CYTOPATHIC EFFECTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY ON HUMAN GLIOBLASTOMA CELLS
V. A. Byvaltsev,
E. L. Zavjalov,
V. V. Kanygin,
A. I. Kasatova,
A. I. Kichigin,
I. A. Razumov,
T. V. Sycheva,
S. Yu. Taskaev https://doi.org/10.21294/1814-4861-2019-18-4-34-42
Abstract
Boron neutron capture therapy (BNCT) is a targeted therapy based on a selective damage to cancer cells due to the interaction between boron-10 isotope and neutron. Reactor-based BNCT has been found to be effective in the treatment of high-grade gliomas. It is believed that compact accelerator-based neutron sources will ensure widespread adoption of the technique in clinical practice. New accelerator-based neutron sources are being actively developed all over the world. At the Institute of Nuclear Physics (Russia), the accelerator-based neutron source was developed for pre-clinical studies of BNCT.
Purpose: to determine the cytopathic effects of accelerator-based BNCT on the human U87-glioblastoma cell line and to select a concentration of boron drugs that do not have a toxic effect on the cells before irradiation in vitro.
Material and Methods. To assess the cytopathic effects (MTT test and colony-forming assay) of various concentrations of boron-containing drugs, U87 cells were incubated with boronophenylalanine (BPA) and sodium borocaptate (BSH) for 1, 2 and 10 days. The effect of BNCT on the U87 cell line was determined using colony-forming assay.
Results. The MTT test showed a decrease in cell survival at a boron-10 isotope concentration of 160 μg/ml after 48 hours and 640 μg/ml after 24 hours of incubation for BPA. The cytopathic effects for sodium BSH appeared at a boron concentration of 80 µg / ml after 48 hours of incubation, and survival fraction of cells was reduced to 89 % compared to the control. According to the colonyforming assay, the cytotoxic effects of BSH and BPA at a boron concentration of 40 µg/ml in the medium were 79.6 and 84 %, respectively. The proportions of surviving cells were 18 ± 2 % and 13 ± 2 % after epithermal neutron irradiation in the presence of boronophenylalanine and in the presence of sodium borocaptate, respectively. Cell death without boron drugs occurred due to the neutron elastic scattering, nuclear reactions of thermal neutron capture by hydrogen and nitrogen, and accompanying gamma radiation.
Conclusion. The study clearly showed a decrease in the proportion of surviving U87 cells after accelerator-based BNCT in the presence of 10B-enriched BSH and BPA.
Keywords
U87 glioblastoma cell line,
BNCT,
accelerator based epithermal neutron source,
boron drugs,
MTT test,
colony formation assay,
brain tumors,
cell death,
radiation therapy
Supporting agencies: The study was supported by Russian Foundation for Basic Research grant (No. 18-29-01007).
About the Authors
V. A. Byvaltsev
Irkutsk State Medical University;
Railway Clinical Hospital;
Center of Surgery and Traumatology
Russian Federation
Russian Federation
MD, DSc, Head Neurosurgery Department, 8, 3 Iyulya Street, 664022-Irkutsk;
Head of Neurosurgery Center of Road Clinical Hospital, 10, Botkina Street, 664005-Irkutsk;
Head of Neurosurgery Department, 1, Bortsov Revolutsii Street, 664003-Irkutsk;
Professor of the Department of Traumatology, Orthopedics and Neurosurgery of Irkutsk State Medical Academy of Postgraduate Education
E. L. Zavjalov
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences;
Novosibirsk State University
Russian Federation
Russian Federation
PhD, Head of Center for Collective Usage «SPF»- vivarium, 10, Lavrentiev Avenue, 630090-Novosibirsk;
Senior Researcher, Laboratory of Medical and Biological Problems of Boron Neutron Capture Therapy, 2, Pirogov St., 630090-Novosibirsk
V. V. Kanygin
Novosibirsk State University
Russian Federation
Russian Federation
PhD, Head of Laboratory of Medical and Biological Problems of Boron Neutron Capture Therapy,
2, Pirogov St., 630090-Novosibirsk
A. I. Kasatova
Irkutsk State Medical University;
Novosibirsk State University
Russian Federation
Russian Federation
MD, Postgraduate, Neurosurgery Department, 8, 3 Iyulya Street, 664022-Irkutsk;
Junior Researcher, Laboratory of Medical and Biological Problems of Boron Neutron Capture Therapy, 2, Pirogov St., 630090-Novosibirsk
A. I. Kichigin
Irkutsk State Medical University;
Novosibirsk State University
Russian Federation
Russian Federation
Postgraduate, Neurosurgery Department, 8, 3 Iyulya Street, 664022-Irkutsk;
Junior Research Associate, Laboratory of Medical and Biological Problems of Boron Neutron Capture Therapy, 2, Pirogov St., 630090-Novosibirsk
I. A. Razumov
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences;
Novosibirsk State University
Russian Federation
Russian Federation
DSc, Senior Research Associate, Laboratory of Molecular Mechanisms of Pathological Processes, 10, Lavrentiev Avenue, 630090-Novosibirsk;
Senior Research Associate, Laboratory of Medical and Biological Problems of Boron Neutron Capture Therapy, 2, Pirogov St., 630090-Novosibirsk
T. V. Sycheva
Novosibirsk State University;
Budker Institute of Nuclear Physics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Experimental Engineer, Laboratory Boron Neutron Capture Therapy, Budker Institute of Nuclear Physics SB RAS,
2, Pirogov St., 630090-Novosibirsk;
10, Lavrentiev Ave., 630090-Novosibirsk
S. Yu. Taskaev
Novosibirsk State University;
Budker Institute of Nuclear Physics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
DSc, Leading Research Associate, Laboratory Boron Neutron Capture Therapy, Budker Institute of Nuclear Physics SB RAS,
2, Pirogov St., 630090-Novosibirsk;
10, Lavrentiev Ave., 630090-Novosibirsk
References
1. Sauerwein W., Wittig A., Moss R., Nakagawa Y. Neutron Capture Therapy: Principles and Applications. Springer, 2012. 533.
