Biological effects of proton radiation: What we know and don't know

Radiation Research

Volumn 179, Issue 3, 2013, Pages 257-272

  Girdhani, Swati ^a   Sachs, Rainer ^a,b   Hlatky, Lynn ^a  

^a TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA FRAGMENT; DOUBLE STRANDED DNA; FIBROBLAST GROWTH FACTOR 2; FREE RADICAL; GELATINASE A; GELATINASE B; GLYCOPROTEIN; HISTONE H2AX; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTERLEUKIN 1; INTERLEUKIN 6; INTERLEUKIN 8; MALONALDEHYDE; MESSENGER RNA; SINGLE STRANDED DNA; STAT5A PROTEIN; STROMELYSIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ANGIOGENESIS; ANTIANGIOGENIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; CANCER RADIOTHERAPY; CANCER RISK; CELL ADHESION; CELL CYCLE; CELL DIVISION; CELL INVASION; CELL KILLING; CELL MIGRATION; CELL SURVIVAL; CLINICAL EFFECTIVENESS; DNA METHYLATION; DNA REPAIR; DOUBLE STRANDED DNA BREAK; EXTRACELLULAR MATRIX; G1 PHASE CELL CYCLE CHECKPOINT; G2 PHASE CELL CYCLE CHECKPOINT; GAMMA RADIATION; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; INTRACELLULAR SIGNALING; IONIZING RADIATION; LINEAR ENERGY TRANSFER; M PHASE CELL CYCLE CHECKPOINT; METASTASIS; NONHUMAN; PRIORITY JOURNAL; PROTON RADIATION; PROTON THERAPY; RADIATION CARCINOGENESIS; RADIATION DOSE; RADIATION RESPONSE; RELATIVE BIOLOGIC EFFECTIVENESS; REVIEW; RISK ASSESSMENT; S PHASE CELL CYCLE CHECKPOINT; SECOND CANCER; SIGNAL TRANSDUCTION; TUMOR RECURRENCE;

PROTONS; SUBCELLULAR FRACTIONS;

EID: 84874971428     PISSN: 00337587     EISSN: 19385404     Source Type: Journal    
DOI: 10.1667/RR2839.1     Document Type: Review

References (126)

1. Wilson RR. Radiological use of fast protons. Radiology 1946; 47(5):487-91.
2. Levy RP, Fabrikant JI, Frankel KA, Phillips MH, Lyman JT, Lawrence JH, et al. Heavy-charged-particle radiosurgery of the pituitary gland: Clinical results of 840 patients. Stereotact Funct Neurosurgery 1991; 57(1-2):22-35.
3. Skarsgard LD. Radiobiology with heavy charged particles: A historical review. Phys Med 1998; (Suppl 1):1-19.
4. Jones B. The case for particle therapy. Br J Radiol 2006; 79(937): 24-31.
5. Jones B. The potential clinical advantages of charged particle radiotherapy using protons or light ions. Clin Oncol 2008; 20(7): 555-63.
6. Jakel O. Medical physics aspects of particle therapy. Radiat Prot Dosim 2009; 137(1-2):156-66.
7. Durante M, Loeffler JS. Charged particles in radiation oncology. Nat Rev Clin Oncol 2010; 7(1):37-43.
8. Timmermann B. Proton beam therapy for childhood malignancies: Status report. Klin Padiatr 2010; 222(3):127-33.
9. Hoppe B, Henderson R, Mendenhall WM, Nichols RC, Li Z, Mendenhall NP. Proton therapy for prostate cancer. Oncology 2011; 25(7):644-52.
10. Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S, Chuganji Y, Kagei K, et al. Proton beam therapy for hepatocellular carcinoma: A retrospective review of 162 patients. Clin Cancer Res 2005; 11(10):3799-805.
11. Skinner HD, Hong TS, Krishnan S. Charged-particle therapy for hepatocellular carcinoma. Semin Radiat Oncol 2011; 21(4): 278-86.
12. Hata M, Miyanaga N, Tokuuye K, Saida Y, Ohara K, Sugahara S, et al. Proton beam therapy for invasive bladder cancer: A prospective study of bladder-preserving therapy with combined radiotherapy and intra-Arterial chemotherapy. Int J Radiat Oncol Biol Phys 2006; 64(5):1371-9.
