Enhancement in cell killing by proton beams in the presence of boron (natural mixture natB: 80% 11B, 20% 10B) was reported, selectively in the Bragg peak region, putatively due to the proton-11B capture reaction. However, as some groups observed no such enhancement or assigned it to secondary neutron-10B capture, proton-boron capture therapy (PBCT) remains controversial. We previously validated this concept for U-87 MG glioblastoma cells. To test its generality and potential applicability for these tumours, we assessed PBCT using three further cell lines widely used in glioblastoma research. In U251 cells, natB enhanced cell killing by protons in Bragg peak but also in plateau regions, effects of 10B were even higher, and were found also for 18MV but not 6 MV photon beams (above and below photo-neutron production thresholds, respectively), suggesting a key role of secondary neutrons. For A172 and T98G cells, no enhancement was found at all. This variability among cell lines may stem from differences in boron uptake and/or in intercellular signalling likely needed to amplify the initial events in a few hit cells to population-level effects. Together with recent negative studies, the results suggest that potential clinical applications of PBCT are less promising than originally thought.

Bulovka University Hospital Budínova 67 2 Praha 180 81 Czech Republic

Czech Metrology Institute Okružní 31 Brno 638 00 Czech Republic

Nuclear Physics Institute of the Czech Academy of Sciences Husinec Řež 130 Řež 250 68 Czech Republic

Proton Therapy Center Czech Budínova 2437 1a Prague Prague 180 00 Czech Republic

Zobrazit více v PubMed

Delaney, G., Jacob, S., Featherstone, C. & Barton, M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. PubMed

Mohan, R. A review of proton therapy – Current status and future directions. PubMed PMC

Chen, Z., Dominello, M. M., Joiner, M. C. & Burmeister, J. W. Proton versus photon radiation therapy: A clinical review. PubMed PMC

Newhauser, W. D. & Zhang, R. The physics of proton therapy. PubMed PMC

Yoon, D. K., Jung, J. Y. & Suh, T. S. Application of proton boron fusion reaction to radiation therapy: a Monte Carlo simulation study.

Cirrone, G. A. P. et al. First experimental proof of proton boron capture therapy (PBCT) to enhance protontherapy effectiveness. PubMed PMC

Barth, R. F., Zhang, Z. & Liu, T. A realistic appraisal of boron neutron capture therapy as a cancer treatment modality. PubMed PMC

Hideghéty, K. et al. 11Boron delivery agents for boron proton-capture enhanced proton therapy. PubMed

Tinganelli, W. & Durante, M. Carbon ion radiobiology. PubMed PMC

Manandhar, M. et al. Effect of boron compounds on the biological effectiveness of proton therapy. PubMed

Hosobuchi, M. et al. Experimental verification of efficacy of PBCT in terms of physical and biological aspects.

Shtam, T. et al. Experimental validation of proton boron capture therapy for glioma cells. PubMed PMC

Mazzone, A., Finocchiaro, P., Lo Meo, S. & Colonna, N. On the (un)effectiveness of proton boron capture in proton therapy.

Tabbakh, F. & Hosmane, N. S. Enhancement of radiation effectiveness in proton therapy: comparison between fusion and fission methods and further approaches. PubMed PMC

Meyer, H. J., Titt, U. & Mohan, R. Technical note: Monte Carlo study of the mechanism of proton-boron fusion therapy. PubMed PMC

Safavi-Naeini, M. et al. Opportunistic dose amplification for proton and carbon ion therapy via capture of internally generated thermal neutrons. PubMed PMC

Jacobsen, V. L., Johansen, J. G., Fynbo, H. O. U. & Bassler, N. A Monte Carlo study of high-LET particle production in proton boron therapy.

Jelínek Michaelidesová, A. et al. First independent validation of the proton-boron capture therapy concept. PubMed PMC

Bláha, P. et al. The proton-boron reaction increases the radiobiological effectiveness of clinical low- and high-energy proton beams: novel experimental evidence and perspectives. PubMed PMC

Ricciardi, V. et al. A new low-energy proton irradiation facility to unveil the mechanistic basis of the proton-boron capture therapy approach.

International Atomic Energy Agency. Handbook on Photonuclear Data for Applications Cross-sections and Spectra, IAEA-TECDOC-11m78, IAEA, Vienna. ; (2000). https://www-pub.iaea.org/MTCD/publications/PDF/te_1178_prn.pdf

Braselmann, H., Michna, A., Heß, J. & Unger, K. CFAssay: statistical analysis of the colony formation assay. PubMed PMC

Werner, C. J. MCNP

Králík, M. et al. Spectral fluence of neutrons generated by radiotherapeutic Linacs. PubMed

Werner, C. J. et al. MCNP Version 6.2 Release Notes. Los Alamos National Laboratory LA-UR-18-20808 (2018).

Chadwick, M. B. et al. ENDF/B-VII.0: next generation evaluated nuclear data library for nuclear science and technology.

Conlin, J. L., Haeck, W., Neudecker, D., Parsons, D. K. & White, M. C. Release of ENDF/B-VIII.0-Based ACE data files. Los Alamos National Laboratory LA-UR-18-24034 (2018).

