Impact of proton therapy on the DNA damage induction and repair in hematopoietic stem and progenitor cells

Abstract

Proton therapy is of great interest to pediatric cancer patients because of its optimal depth dose distribution. In view of healthy tissue damage and the increased risk of secondary cancers, we investigated DNA damage induction and repair of radiosensitive hematopoietic stem and progenitor cells (HSPCs) exposed to therapeutic proton and photon irradiation due to their role in radiation-induced leukemia. Human CD34+ HSPCs were exposed to 6 MV X-rays, mid- and distal spread-out Bragg peak (SOBP) protons at doses ranging from 0.5 to 2 Gy. Persistent chromosomal damage was assessed with the micronucleus assay, while DNA damage induction and repair were analyzed with the γ-H2AX foci assay. No differences were found in induction and disappearance of γ-H2AX foci between 6 MV X-rays, mid- and distal SOBP protons at 1 Gy. A significantly higher number of micronuclei was found for distal SOBP protons compared to 6 MV X-rays and mid- SOBP protons at 0.5 and 1 Gy, while no significant differences in micronuclei were found at 2 Gy. In HSPCs, mid-SOBP protons are as damaging as conventional X-rays. Distal SOBP protons showed a higher number of micronuclei in HSPCs depending on the radiation dose, indicating possible changes of the in vivo biological response.

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

“…Moreover, the normal tissue response may vary depending on the complexity of DNA damage induced by different radiation modalities, as evidenced in the context of proton therapy compared to conventional photon-based radiotherapy for cancer treatment 10 . Indeed, recent studies have revealed that proton irradiation can elicit distinct DNA damage responses and activate specific pathways [11][12][13] , leading to more effective killing of cancer cells 11,14 . However, to date, the understanding of the molecular effects of proton versus photon irradiation on normal tissue is still limited.…”