13. Fossati P, Ricardi U, Orecchia R. Pediatric medulloblastoma: Toxicity of current treatment and potential role of protontherapy. Cancer Treat Rev 2009; 35(1):79-96.
14. Gragoudas ES, Marie Lane A. Uveal melanoma: Proton beam irradiation. Ophthalmol Clin North Am 2005; 18(1):111-8.
15. Dunavoelgyi R, Dieckmann K, Gleiss A, Sacu S, Kircher K, Georgopoulos M, et al. Local tumor control, visual acuity, and survival after hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated between 1997 and 2007. Int J Radiat Oncol Biol Phys 2011; 81(1):199-205.
16. MacDonald SM, Yock TI. Proton beam therapy following resection for childhood ependymoma. Childs Nerv Syst 2010; 26(3):285-91.
17. Nguyen QN, Chang EL. Emerging role of proton beam radiation therapy for chordoma and chondrosarcoma of the skull base. Curr Oncol Rep 2008; 10(4):338-43.
18. Townsend LW. Implications of the space radiation environment for human exploration in deep space. Radiat Prot Dosim 2005; 115(1-4):44-50.
19. Cengel KA, Diffenderfer ES, Avery S, Kennedy AR, McDonough J. Using electron beam radiation to simulate the dose distribution for whole body solar particle event proton exposure. Radiat Environ Biophys 2010; 49(4):715-21.
20. Jakel O. The relative biological effectiveness of proton and ion beams. Z Med Phys 2008; 18(4):276-85.
21. Nelson GA. Fundamental space radiobiology. Gravit Space Biol Bull 2003; 16(2):29-36.
22. Raju MR. Proton radiobiology, radiosurgery and radiotherapy. Int J Radiat Biol 1995; 67(3):237-59.
23. Liamsuwan T, Uehara S, Emfietzoglou D, Nikjoo H. Physical and biophysical properties of proton tracks of energies 1 keV to 300 MeV in water. Int J Radiat Biol 2011; 87(2):141-60.
24. Plante I, Cucinotta FA. Energy deposition and relative frequency of hits of cylindrical nanovolume in medium irradiated by ions: Monte Carlo simulation of tracks structure. Radiat Environ Biophys 2010; 49(1):5-13.
25. Friedland W, Kundra't P, Jacob P. Track structure calculations on hypothetical subcellular targets for the release of cell-killing signals in bystander experiments with medium transfer. Radiat Prot Dosim 2011; 143(2-4):325-9.
26. Goodhead DT. Energy deposition stochastics and track structure: what about the target? Radiat Prot Dosim 2006; 122(1-4):3-15.
27. Berger MJ, Courney JS, Zucker MA, Chang J. ESTAR, PSTAR, and ASTAR: Computer Programs for Calculating Stopping-.Power and Range Tables for Electrons, Protons, and Helium Ions According to Methods Described in ICRU Reports 37 and 49. Version 1.2.3 available online: http://physics.nist.gov/Star. Accessed 02/01/2011. In: Gaithersburg, MD: National Insititue of Standards and Technology, 2005.
28. Chen J, Kellerer AM. Proximity functions for electrons from 100 eV to 10 MeV. Radiat Prot Dosim 2006; 122(1-4):56-60.
29. Grosswendt B. Basic aspects of photon transport through matter with respect to track structure formation. Radiat Environ Biophys 1999; 38(3):147-61.
30. Gueulette J, Bohm L, Slabbert JP, De Coster BM, Rutherfoord GS, Ruifrok A, et al. Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses. Int J Radiat Oncol Biol Phys 2000; 47(4): 1051-8.
31. Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol 1999; 50(2): 135-42.
32. Paganetti H, Niemierko A, Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002; 53(2):407-21.
33. Paganetti H. Significance and implementation of RBE variations in proton beam therapy. Technol Cancer Res Treat 2003; 2(5): 413-26.
34. Roots R, Holley W, Chatterjee A, Irizarry M, Kraft G. The formation of strand breaks in DNA after high-LET irradiation: A comparison of data from in vitro and cellular systems. Int J Radiat Biol 1990; 58(1):55-69.
35. Kundra't P, Stewart RD. On the biophysical interpretation of lethal DNA lesions induced by ionising radiation. Radiat Prot Dosim 2006; 122(1-4):169-72.
