.

The extensive use of low doses of ionizing radiation (≤100 mSv) for diagnostic and therapeutic purposes increases concern on the radiation safety of both patients and physicians. Ionizing radiation exposures have almost doubled in the last decade, mainly due to the rise in medical diagnostic and therapeutic interventions, which are responsible for approximately 40% of the cumulative effective dose of radiation to the population. Despite the wide use of low-ionizing-radiation doses and the recent evidence that cancer risk may increase even at lower doses (between 50-100 mSv)  the effects of such exposures in patients exposed to cardiac images and interventional cardiology procedures remain unclear.

According to epidemiologic literature, the impact of low doses are hampered by limited statistical power at radiation levels of less than 100 mSv, even for very large studies. Alternatively, the investigation of the radiation-induced effects after exposure to low doses could be carried out with radiobiological data. The present study’s objective is to determine the biological effects of low doses in patients exposed to ionizing radiation during interventional cardiology procedures by using several biomarkers and the correlation of these doses with the potential development of cancer.

The 1^st  objective involves the use of molecular and cytogenetic biomarkers to investigate the biological effects delivered to patients after their exposure to cardiovascular procedures at Onassis Cardiac Surgery Centre. Blood samples (6-7 ml) from  patients who undergo ordinary interventional cardiology procedures, such as Coronary Angiography, Percutaneous Transluminal Coronary Angioplasty, and ablation are collected directly before, and immediately after the end of the procedure and incubated in heparin-containing vials for each time interval. The induction and repair of DSBs is visualized and quantified by using the highly sensitive epigenetic biomarker γ-H2AX, a phosphorylated histone H2A variant. Chromosomal aberrations and micronuclei are both crucial predictors of the degree of radiation damage. The frequency of dicentric chromosomes and micronuclei is detected and is compared to the baseline.

Furthermore, the 2^nd objective involves the potentiation of the unrepaired DSBs to induce asymmetric cell divisions and chromosomal instability, is tested by using the methodology of CB-iFISH that combines cytokinesis block mediated cell culturing with interphase Fluorescence in situ Hybridization (CB-iFISH) in human lymphocytes that are irradiated in vitro with low ionizing radiation doses. This combined methodology enables the visualization of centromeric regions in the micronuclei as well as the monitoring of the chemically-induced asymmetric cell divisions. The evaluation of the potential ability of the unrepaired radiation-induced DSBs to induce chromosomal instability and asymmetric cell division, will contribute in the research of radiobiology and radioprotection.

Radiation Therapy (RT) is often used in conjunction with other therapies such as chemotherapy or tumour removal surgery as an integral part of both curative and palliative treatments for cancer. While RT is one of the most effective single modalities in cancer therapy, it can have significant side effects both during and after treatment, which can impact both the quality and the duration of life. Although rapid technological advances have led to a more precise delivery of radiation dose and to a decreased risk of side effects, there is still a significant need for personalized treatment to be achieved through the development of predictive tools that may guide therapy decisions. Project’s objectives are the prediction of individual radiosensitivity in clinical practice, the investigation of the potential of combining radiation therapy with G2/M cell cycle checkpoint abrogators in vitro, as well as, the evaluation of the efficiency of advanced radiotherapy techniques such as VMAT and IMRT, using phantoms in conjunction with cytogenetic techniques.