Skip to main content
Log in

Reduced side effects by proton microchannel radiotherapy: study in a human skin model

  • Original Paper
  • Published:
Radiation and Environmental Biophysics Aims and scope Submit manuscript

Abstract

The application of a microchannel proton irradiation was compared to homogeneous irradiation in a three-dimensional human skin model. The goal is to minimize the risk of normal tissue damage by microchannel irradiation, while preserving local tumor control through a homogeneous irradiation of the tumor that is achieved because of beam widening with increasing track length. 20 MeV protons were administered to the skin models in 10- or 50-μm-wide irradiation channels on a quadratic raster with distances of 500 μm between each channel (center to center) applying an average dose of 2 Gy. For comparison, other samples were irradiated homogeneously at the same average dose. Normal tissue viability was significantly enhanced after microchannel proton irradiation compared to homogeneous irradiation. Levels of inflammatory parameters, such as Interleukin-6, TGF-Beta, and Pro-MMP1, were significantly lower in the supernatant of the human skin tissue after microchannel irradiation than after homogeneous irradiation. The genetic damage as determined by the measurement of micronuclei in keratinocytes also differed significantly. This difference was quantified via dose modification factors (DMF) describing the effect of each irradiation mode relative to homogeneous X-ray irradiation, so that the DMF of 1.21 ± 0.20 after homogeneous proton irradiation was reduced to 0.23 ± 0.11 and 0.40 ± 0.12 after microchannel irradiation using 10- and 50-μm-wide channels, respectively. Our data indicate that proton microchannel irradiation maintains cell viability while significantly reducing inflammatory responses and genetic damage compared to homogeneous irradiation, and thus might improve protection of normal tissue after irradiation.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Albert RE, Burns FJ, Heimbach RD (1967) Skin damage and tumor formation from grid and sieve patterns of electron and beta radiation in the rat. Radiat Res 30(3):525–540

    Article  Google Scholar 

  • Anschel DJ, Bravin A, Romanelli P (2010) Microbeam radiosurgery using synchrotron-generated submillimetric beams: a new tool for the treatment of brain disorders. Neurosurg Rev 34(2):133–142. doi:10.1007/s10143-010-0292-3

    Article  Google Scholar 

  • Arpin D, Mahe MA, Servois V, Claude L (2009) Predictive factors for acute radiation pneumonitis. Rev Pneumol Clin 65(3):177–186. doi:10.1016/j.pneumo.2009.03.011

    Article  Google Scholar 

  • Asur RS, Sharma S, Chang CW, Penagaricano J, Kommuru IM, Moros EG, Corry PM, Griffin RJ (2012) Spatially fractionated radiation induces cytotoxicity and changes in gene expression in bystander and radiation adjacent murine carcinoma cells. Radiat Res 177(6):751–765. doi:10.1667/RR2780.1

    Article  Google Scholar 

  • Belyakov OV, Mitchell SA, Parikh D, Randers-Pehrson G, Marino SA, Amundson SA, Geard CR, Brenner DJ (2005) Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away. Proc Natl Acad Sci USA 102(40):14203–14208. doi:10.1073/pnas.0505020102

    Article  ADS  Google Scholar 

  • Berridge MV, Herst PM, Tan AS (1996) The biochemical and cellular basis of cell proliferation assays that use tetrazolium salts. Biochemica 4:15–19

    Google Scholar 

  • Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N (2009) Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin Cancer Res 15(17):5534–5540. doi:10.1158/1078-0432.CCR-08-2584

    Article  Google Scholar 

  • Brauer-Krisch E, Bravin A, Lerch M, Rosenfeld A, Stepanek J, Di Michiel M, Laissue JA (2003) MOSFET dosimetry for microbeam radiation therapy at the European Synchrotron Radiation Facility. Med Phys 30(4):583–589. doi:10.1118/1.1562169

    Article  Google Scholar 

  • Brauer-Krisch E, Requardt H, Regnard P, Corde S, Siegbahn E, LeDuc G, Brochard T, Blattmann H, Laissue J, Bravin A (2005) New irradiation geometry for microbeam radiation therapy. Phys Med Biol 50(13):3103–3111. doi:10.1088/0031-9155/50/13/009

    Article  Google Scholar 

  • Burns FJ, Albert RE, Bennett P, Sinclair IP (1972) Tumor incidence in rat skin after proton irradiation in a sieve pattern. Radiat Res 50(1):181–190

    Article  Google Scholar 

  • Butterworth KT, McGarry CK, Trainor C, O’Sullivan JM, Hounsell AR, Prise KM (2011) Out-of-field cell survival following exposure to intensity-modulated radiation fields. Int J Radiat Oncol Biol Phys 79(5):1516–1522. doi:10.1016/j.ijrobp.2010.11.034

    Article  Google Scholar 

  • Chen MF, Chen WC, Lai CH, Hung CH, Liu KC, Cheng YH (2010) Predictive factors of radiation-induced skin toxicity in breast cancer patients. BMC Cancer 10:508. doi:10.1186/1471-2407-10-508