36. Blakely EA, Kronenberg A. Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness. Radiat Res 1998; 150(5 Suppl): S126-45.
37. Prise KM, Pinto M, Newman HC, Michael BD. A review of studies of ionizing radiation-induced double-strand break clustering. Radiat Res 2001; 156(5):572-6.
38. Asaithamby A, Chen DJ. Mechanism of cluster DNA damage repair in response to high-Atomic number and energy particles radiation. Mutat Res 2011; 711(1-2):87-99.
39. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: Identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol 1988; 35:95-125.
40. Frankenberg D, Frankenberg-Schwager M, Blo?cher D, Harbich R. Evidence for DNA double-strand breaks as the critical lesions in yeast cells irradiated with sparsely or densely ionizing radiation under oxic or anoxic conditions. Radiat Res 1981; 88(3):524-32.
41. Bryant PE. Enzymatic restriction of mammalian cell DNA: Evidence for double-strand breaks as potentially lethal lesions. Int J Radiat Biol Relat Stud Phys Chem Med 1985; 48(1):55-60.
42. Campa A, Ballarini F, Belli M, Cherubini R, Dini V, Esposito G, et al. DNA DSB induced in human cells by charged particles and gamma rays: Experimental results and theoretical approaches. Int J Radiat Biol 2005; 81(11):841-54.
43. Belli M, Ianzini F, Sapora O, Tabocchini MA, Cera F, Cherubini R, et al. DNA double strand break production and rejoining in V79 cells irradiated with light ions. Adv Space Res 1996; 18(1-2):73-82.
44. Pastwa E, Neumann RD, Mezhevaya K, Winters TA. Repair of radiation-induced DNA double-strand breaks is dependent upon radiation quality and the structural complexity of double-strand breaks. Radiat Res 2003; 159(2):251-61.
45. Rydberg B. Radiation-induced DNA damage and chromatin structure. Acta Oncol 2001; 40(6):682-5.
46. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273(10):5858-68.
47. Wang B, Matsuoka S, Carpenter PB, Elledge SJ. 53BP1, a mediator of the DNA damage checkpoint. Science. 2002; 298(5597):1435-8.
48. Finnberg N, Wambi C, Ware JH, Kennedy AR, El-Deiry WS. Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo. Cancer Biol Ther 2008; 7(12):2023-33.
49. Gerelchuluun A, Hong Z, Sun L, Suzuki K, Terunuma T, Yasuoka K, et al. Induction of in situ DNA double-strand breaks and apoptosis by 200 MeV protons and 10 MV X-rays in human tumour cell lines. Int J Radiat Biol 2011; 87(1):57-70.
50. Green LM, Murray DK, Bant AM, Kazarians G, Moyers MF, Nelson GA, et al. Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution. Radiat Res 2001; 155(1):32-42.
51. Costes SV, Boissie're A, Ravani S, Romano R, Parvin B, Barcellos-Hoff MH. Imaging features that discriminate between foci induced by high- and low-LET radiation in human fibroblasts. Radiat Res 2006; 165(5):505-15.
52. Desai N, Davis E, O'Neill P, Durante M, Cucinotta FA, Wu H. Immunofluorescence detection of clustered gamma-H2AX foci induced by HZE-particle radiation. Radiat Res 2005; 164(4): 518-22.
53. Leatherbarrow EL, Harper JV, Cucinotta FA, O'Neill P. Induction and quantification of gamma-H2AX foci following low and high LET-irradiation. Int J Radiat Biol 2006; 82(2): 111-8.
54. Ibanez IL, Bracalente C, Molinari BL, Palmieri MA, Policastro L, Kreiner AJ, et al. Induction and rejoining of DNA double strand breaks assessed by H2AX phosphorylation in melanoma cells irradiated with proton and lithium beams. Int J Radiat Oncol Biol Phys 2009; 74(4):1226-35.
55. Calugaru V, Nauraye C, Noel G, Giocanti N, Favaudon V, Me'gnin-Chanet F. Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay. Int J Radiat Oncol Biol Phys 2011; 81(4):1136-43.
56. Hada M, Sutherland BM. Spectrum of complex DNA damages depends on the incident radiation. Radiat Res 2006; 165(2): 223-30.
57. Leloup C, Garty G, Assaf G, Cristovao A, Breskin A, Chechik R, et al. Evaluation of lesion clustering in irradiated plasmid DNA. Int J Radiat Biol 2005; 81(1):41-54.
