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Response to letter regarding “An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses”

2019; Elsevier BV; Volume: 139; Linguagem: Inglês

10.1016/j.radonc.2019.07.009

1879-0887

Douglas R. Spitz, Garry R. Buettner, Charles L. Limoli,

Advanced Radiotherapy Techniques

We are gratified that our mechanism-oriented proposal on how FLASH ultra-high dose rate ionizing radiation (FLASH-RT; >40 Gy/s) may protect against normal tissue damage while preserving tumor responses is sparking discussion in the research community [ [1] Spitz D.R. Buettner G.R. Petronek M.S. St-Aubin J.J. Flynn R.T. Waldron T.J. et al. An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses. Radiother Oncol. 2019; 139: 23-27 Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar ]. The current use of fractionated ionizing radiation to treat cancer with relatively low-dose rates is designed to provide a differential toxicity between normal and cancer tissue based on approaches that maximize the presence of oxygen and reoxygenation in the tumor tissue during treatment. These approaches have been largely based on the assumption that normal tissue is always well-oxygenated radio-biologically and therefore relatively unaffected by O2 tension. In stark contrast to the results with relatively low dose rates, excess normal tissue oxygenation beyond physiological concentrations (using carbogen breathing in animals) has recently been reported to significantly reduce the normal tissue protection seen in brain with the ultra-high dose rates used in FLASH-RT [ [2] Montay-Gruel P. Acharya M.M. Petersson K. Alikhani L. Yakkala C. Allen B.D. et al. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. Proc Natl Acad Sci U S A. 2019; 116: 10943-10951 Crossref PubMed Scopus (214) Google Scholar ]. Our proposed mechanistic hypothesis for how FLASH-RT can minimize oxidative distress to normal tissue compared to tumor tissue is based on a thorough reconsideration of the fundamental principles of free radical radio-chemistry occurring both at the time of exposure and shortly thereafter that will modify the entire biological response following exposure to ultra-high dose ionizing radiation. We appreciate the comments made by our esteemed colleagues and have carefully considered each one to help guide experimentation focused on validating mechanistic studies for accepting or refuting our proposed hypothesis explaining the remarkable normal tissue sparing effects of FLASH-RT. The many estimations we made in this hypothesis were generated in the spirit of a "Fermi estimate". Several points for discussion that were initiated by our colleagues are addressed below: 1.Time scale: Indeed as Professor Wardman has summarized, time is undeniably a key and complex variable for the delivery of ionizing radiation and the subsequent biochemical and biological consequences [ [3] Wardman P. Time as a variable in radiation biology: the oxygen effect. Radiat Res. 2016; 185: 1-3 Crossref PubMed Scopus (14) Google Scholar ]. Moreover, the time structure of the FLASH beam is an important characteristic, and will help distinguish between important parameters such as the mean dose rate and the instantaneous (intra-pulse) dose rate as critical determinants for the FLASH effect (8). Thus, given our current knowledge, the statement that the "pulsatile nature of the LINAC is likely irrelevant" is simply inaccurate. Importantly, our goal was to specifically emphasize that upon FLASH-RT a great deal, if not all, of the available tissue dioxygen could be consumed in a single, very short pulse. Well-known radiation chemistry would indicate that a substantial fraction of the dioxygen present at the "instant" of FLASH-RT will react rapidly with the downstream carbon-centered radicals (R) formed, yielding oxidizing peroxyl radicals (ROO). These peroxyl radicals will abstract hydrogen atoms from neighboring substances yielding an organic hydroperoxide (ROOH) and a new organic free radical (R). These radicals can in turn initiate new chain reactions. This amplification could result in the complete depletion of oxygen. Any H2O2 formed can also feed into these chain reactions via Fenton Chemistry [ [4] Wardman P. Candeias L.P. Fenton chemistry: an introduction. Radiat Res. 1996; 145: 523-531 Crossref PubMed Scopus (474) Google Scholar ]. Thus, the time scale for the delivery of the ionizing radiation and the ensuing radiation chemistry with tissue O2 are indeed important considerations. 2.DSB and cell killing: We agree that double strand breaks contribute to the cytotoxicity observed after FLASH-RT and we are well aware of the microdosimetric nuances of ionizing radiation and resultant "locally multiply damaged sites" [ [5] Ward J.F. The complexity of DNA damage: relevance to biological consequences. Int J Radiat Biol. 1994; 66: 427-432 Crossref PubMed Scopus (518) Google Scholar ]. Furthermore, data to date (unpublished) have not revealed a significant difference in the response to DNA damage between FLASH and conventional dose rate exposures, increasing the likelihood that late normal tissue toxicities (brain, lung) are driven by fundamentally different reactivities and signaling pathways. In this regard, the oxidative challenge posed by the different redox environment of tumor cells (relative to normal cells) may be overwhelming and contribute to cell death via additional pathways, i.e. normal cells are much better able to cope with the oxidative challenge presented by FLASH-RT, yielding the differential biological effects needed for successful enhancement of the therapeutic window. This will need to be investigated using manipulations of hydroperoxide metabolism as well as quantitative examination of the oxidative damage to critical biomolecules including lipids, proteins, and nucleic acids.