Radiation induced DNA damage response
Conor H. McFadden, David B. Flint and Gabriel O. Sawakuchi
Radiation-induced clustered DNA lesions are becoming recognized as a determinant in activation of various DNA repair pathways. Clustered DNA lesions are defined as spatial clusters of various forms of direct DNA damage: base damage (BD), single strand breaks (SSBs), and double strand breaks (DSBs). Formation of radiation-induced clustered DNA lesions directly correlates with linear energy transfer (LET). Low-LET radiation, such as x-ray or high-energy proton beams, induces relatively few clustered DNA lesions. Most of the damage is caused indirectly via reactive oxygen species (ROS). These damages are repaired mainly through base excision repair (BER), SSB repair, and non-homologous end-joining (NHEJ).
Unlikely, high-LET radiation, such as low-energy proton and heavy ion beams (He, C, and O), is less affected by hypoxic conditions because it directly induces numerous clustered DNA lesions that have significantly slower repair kinetics and arrest cells in the G2 phase of the cell cycle. The physical proximity of clustered DNA lesions is thought to trigger cell cycle arrest and activation of homologous recombination (HR) repair. The hypothesis is that clustered DNA damage induced by proton and heavy ion beams trigger cells to repair DNA via HR repair. To test this hypothesis we are using time lapsed confocal microscopy imaging of live cells in proton and heavier ion beams in conjunction with fluorescent nuclear track detectors to measure radiation at the nanoscopic scale in live cells in real time. In addition we use Monte Carlo simulations to understand how radiation energy is deposited in subcellular compartments.
Collaborators: UTSW, DKFZ, HIT, NIRS
C.H. McFadden, T. Hallacy, D.B. Flint, D.A. Granville, A. Asaithamby, N. Sahoo, G.O. Sawakuchi, "Co-localization of DNA damage and particle tracks at the single cell level in real time," Int. J. Radiat. Oncol., Biol., Phys. 96, 221-227 (2016).
G.O. Sawakuchi, F.A. Ferreira, C.H. McFadden, T. Hallacy, D.A. Granville, N. Sahoo, M.S. Akselrod, "Nanoscale measurements of proton tracks using fluorescent nuclear track detectors," Med. Phys. 43, 2485-2490 (2016).
Gold nanoparticle radiosensitization
David B. Flint, Conor H. McFadden, Natcha Sadetaporn and Gabriel O. Sawakuchi
Nanoparticles have been investigated for a number of applications in cancer therapy, in particular radiation therapy (RT). The presence of gold nanoparticles (AuNPs) during radiation therapy has been shown to increase long term survival in mice when injected into tumors during RT, and increase cell killing in vitro. In addition to their great potential for improving radiation therapy, as they have a low toxicity and can be readily functionalized or conjugated with targeting agents or drugs, AuNPs have also shown great promise for targeted drug delivery. This, in turn, suggests that AuNPs might be employed in combined chemotherapy and radiation treatments, both enhancing the effectiveness of the radiation treatment, and delivering or enhancing the treatment of the chemotherapy.
However, the mechanisms governing AuNP radiosensitization are not fully understood. The magnitude of radiosensitization observed due the presence of AuNPs in vitro is at odds with the theoretically predicted magnitude of the physical dose enhancement due to physical radiation interactions with the gold, particularly for low gold concentrations and high photon energies. Our work therefore aims to determine what contribution of the local energy deposition enhancement has in AuNP radiosensitization, as well to determine to what extent the presence of AuNPs affects different biological pathways to induce sensitization. We hypothesize that biological processes, rather than physical radiation processes, play a more important role in AuNP radiosensitization.
Dosimetry in the presence of strong magnetic fields
Daniel J. O'Brien and Gabriel O. Sawakuchi
Magnetic resonance imaging-guided radiotherapy (MRIgRT) provides superior soft-tissue contrast and real-time imaging compared with standard image-guided RT, which uses x-ray based imaging. Radiation measurements in these new machines requires accounting for the effects of the magnetic (B-)field on the response of the detectors. Thus, Implementation and safe use of MR-linac units will only be possible with the development of methods that can provide accurate dosimetric calibration and quality assurance (QA) measurements of the MR-linac unit. Because ionization chambers (ICs) have been used as the gold standard for calibration and QA measurements of conventional radiotherapy units, it would be ideal to use these detectors and similar procedures to also perform calibration and QA measurements of MR-linac units. This research aims to determine new methods for accurate dosimetry in the presence of B-fields. This will make possible the implementation and safe use of new MR-linac units. Of particular importance, this project will generate essential data and methods for MR-linac dosimetry with ICs.
D.J. O’Brien, D.A. Roberts, G.S. Ibbott and G.O. Sawakuchi. "Reference dosimetry in magnetic fields: formalism and ionization chamber correction factors", Med. Phys. 43, 4915 (2016).
D.J. O’Brien, S.L. Hackett, B. van Asselen, G.S. Ibbott, B.W. Raaymakers, G.O. Sawakuchi and J.W.H. Wolthaus. "TH-CD-304-08: Small Air-Gaps Affect the Response of Ionization Chambers in the Presence of a 1.5 T Magnetic Field", Med. Phys. 42, 3724 (2015).