Karakterisering van de biologische effecten van ultra-hoog dosistempo FLASH protontherapie

FLASH radiotherapy is an innovative, experimental cancer treatment that delivers the radiation dose in an ultra-fast and very short treatment session. This approach reduces radiation-induced toxicity to normal tissues while maintaining a similar tumor response compared to conventional dose rate (CONV) radiotherapy. This phenomenon, known as the FLASH effect, has already been confirmed in several animal studies. However, the exact biological mechanisms behind this normal tissue sparing effect remain unclear. In this thesis, we aimed to characterize the potential FLASH effect on various proton irradiation systems, both in vitro and in vivo, to better understand the underlying biological mechanisms in normal tissue. This is crucial for optimizing its clinical application. First, we investigated the sparing potential of FLASH proton irradiation in normal and cancerous pancreatic cells by performing two in vitro DNA damage assays. We found that FLASH irradiation under hypoxic conditions significantly reduced DNA damage in normal cells compared to CONV irradiation when a high dose (15 Gy) was applied. These findings suggest that low oxygen levels and high doses are required for observation of the FLASH effect. Next, we used the zebrafish embryo model to further explore the biological effects of FLASH proton irradiation on normal tissue. We found that FLASH irradiation increased embryo body length and reduced the severity of pericardial edema compared to CONV irradiation. Moreover, FLASH treatment induced less DNA damage and less downstream transcriptional activation of DNA damage response pathways than CONV treatment, resulting in reduced cell death in the embryonic tail. Lastly, we tested whether FLASH proton irradiation could better protect healthy intestinal tissue in mice using a clinical proton therapy system. The results showed that FLASH irradiation improved mouse survival and mitigated both short- and long-term intestinal toxicity compared to CONV irradiation. This suggests that FLASH proton therapy could be useful for treating tumors in the sensitive gastrointestinal tract. In conclusion, this work contributes to a better understanding of the biological effects of the FLASH phenomenon which brings us one step closer to the integration of FLASH proton therapy into cancer treatment. Nevertheless, further experimental research, clinical studies, and technological innovations are vital to address current limitations and ensure its safe and effective implementation.