2. Barth R.F., Zhang Z., Liu T. A realistic appraisal of boron neutron capture therapy as a cancer treatment modality. Cancer Commun (Lond). 2018 Jun 19; 38(1): 36. doi: 10.1186/s40880-018-0280-5.
3. Sun T., Zhang Z., Li B., Chen G., Xie X., Wei Y., Wu J., Zhou Y., Du Z. Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro. Radiat Oncol. 2013 Aug 6; 8(1): 195. doi: 10.1186/1748-717X-8-195.
4. Kubota R., Yamada S., Ishiwata K., Tada M., Ido T., Kubota K. Cellular accumulation of 18F-labelled boronophenylalanine depending on DNA synthesis and melanin incorporation: a double-tracer microautoradiographic study of B16 melanomas in vivo. Br J Cancer. 1993 Apr; 67(4): 701–705. doi: 10.1038/bjc.1993.129
5. Yang F.Y., Chen Y.W., Chou F.I., Yen S.H., Lin Y.L., Wong T.T. Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood-brain barrier disruption induced by focused ultrasound. Future Oncol. 2012; 8(10): 1361–1369. doi: 10.2217/fon.12.118.
6. Barth R.F., Yang W., Rotaru J.H., Moeschberger M.L., Boesel C.P., Soloway A.H., Joel D.D., Nawrocky M.M., Ono K., Goodman J.H. Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of sodium borocaptate with or without blood-brain barrier disruption. Int J Radiat Oncol Biol Phys. 1997 July; 37(3): 663–72. doi: 10.1016/S0360-3016(00)00421-1.
7. Wang P., Zhen H., Jiang X., Zhang W., Cheng X., Guo G., Mao X., Zhang X. Boron neutron capture therapy induces apoptosis of glioma cells through Bcl-2/Bax. BMC Cancer. 2010 Dec 2; 10: 661. doi: 10.1186/1471- 2407-10-661.
8. Kinashi Y., Okumura K., Kubota Y., Kitajima E., Okayasu R., Ono K., Takahashi S. Dose-rate effect was observed in T98G glioma cells following BNCT. Appl Radiat Isot. 2014 Jun; 88: 81–5. doi: 10.1016/j.apradiso.2013.11.117.
9. Таскаев С.Ю., Каныгин В.В. Бор-нейтронозахватная терапия. Новосибирск, 2016. 216. [Taskaev S.Yu., Kanygin V.V. Boron Neutron Capture Therapy. Novosibirsk, 2016. 216. (in Russian)].
10. Taskaev S.Yu. Accelerating source of epithermal neutrons. Physics of Elementary Particles and Atomic Nuclei. 2015; 46(16): 1770–1830. (in Russian).
11. Byvaltsev V., Kanygin V., Belykh E., Taskaev S. Prospects in Boron Neutron Capture Therapy of Brain Tumors. World Neurosurg. 2012 Jul; 78(1–2): 8–9. doi: 10.1016/j.wneu.2012.05.026.
12. Volkova O.Yu., Mechetina L.V., Taranin A.V., Zaboronok A.A., Nakai K., Lezhnin S.I., Frolov S.A., Kasatov D.A., Makarov A.N., Sorokin I.N., Sycheva T.V., Shchudlo I.M., Taskaev S.Yu. Impact of neutron radiation on the viability of tumor cells cultured in the presence of boron-10 isotope. Journal of radiology and nuclear medicine. 2016; 97(5): 283–8. (in Russian). doi: 10.20862/0042-4676-2016-97-5-283-288.
13. Sato E., Zaboronok A., Yamamoto T., Nakai K., Taskaev S., Volkova O., Mechetina L., Taranin A., Kanygin V., Isobe T., Mathis B.J., Matsumura A. Radiobiological response of U251MG, CHO-K1 and V79 cell lines to accelerator-based boron neutron capture therapy. J Radiat Res. 2018; 59(2): 101–107. doi: 10.1093/jrr/rrx071.