    Article  Google Scholar 

  • Curren RD, Mun GC, Gibson DP, Aardema MJ (2006) Development of a method for assessing micronucleus induction in a 3D human skin model (EpiDerm). Mutat Res 607(2):192–204. doi:10.1016/j.mrgentox.2006.04.016

    Article  Google Scholar 

  • Deasy JO, Blanco AI, Clark VH (2003) CERR: a computational environment for radiotherapy research. Med Phys 30(5):979–985

    Article  Google Scholar 

  • Dickey JS, Zemp FJ, Altamirano A, Sedelnikova OA, Bonner WM, Kovalchuk O (2011) H2AX phosphorylation in response to DNA double-strand break formation during bystander signalling: effect of microRNA knockdown. Radiat Prot Dosim 143(2–4):264–269. doi:10.1093/rpd/ncq470

    Article  Google Scholar 

  • Dilmanian AF, Meek AG (2010) Heavy Ion therapy with microbeams. US Patent 2010/0187446 A1; www.freepatentsonline.com/y2010/0187446.html

  • Dilmanian FA, Zhong Z, Bacarian T, Benveniste H, Romanelli P, Wang R, Welwart J, Yuasa T, Rosen EM, Anschel DJ (2006) Interlaced x-ray microplanar beams: a radiosurgery approach with clinical potential. Proc Natl Acad Sci USA 103(25):9709–9714. doi:10.1073/pnas.0603567103

    Article  ADS  Google Scholar 

  • Durante M, Loeffler JS (2010) Charged particles in radiation oncology. Nat Rev Clin Oncol 7(1):37–43. doi:10.1038/nrclinonc.2009.183

    Article  Google Scholar 

  • Fleckenstein K, Gauter-Fleckenstein B, Jackson IL, Rabbani Z, Anscher M, Vujaskovic Z (2007) Using biological markers to predict risk of radiation injury. Semin Radiat Oncol 17(2):89–98. doi:10.1016/j.semradonc.2006.11.004

    Article  Google Scholar 

  • Greubel C, Hable V, Drexler GA, Hauptner A, Dietzel S, Strickfaden H, Baur I, Krucken R, Cremer T, Friedl AA, Dollinger G (2008) Quantitative analysis of DNA-damage response factors after sequential ion microirradiation. Radiat Environ Biophys 47(4):415–422. doi:10.1007/s00411-008-0181-0

    Article  Google Scholar 

  • Griffin RJ, Koonce NA, Dings RPM, Siegel E, Moros EG, Bräuer-Krisch E, Corry PM (2012) Microbeam radiation therapy alters vascular architecture and tumor oxygenation and is enhanced by a galectin-1 targeted anti-angiogenic peptide. Radiat Res 177(6):804–812. doi:10.1667/RR2784.1

    Article  Google Scholar 

  • Hauptner A, Dietzel S, Drexler GA, Reichart P, Krucken R, Cremer T, Friedl AA, Dollinger G (2004) Microirradiation of cells with energetic heavy ions. Radiat Environ Biophys 42(4):237–245. doi:10.1007/s00411-003-0222-7

    Article  Google Scholar 

  • Hu T, Kaluzhny Y, Mun GC, Barnett B, Karetsky V, Wilt N, Klausner M, Curren RD, Aardema MJ (2009) Intralaboratory and interlaboratory evaluation of the EpiDerm 3D human reconstructed skin micronucleus (RSMN) assay. Mutat Res 673(2):100–108. doi:10.1016/j.mrgentox.2008.12.003

    Article  Google Scholar 

  • ICRU (1993). International commission on radiation units and measurements. ICRU Report 49, stopping powers and ranges for protons and alpha particles

  • Kidd DA, Johnson M, Clements J (2007) Development of an in vitro corrosion/irritation prediction assay using the EpiDerm skin model. Toxicol In Vitro 21(7):1292–1297. doi:10.1016/j.tiv.2007.08.018

    Article  Google Scholar 

  • Laissue JA, Blattmann H, Wagner HP, Grotzer MA, Slatkin DN (2007) Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae. Dev Med Child Neurol 49(8):577–581. doi:10.1111/j.1469-8749.2007.00577.x

    Article  Google Scholar 

  • Liu W, Ding I, Chen K, Olschowka J, Xu J, Hu D, Morrow GR, Okunieff P (2006) Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis. Radiat Res 165(2):181–191. doi:10.1667/RR3478.1

    Article  Google Scholar 

  • Martin M, Lefaix J, Delanian S (2000) TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47(2):277–290

    Article  Google Scholar 

  • Mun GC, Aardema MJ, Hu T, Barnett B, Kaluzhny Y, Klausner M, Karetsky V, Dahl EL, Curren RD (2009) Further development of the EpiDerm 3D reconstructed human skin micronucleus (RSMN) assay. Mutat Res 673(2):92–99. doi:10.1016/j.mrgentox.2008.12.004