Trellue, H., Little, R., Lee, M. B. & New, A. C. E. F. Neutron and Proton Libraries Based on ENDF/B-VII.0. Los Alamos National Laboratory LA-UR-08-1999 (2008).

Paganetti, H. Relating proton treatments to photon treatments via the relative biological effectiveness – should we revise current clinical practice? PubMed

Stave, S. et al. Understanding the B11(p,α)αα reaction at the 0.675 Mev resonance.

ICRU Report 49. Stopping Powers and Ranges for Protons and Alpha Particles. International Commission on Radiation Units and Measurements (Bethesda, 1993).

Kundrát, P. A semi-analytical radiobiological model may assist treatment planning in light ion radiotherapy. PubMed

Hatton, I. A. et al. The human cell count and size distribution. PubMed PMC

International Atomic Energy Agency & Vienna Advances in Boron Neutron Capture Therapy. Non-serial Publications (IAEA, 2023). https://www-pub.iaea.org/MTCD/publications/PDF/CRCP-BOR-002_web.pdfaccessed 05-06-2024.

Database, Experimental Nuclear Reaction Data (EXFOR) Database. https://www-nds.iaea.org/exfor/, accessed 02-05-2024.

Otuka, N. et al. Towards a more complete and accurate experimental nuclear reaction data library (EXFOR): international collaboration between nuclear reaction data centres (NRDC).

Sato, T., Masunaga, S. I., Kumada, H. & Hamada, N. Microdosimetric modeling of biological effectiveness for boron neutron capture therapy considering intra- and intercellular heterogeneity in 10B distribution. PubMed PMC

ICRU Report 49 and 73, Stopping of Ions Heavier than Helium. International Commission on Radiation Units and Measurements & Bethesda Maryland, USA ; Errata and Addenda (2009), (2005). https://www.icru.org/wp-content/uploads/2020/12/Errata_and_Addenda_73.pdf

Cammarata, F. P. et al. Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model. PubMed PMC

Jung, J. Y. et al. Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a Monte Carlo study. PubMed PMC

Jamborová, Z. et al. Radiation damage to DNA plasmids in the presence of borocaptates. PubMed

Watkins, S. & Sontheimer, H. Hydrodynamic cellular volume changes enable glioma cell invasion. PubMed PMC

Friedland, W., Schmitt, E., Kundrát, P., Baiocco, G. & Ottolenghi, A. Track-structure simulations of energy deposition patterns to mitochondria and damage to their DNA. PubMed

Prise, K. M. & O’Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. PubMed PMC

Nagasawa, H. & Little, J. B. Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect. PubMed

Zhou, H. et al. Induction of a bystander mutagenic effect of alpha particles in mammalian cells. PubMed PMC

Kundrát, P. et al. Boron-enhanced biological effectiveness of proton irradiation: strategy to assess the underpinning mechanism. PubMed

Ferrell, J. E. & Xiong, W. Bistability in cell signalling: how to make continuous processes discontinuous, and reversible processes irreversible. PubMed

Bauer, G. Low dose radiation and intercellular induction of apoptosis: potential implications for the control of oncogenesis. PubMed

Kundrát, P., Bauer, G., Jacob, P. & Friedland, W. Mechanistic modelling suggests that the size of preneoplastic lesions is limited by intercellular induction of apoptosis in oncogenically transformed cells. PubMed PMC

Kundrát, P. & Friedland, W. Enhanced release of primary signals may render intercellular signalling ineffective due to Spatial aspects. PubMed PMC

Ryan, L. A., Smith, R. W., Seymour, C. B. & Mothersill, C. E. Dilution of irradiated cell conditioned medium and the bystander effect. PubMed

Kundrát, P. & Friedland, W. Non-linear response of cells to signals leads to revised characteristics of bystander effects inferred from their modelling. PubMed

Friedland, W., Kundrát, P. & Jacob, P. Track structure calculations on hypothetical subcellular targets for the release of cell-killing signals in bystander experiments with medium transfer. PubMed

Kundrát, P. & Friedland, W. Track structure calculations on intracellular targets responsible for signal release in bystander experiments with transfer of irradiated cell-conditioned medium. PubMed

Kundrát, P. & Friedland, W. Mechanistic modelling of radiation-induced bystander effects. PubMed

Hannafon, B. N. & Ding, W. Q. Intercellular communication by exosome-derived microRNAs in cancer. PubMed PMC

Jella, K. K. et al. Exosomes, their biogenesis and role in inter-cellular communication, tumor microenvironment and cancer immunotherapy. PubMed PMC

Dai, X. et al. AHIF promotes glioblastoma progression and radioresistance via exosomes. PubMed

Mothersill, C., Saroya, R., Smith, R. W., Singh, H. & Seymour, C. B. Serum serotonin levels determine the magnitude and type of bystander effects in medium transfer experiments. PubMed

Mothersill, C. et al. A laboratory inter-comparison of the importance of serum serotonin levels in the measurement of a range of radiation-induced bystander effects: overview of study and results presentation. PubMed

Chapman, K. L., Al-Mayah, A. H., Bowler, D. A., Irons, S. L. & Kadhim, M. A. No influence of serotonin levels in foetal bovine sera on radiation-induced bystander effects and genomic instability. PubMed