14. Mostovich L.A., Gubanova N.V., Kutsenko O.S., Aleinik V.I., Kuznetsov A.S., Makarov A.N., Soroki, I.N., Taskaev S.Yu., Nepomnyashchikh G.I., Grigor’eva E.V. Effect of Epithermal Neutrons on Viability of Glioblastoma Tumor Cells in Vitro. Bulletin of Experimental Biology & Medicine. 2011; 151(2): 264–267. doi: 10.1007/s10517-011-1304-1.
15. Rossini A.E., Dagrosa M.A., Portu A., Saint Martin G., Thorp S., Casal M., Navarro A., Juvenal G.J., Pisarev M.A. Assessment of biological effectiveness of boron neutron capture therapy in primary and metastatic melanoma cell lines. Int J Radiat Biol. 2015; 91(1): 81–9. doi: 10.3109/09553002.2014.942013.
16. Yamamoto T., Nakai K., Tsurubuchi T., Matsuda M., Shirakawa M., Zaboronok A., Endo K., Matsumura A. Boron neutron capture therapy for newly diagnosed glioblastoma: a pilot study in Tsukuba. Appl Radiat Isot. 2009 Jul; 67(7–8 Suppl): S25–6. doi: 10.1016/j.apradiso.2009.03.011.
17. Seki K., Kinashi Y., Takahashi S. Influence of p53 status on the effects of boron neutron capture therapy in glioblastoma. Anticancer Res. 2015; 35(1): 169–74. doi: 10.1186/1748-717X-8-280.
18. Barth R.F., Vicente M.G., Harling O.K., Kiger W.S., Riley K.J., Binns P.J., Wagner F.M., Suzuki M., Aihara T., Kato I., Kawabata S. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat Oncol. 2012; 7: 146. doi: 10.1186/1748-717X-7-146.
19. Shchudlo I., Taskaev S., Kasatov D., Dokutovich V., Makarov A., Sorokin I., Kolesnikov Ya., Sokolova E., Kuznetsov A., Ostreinov Yu. Threefold increase of the proton beam current in the vacuum insulation tandem accelerator. 7th International Particle Accelerator Conference; 2016 May 8–13; Busan. Korea: TUPMR003; 2016. 12281229. doi: 10.1088/1748-0221/9/12/P12016.
20. Zaboronok A., Byvaltsev V., Kanygin V., Iarullina A., Kichigin A., Taranin A., Volkova O., Mechetina L., Taskaev S., Muhamadiyarov R., Zavyalov E., Nakai K., Sato E., Yamamoto T., Mathis B., Matsumura A. Boron-neutron capture therapy in Russia: preclinical evaluation of efficacy and perspectives of its application in neurooncology. New Armenian Medical Journal. 2017; 11(1): 6–15. doi: 10.18632/oncotarget.24078.
21. De Simone U., Manzo L., Ferrari C., Bakeine J., Locatelli C., Coccini T. Short and long-term exposure of CNS cell lines to BPA-f a radiosensitizer for boron neutron capture therapy: safety dose evaluation by a battery of cytotoxicity tests. Neurotoxicology. 2013; 35: 84–90. doi: 10.12691/ajn-3-2-1.
22. Doi A., Kawabata S., Iida K., Yokoyama K., Kajimoto Y., Kuroiwa T., Shirakawa T., Kirihata M., Kasaoka S., Maruyama K., Kumada H., Sakurai Y., Masunaga S., Ono K., Miyatake S. Tumor-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy. J Neurooncol. 2008 May; 87(3): 287–94. doi: 10.1007/s11060-008-9522-8.
23. Carpano M., Perona M., Rodriguez C., Nievas S., Olivera M., Santa Cruz G.A., Brandizzi D., Cabrini R., Pisarev M., Juvenal G.J., Dagrosa M.A. Experimental Studies of Boronophenylalanine ((10)BPA) Biodistribution for the Individual Application of Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma Treatment. Int J Radiat Oncol Biol Phys. 2015 Oct 1; 93(2): 344–52. doi: 10.1016/j.ijrobp.2015.05.039.
24. Coderre J.A., Makar M.S., Micca P.L., Nawrocky M.M., Liu H.B., Joel D.D., Slatkin D.N., Amols H.I. Derivations of relative biological effectiveness for the high-let radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1993 Dec 1; 27(5): 1121–9.
25. Menichetti L., Gaetano L., Zampolli A., Del Turco S., Ferrari C., Bortolussi S., Stella S., Altieri S., Salvadori P.A., Cionini L. In vitro neutron irradiation of glioma and endothelial cultured cells. Appl Radiat Isot. 2009; 67(7–8 Suppl): S336–40. doi: 10.1016/j.apradiso.2009.03.058.
Review
For citations:
Byvaltsev V.A., Zavjalov E.L., Kanygin V.V., Kasatova A.I., Kichigin A.I., Razumov I.A., Sycheva T.V., Taskaev S.Yu. CYTOPATHIC EFFECTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY ON HUMAN GLIOBLASTOMA CELLS. Siberian journal of oncology. 2019;18(4):34-42. (In Russ.) https://doi.org/10.21294/1814-4861-2019-18-4-34-42
Views:
1470
Email this article 