    Article  Google Scholar 

  • Porock D, Kristjanson L (1999) Skin reactions during radiotherapy for breast cancer: the use and impact of topical agents and dressings. Eur J Cancer Care 8(3):143–153

    Article  Google Scholar 

  • Rothkamm K, Crosbie JC, Daley F, Bourne S, Barber PR, Vojnovic B, Cann L, Rogers PA (2012) In situ biological dose mapping estimates the radiation burden delivered to ‘spared’ tissue between synchrotron X-ray microbeam radiotherapy tracks. PLoS ONE 7(1):e29853. doi:10.1371/journal.pone.0029853

    Article  ADS  Google Scholar 

  • Sakka M, Kamata R (1958) An increase in tolerance in mice by field-fractionated (sieve) x-irradiation. Radiat Res 9(3):341–345

    Article  Google Scholar 

  • Salvo N, Barnes E, van Draanen J, Stacey E, Mitera G, Breen D, Giotis A, Czarnota G, Pang J, De Angelis C (2010) Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature. Curr Oncol 17(4):94–112

    Google Scholar 

  • Schell S, Wilkens JJ (2010) Advanced treatment planning methods for efficient radiation therapy with laser accelerated proton and ion beams. Med Phys 37(10):5330–5340. doi:10.1118/1.3491406

    Article  Google Scholar 

  • Schmid TE, Dollinger G, Hable V, Greubel C, Zlobinskaya O, Michalski D, Molls M, Roper B (2010) Relative biological effectiveness of pulsed and continuous 20 MeV protons for micronucleus induction in 3D human reconstructed skin tissue. Radiother Oncol 95(1):66–72. doi:10.1016/j.radonc.2010.03.010

    Article  Google Scholar 

  • Sedelnikova OA, Nakamura A, Kovalchuk O, Koturbash I, Mitchell SA, Marino SA, Brenner DJ, Bonner WM (2007) DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models. Cancer Res 67(9):4295–4302. doi:10.1158/0008-5472.CAN-06-4442

    Article  Google Scholar 

  • Sepah SC, Bower JE (2009) Positive affect and inflammation during radiation treatment for breast and prostate cancer. Brain Behav Immun 23(8):1068–1072. doi:10.1016/j.bbi.2009.06.149

    Article  Google Scholar 

  • Serduc R, Christen T, Laissue J, Farion R, Bouchet A, Sanden B, Segebarth C, Brauer-Krisch E, Le Duc G, Bravin A, Remy C, Barbier EL (2008a) Brain tumor vessel response to synchrotron microbeam radiation therapy: a short-term in vivo study. Phys Med Biol 53(13):3609–3622. doi:10.1088/0031-9155/53/13/015

    Article  Google Scholar 

  • Serduc R, van de Looij Y, Francony G, Verdonck O, van der Sanden B, Laissue J, Farion R, Brauer-Krisch E, Siegbahn EA, Bravin A, Prezado Y, Segebarth C, Remy C, Lahrech H (2008b) Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy. Phys Med Biol 53(5):1153–1166. doi:10.1088/0031-9155/53/5/001

    Article  Google Scholar 

  • Slatkin DN, Spanne P, Dilmanian FA (1994) Method for microbeam radiation therapy.US patent 5339347. The United States of America. http://www.freepatentsonline.com/5339347.html

  • Sugawara T, Gallucci RM, Simeonova PP, Luster MI (2001) Regulation and role of interleukin 6 in wounded human epithelial keratinocytes. Cytokine 15(6):328–336. doi:10.1006/cyto.2001.0946

    Article  Google Scholar 

  • Telgenhoff D, Shroot B (2005) Cellular senescence mechanisms in chronic wound healing. Cell Death Differ 12(7):695–698. doi:10.1038/sj.cdd.4401632

    Article  Google Scholar 

  • Weindl G, Castello F, Schafer-Korting M (2011) Evaluation of anti-inflammatory and atrophogenic effects of glucocorticoids on reconstructed human skin. Altern Lab Anim 39(2):173–187

    Google Scholar 

  • Withers HR, Taylor JM, Maciejewski B (1988) Treatment volume and tissue tolerance. Int J Radiat Oncol Biol Phys 14(4):751–759

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the DFG-Cluster of Excellence “Munich-Centre for Advanced Photonics,” and by the Maier Leibnitz Laboratory Munich. We thank Sabine Reinhardt for her support with the Gafchromic film dosimetry and Stefan Schell and Florian Kamp for their excellent technical assistance with the simulations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stefanie Girst.

Additional information

Olga Zlobinskaya and Stefanie Girst contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zlobinskaya, O., Girst, S., Greubel, C. et al. Reduced side effects by proton microchannel radiotherapy: study in a human skin model. Radiat Environ Biophys 52, 123–133 (2013). https://doi.org/10.1007/s00411-012-0450-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00411-012-0450-9

Keywords

Navigation