Skip to main content
SpringerLink
Log in

A Critical Analysis of Possible Mechanisms for the Oxygen Effect in Radiation Therapy with FLASH

  • Conference paper
  • First Online:
Oxygen Transport to Tissue XLIV (ISOTT 2022)

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1438))

Included in the following conference series:

Abstract

The aim of this review is to stimulate readers to undertake appropriate investigations of the mechanism for a possible oxygen effect in FLASH. FLASH is a method of delivery of radiation that empirically, in animal models, appears to decrease the impact of radiation on normal tissues while retaining full effect on tumors. This has the potential for achieving a significantly increased effectiveness of radiation therapy. The mechanism is not known but, especially in view of the prominent role that oxygen has in the effects of radiation, investigations of mechanisms of FLASH have often focused on impacts of FLASH on oxygen levels. We and others have previously shown that simple differential depletion of oxygen directly changing the response to radiation is not a likely mechanism. In this review we consider how time-varying changes in oxygen levels could account for the FLASH effect by changing oxygen-dependent signaling in cells. While the methods of delivering FLASH are still evolving, current approaches for FLASH can differ from conventional irradiation in several ways that can impact the pattern of oxygen consumption: the rate of delivery of the radiation (40 Gy/s vs. 0.1 Gy/s), the time over which each fraction is delivered (e.g., <0.5 s. vs. 300 s), the delivery in pulses, the number of fractions, the size of the fractions, and the total duration of treatment. Taking these differences into account and recognizing that cell signaling is an intrinsic component of the need for cells to maintain steady-state conditions and, therefore, is activated by small changes in the environment, we delineate the potential time dependent changes in oxygen consumption and overview the cell signaling pathways whose differential activation by FLASH could account for the observed biological effects of FLASH. We speculate that the most likely pathways are those involved in repair of damaged DNA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Al-Hallaq H, Cao M, Kruse J et al (2019) Cured in a FLASH: reducing normal tissue toxicities using ultra-high-dose rates. Int J Radiat Onc Biol Phys 104:257–260

    Article  Google Scholar 

  2. Favaudon V, Caplier L, Monceau V et al (2014) Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med 6:245–293

    Article  Google Scholar 

  3. Wilson JD, Hammond EM, Higgins GS et al (2020) Ultra-high dose rate (FLASH) radiotherapy: silver bullet or fool’s gold? Front Oncol 9(1–12):1563

    Article  PubMed  PubMed Central  Google Scholar 

  4. Friedl AA, Prise KM, Butterworth KT, Montay-Gruel P, Favaudon V (2022) Radiobiology of the FLASH effect. Med Phys 49:1993–2013

    Article  PubMed  Google Scholar 

  5. Jansen J, Beyreuther E, García-Calderón D, Karsch L, Knoll J, Pawelke J, Schürer M, Seco J (2022) Changes in radical levels as a cause for the FLASH effect: impact of beam structure parameters at ultra-high dose rates on oxygen depletion in water. Radiother Oncol 175:193–196

    Article  CAS  PubMed  Google Scholar 

  6. Cao X, Zhang R, Esipova TV et al (2021) Quantification of oxygen depletion during FLASH irradiation in vitro and in vivo. Int J Radiat Oncol Biol Phys 111:240–248

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hall EJ, Giaccia AJ (2018) Radiobiology for the radiologist, 8th edn. Lippincott Williams & Wilkins. Philadelphia, PA

    Google Scholar 

  8. Swartz HM, Hoopes PJ, Gladstone DJ, Demidov V, Vaupel P, Flood AB, Williams BB, Zhang R, Pogue BW (2022) A radiation biological analysis of the oxygen effect as a possible mechanism in FLASH. Adv Exp Med Biol 1395:315–321

    Article  PubMed  Google Scholar 

  9. Perstin A, Poirier Y, Sawant A, Tambasco M (2022) Quantifying the DNA-damaging effects of FLASH irradiation with plasmid DNA. Int J Radiat Oncol Biol Phys 113(2):437–447