58. Goetz W, Morgan MN, Baulch JE. The effect of radiation quality on genomic DNA methylation profiles in irradiated human cell lines. Radiat Res 2011; 175(5):575-87.
59. Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong-ngam D, et al. Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 2004; 23(54):8841-6.
60. Este'cio MR, Gharibyan V, Shen L, Ibrahim AE, Doshi K, He R, et al. LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability. PLoS One 2007; 2(5):e399.
61. Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol 1999; 9(5):359-67.
62. Prise KM, Schettino G, Folkard M, Held KD. New insights on cell death from radiation exposure. Lancet Oncol 2005; 6(7): 520-8.
63. Di Pietro C, Piro S, Tabbi' G, Ragusa M, Di Pietro V, Zimmitti V, et al. Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy. Apoptosis 2006; 11(1):57-66.
64. Lee KB, Lee JS, Park JW, Huh TL, Lee YM. Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases. Exp Mol Med 2008; 40(1): 118-29.
65. Giedzinski E, Rola R, Fike JR, Limoli CL. Efficient production of reactive oxygen species in neural precursor cells after exposure to 250 MeV protons. Radiat Res 2005; 164(4):540-4.
66. Baluchamy S, Ravichandran P, Periyakaruppan A, Ramesh V, Hall JC, Zhang Y, et al. Induction of cell death through alteration of oxidants and antioxidants in lung epithelial cells exposed to high energy protons. J Biol Chem 2010; 285(32):24769-74.
67. Chang JY, Zhang X, Vassiliev O, Gillin M, Mohan R. Proton therapy targets cancer stem cells in treatment-resistant non-small lung cancer. Int J Radiat Oncol Biol Phys 2010; 78(3 Suppl): S644.
68. Mishra KP. Cell membrane oxidative damage induced by gamma-radiation and apoptotic sensitivity. J Environ Pathol Toxicol Oncol 2004; 23(1):61-6.
69. Agrawal A, Kale RK. Radiation induced peroxidative damage: Mechanism and significance. Indian J Exp Biol 2001; 39(4): 291-309.
70. Somosy Z. Radiation response of cell organelles. Micron 2000; 31(2):165-81.
71. Benderitter M, Vincent-Genod L, Pouget JP, Voisin P. The cell membrane as a biosensor of oxidative stress induced by radiation exposure: A multiparameter investigation. Radiat Res 2003; 159(4):471-83.
72. Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994; 180(2):525-35.
73. Corre I, Niaudet C, Paris F. Plasma membrane signaling induced by ionizing radiation. Mutat Res 2010; 704(1-3):61-7.
74. Luotola J. Membrane damage caused by free radicals-radiation perspective. Med Biol 1984; 62(2):115-8.
75. Baluchamy S, Ravichandran P, Ramesh V, He Z, Zhang Y, Hall JC, et al. Reactive oxygen species mediated tissue damage in high energy proton irradiated mouse brain. Mol Cell Biochem 2012; 360(1-2):189-95.
76. Baluchamy S, Zhang Y, Ravichandran P, Ramesh V, Sodipe A, Hall JC, et al. Differential oxidative stress gene expression profile in mouse brain after proton exposure. In Vitro Cell Dev Biol Anim 2010; 46(8):718-25.
77. Mao XW, Green LM, Mekonnen T, Lindsey N, Gridley DS. Gene expression analysis of oxidative stress and apoptosis in proton-irradiated rat retina. In Vivo 2010; 24(4):425-30.
78. Tariq MA, Soedipe A, Ramesh G, Wu H, Zhang Y, Shishodia S, et al. The effect of acute dose charge particle radiation on expression of DNA repair genes in mice. Mol Cell Biochem 2011; 349(1-2):213-8.
79. Girdhani S, Lamont C, Hahnfeldt P, Abdollahi A, Hlatky L. Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth. Radiat Res 2012; 178(1):33-45.
80. Tian J, Zhao W, Tian S, Slater JM, Deng Z, Gridley DS. Expression of genes involved in mouse lung cell differentiation/regulation after acute exposure to photons and protons with or without low-dose preirradiation. Radiat Res 2011; 176(5): 553-64.
