7th Annual Symposium
Physics of Cancer
Leipzig, Germany
October 4-6, 2016
Contributed Talk
Insights about the role of single- and double-strand breaks in cancer radiotherapy
FABRIZIO CLERI1, DOMINIQUE COLLARD2, HIROYUKI FUJITA3, ERIC LARTIGAU4, CORINNE ABBADIE5
1Universite de Lille I, IEMN, Av. Poincare, 59652 Villeneuve d'Ascq, France
2CNRS and IRCL, SMMIL-E Project, Place de Verdun, 59045 Lille, France
3University of Tokyo, CIRMM, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
4Regional Cancer Center, Rue F. Combemale, 59000 Lille, France
5Universite de Lille I and Institut de Biologie, Rue Calmette, 59021 Lille, France
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Among the defects produced in DNA by various endogenous and external agents, single- and double-strand breaks (SSB and DSB) stand out as the most critical for cell survival and multiplication. Controlled production of such defects, and most notably DSBs, is indeed at the heart of cancer radiotherapy. However, the detailed microscopic mechanisms of production of SSB and DSB defects in DNA is not well understood: practically, all the information is currently obtained from chemical methods, by post-processing at much later stages after the time of irradiation, and the clinical relevance of such defects is empirically deduced from "cell survival" radiobiological curves, to be further interpreted with few-parameter phenomenological models (such as the venerable Linear-Quadratic model).
In the past few years, we started a wide-scoped biophysical program, involving biophysicists, engineers, biologists and clinicians, dedicated to the investigation of SSB and DSB production in both isolated DNA and in live cells by means of therapeutic photon beams. We demonstrated the first ever causal observation of DNA degradation in real-time by a custom developed micro-electro mechanical device (MEMS) [1], and developed a theoretical framework based on the statistical mechanics of damaged fibre bundles [2]. In our approach, DNA bundles of a few thousand parallel molecules are captured between the vibrating tips of the MEMS with a few micrometer opening, and irradiated by a 20-MeV Cyberknife photon beam; by monitoring in real-time the variation of resonant frequency and quality factor, the number (and possibly, the quality) of defects produced in the DNA bundle can be detected. The biophysical analysis with a second-order kinetics equation allows interpreting the experimental observations.
In parallel, we developed a program of in-vitro irradiation of live fibroblast cells under the 6-MeV Varian LINAC photon beam, to investigate the differential production of SSBs and DSBs according to the distance of the cells from the beam center, as well as other biological and physical parameters. The production of DNA defects is monitored by fixing the irradiated cells at different times, and correspondingly detecting the fluorescence of XRCC1 and 53BP1 repair proteins, as well as by comet assays. In this case, an agent-based Monte Carlo simulation model has been developed [3], to test different hypotheses of cell population evolution under irradiation, and compare the results to the experimental observations.
In a third, parallel line of research, we are developing molecular simulations by both classical and ab-initio molecular dynamics, to describe the early stages of strand-break defect formation and evolution. We study the role of oxidative and reducing pathways in attacking the DNA backbone by hybrid quantum/classical dynamics, while by large-scale classical simulations we attempt at following the complex defect evolution, after the initial breaking of O-P-O backbone covalent bonds. Another companion experimental program based on singe-molecule spectroscopy with optical tweezers, to couple to such microscopic simulations, is just starting.
The ensemble of such coupled theoretical/experimental actions is providing numerous new insights about the relative role and efficacy of DNA defects in cancer radiobiology. We are starting to formulate some novel hypotheses, also at variance with the common wisdom, which will be main subject of discussion of this talk, after a brief overview of our program.
[1]G. Perret et al.Real-time mechanical characterization of DNA degradation under therapeutic x-ray and theoretical modelling, NPG Microsystems and Nanoengineering, in press (2016)
[2]F. Manca, S. Giordano, P. L. Palla, F. CleriScaling shift in multi-cracked fiber bundles, Phys. Rev. Lett. 113, 255501 (2014)
[3]M. Tomezak, C. Abbadie, E. Lartigau, F. CleriA biophysical model of cell evolution after cytotoxic treatments: Damage, repair and cell response, J. Theor. Biol. 389, 146-158 (2016)
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