    Article  PubMed  Google Scholar 

  10. Grote J, Suesskind R, Vaupel P (1977) Oxygen diffusivity in tumor tissue (DS-Carcinosarcoma) under temperature conditions within the range of 20-40°C. Pflug Arch 372:37–42

    Article  CAS  Google Scholar 

  11. Nikitaki Z, Velalopoulou A, Zanni V, Tremi I, Havaki S, Kokkoris M, Gorgoulis VG, Koumenis C, Georgakilas AG (2022) Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair. Expert Rev Molecul Med 24(e15):1–15

    Google Scholar 

  12. Yeung YT, Aziz F, Guerrero-Castilla A, Arguelles S (2018) Signaling pathways in inflammation and anti-inflammatory therapies. Curr Pharm Des 24(14):1449–1484. https://doi.org/10.2174/1381612824666180327165604 PMID: 29589535

  13. US Dept Human Service REMM (Radiation Emergency Medical Management). Radiation + Trauma (Combined Injury) https://remm.hhs.gov/radtrauma.htm. Accessed 6 Nov 2022

  14. Hotamisligil GS, Davis RJ (2016) Cell signaling and stress responses. Cold Spring Harb Perspect Biol 8(10):a006072. https://doi.org/10.1101/cshperspect.a006072. PMID: 27698029; PMCID: PMC5046695

  15. Wang Z (2021) Regulation of cell cycle progression by growth factor-induced cell signaling. Cell 10:3327. https://doi.org/10.3390/cells10123327

    Article  CAS  Google Scholar 

  16. O’Hara JA, Blumenthal RD, Grinberg OY et al (2001) Response to radioimmunotherapy correlates with tumor pO2 measured by EPR oximetry in human tumor xenografts. Radiat Res 155:466–473

    Article  PubMed  Google Scholar 

  17. Ohta A (2018) Oxygen-dependent regulation of immune checkpoint mechanisms. Int Immunol 30(8):335–343. https://doi.org/10.1093/intimm/dxy038

    Article  CAS  PubMed  Google Scholar 

  18. Multhoff G, Vaupel P (2020) Hypoxia compromises anti-cancer immune responses. Adv Exp Med Biol 1232:131–143. https://doi.org/10.1007/978-3-030-34461-0_18 PMID: 31893404

Download references

Acknowledgments

This work was supported by NIH grant U01 CA260446.

Author information

Authors and Affiliations

  1. Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    Harold M. Swartz & Ann Barry Flood

  2. Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Harold M. Swartz & Ann Barry Flood

  3. Thayer School of Engineering, Dartmouth College, Hanover, NH, USA

    Harold M. Swartz

  4. Department of Radiation Oncology, University Medical Center, University of Freiburg/Brsg., Freiburg, Germany

    Peter Vaupel

  5. German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Peter Vaupel

Authors
  1. Harold M. Swartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Vaupel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann Barry Flood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harold M. Swartz .

Editor information

Editors and Affiliations

  1. Institute of Complementary and Integrative Medicine, University of Bern, Bern, Switzerland

    Felix Scholkmann

  2. Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA

    Joseph LaManna

  3. Institute of Complementary and Integrative Medicine, University of Bern, Bern, Switzerland

    Ursula Wolf

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Swartz, H.M., Vaupel, P., Flood, A.B. (2023). A Critical Analysis of Possible Mechanisms for the Oxygen Effect in Radiation Therapy with FLASH. In: Scholkmann, F., LaManna, J., Wolf, U. (eds) Oxygen Transport to Tissue XLIV. ISOTT 2022. Advances in Experimental Medicine and Biology, vol 1438. Springer, Cham. https://doi.org/10.1007/978-3-031-42003-0_21

Download citation

Publish with us

Policies and ethics

Search

Navigation