81. Hlatky L, Hahnfeldt P, Tsionou C, Coleman CN. Vascular endothelial growth factor: Environmental controls and effects in angiogenesis. Br J Cancer Suppl 1996; 27:S151-6.
82. Sgura A, Antoccia A, Cherubini R, Dalla Vecchia M, Tiveron P, Degrassi F, et al. Micronuclei, CREST-positive micronuclei and cell inactivation induced in Chinese hamster cells by radiation with different quality. Int J Radiat Biol 2000; 76(3):367-74.
83. Bettega D, Calzolari P, Chauvel P, Courdi A, Herault J, Iborra N, et al. Radiobiological studies on the 65 MeV therapeutic proton beam at Nice using human tumour cells. Int J Radiat Biol 2000; 76(10):1297-303.
84. Lee KB, Kim KR, Huh TL, Lee YM. Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. Int J Oncol 2008; 33(6):1247-56.
85. Green LM, Tran DT, Murray DK, Rightnar SS, Todd S, Nelson GA. Response of thyroid follicular cells to gamma irradiation compared to proton irradiation: II. The role of connexin 32. Radiat Res 2002; 158(4):475-85.
86. Ristic-Fira AM, Todorovic DV, Koricanac LB, Petrovic IM, Valastro LM, Cirrone PG, et al. Response of a human melanoma cell line to low and high ionizing radiation. Ann N Y Acad Sci 2007; 1095:165-74.
87. Radojcic M, Crompton NE. Age dependence of T-lymphocyte apoptosis induced by high-energy proton exposure. Radiat Environ Biophys 2001; 40(2):131-5.
88. Narang H, Bhat N, Gupta SK, Santra S, Choudhary RK, Kailash S, et al. Differential activation of mitogen-Activated protein kinases following high and low LET radiation in murine macrophage cell line. Mol Cell Biochem 2009; 324(1-2):85-91.
89. Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59(4):928-42.
90. Fokas E, Kraft G, An H, Engenhart-Cabillic R. Ion beam radiobiology and cancer: Time to update ourselves. Biochim Biophys Acta 2009; 1796(2):216-29.
91. Moertel H, Georgi JC, Distel L, Eyrich W, Fritsch M, Grabenbauer G, et al. Effects of low energy protons on clonogenic survival, DSB repair and cell cycle in human glioblastoma cells and B14 fibroblasts. Radiother Oncol 2004; 73(Suppl 2):S115-8.
92. Antoccia A, Sgura A, Berardinelli F, Cavinato M, Cherubini R, Gerardi S, et al. Cell cycle perturbations and genotoxic effects in human primary fibroblasts induced by low-energy protons and X/gamma-rays. J Radiat Res 2009; 50(5):457-68.
93. Barcellos-Hoff MH, Costes SV. A systems biology approach to multicellular and multi-generational radiation responses. Mutat Res 2006; 597(1-2):32-8.
94. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407(6801):249-57.
95. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004; 5(5):429-41.
96. Sonveaux P, Brouet A, Havaux X, Gre'goire V, Dessy C, Balligand JL, et al. Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: Implications for tumor radiotherapy. Cancer Res 2003; 63(5):1012-9.
97. Park CM, Park MJ, Kwak HJ, Lee HC, Kim MS, Lee SH, et al. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res 2006; 66(17):8511-9.
98. Ogata T, Teshima T, Kagawa K, Hishikawa Y, Takahashi Y, Kawaguchi A, et al. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res 2005; 65(1):113-20.
99. Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L. Tumor development under angiogenic signaling: A dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 1999; 59(19):4770-5.
100. Geng L, Donnelly E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 2001; 61(6):2413-9.
101. Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxiainduced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 1994; 54(23):6083-6.
102. Sofia Vala I, Martins LR, Imaizumi N, Nunes RJ, Rino J, Kuonen F, et al. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLoS One 2010; 5(6): E11222.
103. Gorski DH, Beckett MA, Jaskowiak NT, Calvin DP, Mauceri HJ, Salloum RM, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999; 59(14):3374-8.
104. Jang GH, Ha JH, Huh TL, Lee YM. Effect of proton beam on blood vessel formation in early developing zebrafish (Danio rerio) embryos. Arch Pharm Res 2008; 31(6):779-85.
105. Grabham P, Hu B, Sharma P, Geard C. Effects of ionizing radiation on three-dimensional human vessel models: Differential effects according to radiation quality and cellular development. Radiat Res 2011; 175(1):21-8.
