RBE-LET Relationship for the Survival of V79 Cells Irradiated with Low Energy Protons

Belli, M.; Cherubini, R.; Finotto, Susetta; Moschini, G.; Sapora, O.; Simone, G.; Tabocchini, M. A.

doi:10.1080/09553008914550101

Cited by 133 publications

(60 citation statements)

References 10 publications

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“…In general, experimental data on proton RBE versus LET d (Folkard et al 1996, Belli et al 1989, 1993, Perris et al 1986, Coutrakon et al 1997, Wouters et al 1996, Schettino et al 2001 and proton RBE versus (α/β) x (Gerweck andKozin 1999, Paganetti et al 2000) indicate that RBE increases with increasing LET d (note that for protons the eventual decrease with LET d happens at LET d values irrelevant for clinical considerations) but decreases with increasing (α/β) x . The current data sets used to relate RBE with LET d and (α/β) x are subject to uncertainties (Carabe et al 2012, Carabe 2013).…”

Section: Methodsmentioning

confidence: 99%

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver

et al. 2013

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Proton relative biological effectiveness (RBE) is known to depend on the (α/β) x of irradiated tissues, with evidence of ∼60% variation over (α/β) x values from 1-10 Gy. The range of (α/β) x values reported for prostate tumors (1.2-5.0 Gy), brain tumors (10-15 Gy) and liver tumors (13-17 Gy) imply that the proton RBE for these tissues could vary significantly compared to the commonly used generic value of 1.1. Our aim is to evaluate the impact of this uncertainty on the proton dose in Gy(RBE) absorbed in normal and tumor tissues. This evaluation was performed for standard and hypofractionated regimens. RBE-weighted total dose (RWTD) distributions for 15 patients (five prostate tumors, five brain tumors and five liver tumors) were calculated using an in-house developed RBE model as a function of dose, dose-averaged linear energy transfer (LET d ) and (α/β) x . Variations of the dose-volume histograms (DVHs) for the gross tumor volume (GTV) and the organs at risk due to changes of (α/β) x and fractionation regimen were calculated and the RWTD received by 10% and 90% of the organ volume reported. The goodness of the plan, bearing the uncertainties, was then evaluated compared to the delivered plan, which considers a constant RBE of 1.1. For standard fractionated regimens, the prostate tumors, liver tumors and all critical structures in the brain showed typically larger RBE values than 1.1. However, in hypofractionated regimens lower values of RBE than 1.1 were observed in most cases. Based on DVH analysis we found that the RBE variations were clinically significant in particular for the prostate GTV and the critical structures in the brain. Despite the uncertainties in the biological input parameters when estimating RBE values, the results show that the use of a variable RBE with dose, LET d and (α/β) x could help to further optimize the target dose in proton treatment

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Section: Methodsmentioning

confidence: 99%

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver

et al. 2013

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“…One study has suggested that DNA double-strand breaks, potentially lethal damage and sublethal damage, depend on LET and are closely between RBE and LET for protons is not clear and only few data are available. However, at LET values ranging from about 6 to 30 keV ,um-', RBE values drastically increase, and reach a peak value at about 30 keV im-' (Belli et al, 1989;1993;Folkard et al, 1989;Prise et al, 1990). We were therefore interested in whether there is a uniformity of radiobiological effectiveness in a relatively poorly understood region.…”

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confidence: 99%

Comparison of radiobiological effective depths in 65-MeV modulated proton beams

Tang

Inoue²,

Yamazaki³

et al. 1997

Br J Cancer

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Summary To assess the achievement of uniformity of radiobiological effectiveness at different depths in the proton spread-out Bragg peak (SOBP), Chinese hamster ovary (CHO) cells were exposed to 65-MeV modulated proton beams at the Research Center for Nuclear Physics (RCNP) of Osaka University. We selected four different irradiation positions: 2 mm depth, corresponding to the entrance, and 10, 18 and 23 mm depths, corresponding to different positions in the SOBP. Cell survival curves were generated with the in vitro colony formation method and fitted to the linear-quadratic model. With 137CS gamma-rays as the reference irradiation, the relative biological effectiveness (RBE) values for a surviving fraction (SF) level of 0.1 are 1.05, 1.10, 1.12 and 1.19 for depths of 2, 10, 18 and 23 mm respectively. A significant difference was found between the survival curves at 10 and 23 mm (P < 0.05), but not between 18 and 10 mm or between 18 and 23 mm. There was a significant dependence of RBE on depths in modulated proton beams at the 0.1 surviving fraction level (P< 0.05). Moreover, the rise of RBEs significantly depended on increasing SF level or decreased approximately in correspondence with irradiation dose (P = 0.0001). To maintain uniformity of radiobiological effectiveness for the target volume, careful attention should be paid to the influence of depth of beam and irradiation dose.Keywords: proton; spread-out Bragg peak; relative biological effectiveness; Chinese hamster ovary cellThe depth-dose curve for the single-energy proton beam has limited applications in clinical radiation therapy owing to the excessively narrow high-dose region. This region, also known as the Bragg peak, can be modulated by appropriate selection of a distribution of proton energies to produce a spread-out Bragg peak (SOBP) or a uniform region of full dose at the depth of interest. Dose uniformity across a target volume can be achieved with multiple X-ray beams. However, each X-ray beam features a greater dose in the entrance region than a corresponding proton beam, has a dose gradient across the target volume and delivers an undesirable dose to normal tissues distal to the target. Proton beams have none of these undesirable characteristics (Suit and Urie, 1992; Munzenrider and Crowell, 1994;Raju, 1996).Although SOBP produces an excellent physical dose distribution, there is a variation of linear energy transfer (LET) values at different depths in the SOBP, known as the LET gradient, from proximal to distal SOBP. The proton is a lower LET particle than other heavy-charged particles; for example, the mean LET values of the 65-MeV modulated proton beams (SOBP) are always less than 7 keV .m-' (Courdi et al, 1994).The achievement of uniformity of radiobiological effectiveness for target volumes is always a matter of concern. In fact, there is no uniformity of LET within target volumes. One study has suggested that DNA double-strand breaks, potentially lethal damage and sublethal damage, depend on LET and are closely

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“…Actual RBE value is important for the determination of the effective dose to the tumor region. When irradiated with low energy proton, RBE is increased in non-human cell line (Belli et al, 1989(Belli et al, , 1998. RBE values for proton beam therapy with SOBP relative to γ-ray are evaluated in vitro and in vivo system; for various cells ranging from 0.7 to 2.1 (Paganetti et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Lee

Park

et al. 2008

Exp Mol Med

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Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to γ-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathways may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.

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RBE-LET Relationship for the Survival of V79 Cells Irradiated with Low Energy Protons

Cited by 133 publications

References 10 publications

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver

Comparison of radiobiological effective depths in 65-MeV modulated proton beams

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

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