gms | German Medical Science

48th Meeting of the Particle Therapy Co-Operative Group

Particle Therapy Co-Operative Group (PTCOG)

28.09. - 03.10.2009, Heidelberg

Differential DNA Repair Mechanisms in Response to Proton and Photon Irradiation

Meeting Abstract

  • N. Frenzel - Radiooncology, University Hospital Zurich, Laboratory for Molecular Radiobiology, Zurich, Switzerland
  • E. Hug - Paul Scherrer Institute, Center for Proton Therapy, Villigen, Switzerland
  • A. Lomax - Paul Scherrer Institute, Center for Proton Therapy, Villigen, Switzerland
  • A. Staab - Paul Scherrer Institute, Center for Proton Therapy, Villigen, Switzerland
  • A. Sartori - Medical Faculty University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
  • M. Pruschy - Radiooncology, University Hospital Zurich, Laboratory for Molecular Radiobiology, Zurich, Switzerland

PTCOG 48. Meeting of the Particle Therapy Co-Operative Group. Heidelberg, 28.09.-03.10.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. Doc09ptcog064

DOI: 10.3205/09ptcog064, URN: urn:nbn:de:0183-09ptcog0642

Veröffentlicht: 24. September 2009

© 2009 Frenzel et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Purpose/objective(s): A relative biological effectiveness (RBE) factor for proton irradiation of 1.1–1.2 is presently used in clinical proton radiotherapy. However, the molecular damage pattern and damage response, which are the basis of this RBE value remain largely unknown. We investigated the impact of various DNA repair machineries (non-homologous end joining, homologous recombination, base excision repair) on the treatment response to proton versus photon irradiation using an indirect cellular approach.

Materials/methods: SiRNA-mediated downregulation of specific DNA-repair key enzymes (XRCC1, XRCC3, Rad51, XRCC4) was successfully performed in the human p53-wildtype, osteosarcoma cell line U2OS. SiRNA against HSP70B, which is not expressed in these cells, was used as control. U2OS cells were treated with increasing doses (2–8 Gy) of either proton (PSI scanning beam mid spread-out Bragg peak; energy at target 36.5 MeV; 2keV/µm LET) or photon irradiation (Pantak Therapax 300kV X ray; 0.7Gy/min), followed by clonogenic survival assays and RBE calculation.

Results: An RBE<font size="1">10 at 10 percent cell survival of 1.34±0.06 was determined for the control siRNA-treated cells. Downregulation of XRCC1, involved in single strand break and base excision repair, sensitized cells towards both proton and photon irradiation, resulting in a slight decrease in the RBE10 to 1.21±0.06. Interestingly, targeting the two main DNA double strand break repair pathways resulted in differential cellular hypersensitivity to proton and photon irradiation: By targeting non-homologous end joining (siXRCC4), the observed increase in sensitivity to proton vs. photon irradiation was similar to control cells as the RBE remained unchanged (RBE10 of 1.30±0.11). However, the RBE of proton vs. photon irradiation treatment was different when we silenced Rad51, a key factor involved in the initiation of homologous recombination (RBE10 1.14±0.05). Experiments targeting XRCC3 (RBE10 1.18±0.08), another downstream component of the homologous recombination pathway, also pointed towards the relevance of homologous recombination in a differential response to photon vs. proton irradiation.

Conclusion: We show that cells lacking specific DNA repair proteins display differential sensitivities for the two types of low LET radiation. This might indicate either the formation of different types of DNA damage lesions and/or a different cellular stress response for "traditional" photon compared to proton irradiation. While the underlying mechanism has yet to be defined, an important involvement of homologous recombination can be assumed. A differential cellular response to photon vs. proton irradiation could lead to the development of novel proton-versus-photon specific combined treatment modalities by targeting specific DNA-repair machineries.