106. Boyd SR, Gittos A, Richter M, Hungerford JL, Errington RD, Cree IA. Proton beam therapy and iris neovascularisation in uveal melanoma. Eye 2006; 20(7):832-6.
107. Gridley DS, Bonnet RB, Bush DA, Franke C, Cheek GA, Slater JD, et al. Time course of serum cytokines in patients receiving proton or combined photon/proton beam radiation for resectable but medically inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 60(3):759-66.
108. Kajioka EH, Andres ML, Mao XW, Moyers MF, Nelson GA, Gridley DS. Hematological and TGF-beta variations after wholebody proton irradiation. In Vivo 2000; 14(6):703-8.
109. Rithidech KN, Reungpatthanaphong P, Honikel L, Rusek A, Simon SR. Dose-rate effects of protons on in vivo activation of nuclear factor-kappa B and cytokines in mouse bone marrow cells. Radiat Environ Biophys 2010; 49(3):405-19.
110. Chang PY, Bjornstad KA, Rosen CJ, Lin S, Blakely EA. Particle radiation alters expression of matrix metalloproteases resulting in ECM remodeling in human lens cells. Radiat Environ Biophys 2007; 46(2):187-94.
111. McNamara MP, Bjornstad KA, Chang PY, Chou W, Lockett SJ, Blakely EA. Modulation of lens cell adhesion molecules by particle beams. Phys Med 2001; 17(Suppl 1):247-8.
112. Tian J, Pecaut MJ, Coutrakon GB, Slater JM, Gridley DS. Response of extracellular matrix regulators in mouse lung after exposure to photons, protons and simulated solar particle event protons. Radiat Res 2009; 172(1):30-41.
113. Olsen DR, Bruland OS, Frykholm G, Norderhaug IN. Proton therapy-A systematic review of clinical effectiveness. Radiother Oncol 2007; 83(2):123-32.
114. Ramaekers BL, Pijls-Johannesma M, Joore MA, van den Ende P, Langendijk JA, Lambin P, et al. Systematic review and metaanalysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons. Cancer Treat Rev 2011; 37(3):185-201.
115. Pijls-Johannesma M, Grutters JP, Verhaegen F, Lambin P, De Ruysscher D. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist 2010; 15(1):93-103.
116. Grutters JP, Kessels AG, Pijls-Johannesma M, De Ruysscher D, Joore MA, Lambin P. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for nonsmall cell lung cancer: A meta-Analysis. Radiother Oncol 2010; 95(1):32-40.
117. Gragoudas ES, Lane AM, Munzenrider J, Egan KM, Li W. Longterm risk of local failure after proton therapy for choroidal/ciliary body melanoma. Trans Am Ophthalmol Soc 2002; 100:43-9.
118. Marucci L, Lane AM, Li W, Egan KM, Gragoudas ES, Adams JA, et al. Conservation treatment of the eye: Conformal proton reirradiation for recurrent uveal melanoma. Int J Radiat Oncol Biol Phys 2006; 64(4):1018-22.
119. Munzenrider JE, Verhey LJ, Gragoudas ES, Seddon JM, Urie M, Gentry R, et al. Conservative treatment of uveal melanoma: local recurrence after proton beam therapy. Int J Radiat Oncol Biol Phys 1989; 17(3):493-8.
120. Newhauser WD, Durante M. Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 2011; 11(6):438-48.
121. Chung CS, Keating N, Yock T, Tarbell N. Comparative analysis of second malignancy risk in patients treated with proton therapy versus conventional photon therapy. Int J Radiat Oncol Biol Phys 2008; 72(Suppl 1):S8.
122. Schneider U, Lomax A, Timmermann B. Second cancers in children treated with modern radiotherapy techniques. Radiother Oncol 2008; 89(2):135-40.
123. Cucinotta FA, Nikjoo H, Goodhead DT. Applications of amorphous track models in radiation biology. Radiat Environ Biophys 1999; 38(2):81-92.
124. Rich JN. Cancer stem cells in radiation resistance. Cancer Res 2007; 67(19):8980-4.
125. Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer 2005; 93(8):849-54.
126. Chen J. Microdosimetric characteristics of proton beams from 50 keV to 200 MeV. Radiat Prot Dosim 2011; 143(2-4):436-9.