General patterns of synergistic and antagonistic interactions in radiobiology

«Radiation and Risk», 2023, vol. 32, No. 2, pp.132-141

DOI: 10.21870/0131-3878-2023-32-2-132-141

Authors

Evstratova E.S.– Head of Lab., C. Sc., Biol. NMRRC. Contacts: 4 Korolyev str., Obninsk, Kaluga region, Russia, 249035. Tel.: 89108627240, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Geras’kin S.A. – Head of Lab., D. Sc., Biol., Prof. RIRAE.
Zhurakovskaya G.P. – Lead. Researcher, D. Sc., Biol.
Tolkaeva M.S. – Engineer (Ecologist)
Petin V.G. – Main Researcher, D. Sc., Biol., Prof. A. Tsyb MRRC.
¹ NMRRC, Obninsk
² Russian Institute of Radiology and Agroecology, Obninsk
³ A. Tsyb MRRC, Obninsk

Abstract

Currently multimodal therapy is widely used for treatment of chronic diseases including cancer. The joint use of ionizing or on-ionizing radiation with hyperthermia or chemotherapeutic agents increases the effectiveness of the treatment. A response of living things to combination treatment may be synergistic, additive or antagonistic. The study is aimed to examine the common regularities of synergistic and antagonistic effects development following exposure of biological objects to various factors. The article presents analysis of experimental data received by the authors of the paper and the data published by other teams. It has been found that therapeutic effects of the same factors do not de-pend on the objects under study, it depends on the agents parameters: a dose rate, intensity, degree of heating (temperature), concentration of chemotherapeutic agents, etc. The common regularities of synergistic interactions are: 1) synergistic effect is maximum, if the agents act simultaneously, it depends on the ratio of injuries induced by each agent; 2) the optimal correlation between influencing factors provides the maximum synergistic effect; 3) in order to maintain maximum synergistic or antagonistic effects interaction, it is necessary to reduce or to increase the intensity of one of the agents and proportionally to increase or to reduce the intensity of the second agent. The combined effects of hyperthermia and glycerol on bacterial cells are considered as an example of the antagonistic effect. Exposure to different concentrations of sodium chloride, NaCl, in combination with ionizing radiation, or ultrasound, or hyperthermia forms a stable antagonistic effect. Both glycerol and NaCl are osmotic substances and their negative effects can be attenuated by means that stabilize the osmotic homeostasis system. Yeast cells shown the synergistic interaction of ultraviolet light and hyperthermia then it began smoothly passed into antagonistic interaction as the temperature load decreased and the parameters of the influencing factors deviated from the optimal. At the same time, the antagonistic effects are also characterized by the optimal ratio of doses of the agents used, at which the observed effect has the maximum value. The conclusion is made about the commonality of the main regularities of the manifestation of the effects of synergy and antagonism at the interaction of factors of different nature regardless of the biological object, which is subjected to combined influence.

Key words
antagonism, synergism, general patterns, hyperthermia, ionizing radiation, ultrasound, UV light, osmolytes, cisplatin, bacteria, yeast, mammalian cells.

References

1. Terapevticheskaya radiologiya: natsional'noe rukovodstvo [Therapeutic radiology: a national guide]. Eds.: A.D. Kaprin, Yu.S. Mardynsky. Moscow, GEOTAR-Media, 2019. 704 p.

2. Basic clinical radiobiology. Eds: M. Joiner, A. van der Kogel. London, CRC Press, 2009. 375 p.

3. Chou T.-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, vol. 70, no. 2, pp. 440-446.

4. Chemoradiation in cancer therapy. Ed.: H. Choy. Totowa, NJ, USA, Humana Press, 2003. 420 p.

5. Hahn G.M. Hyperthermia and cancer. New-York, Plenum Press, 1982. 285 p.

6. Hall E.J., Giaccia A.J. Radiobiology for the radiologist. Philadelphia, Wolters Kluwer, 2018. 576 p.

7. Streffer C., Vauper P., Hahn G. Biological basis of oncologic thermotherapy. Berlin, Heidelberg, New York, London, Paris, Tokyo, Hong Kong, Springer-Verlag, 1990. 169 p.

8. Petin V.G., Zhurakovskaya G.P., Komarova L.N. Radiobiologicheskie osnovy sinergicheskogo vzaimodejst-viya v biosfere [Radiobiological bases of synergistic interaction in the biosphere]. Moscow, GEOS, 2012. 219 p.

9. Petin V.G., Kim J.K. Synergistic interaction and cell responses to environmental factors. New York, Nova Sciences Publisher, 2016. 337 p.

10. Evstratova E.S., Petin V.G., Zhurakovskaya G.P. Synergistic effects and their potential significance for the influence of natural intensities of environmental factors on cell growth. Synergy, 2018, vol. 6, no. 1, pp. 1-8.

11. Mitchel R.E.J., Morrison D.P. Heat-shock induction of ultraviolet light resistance in Saccharomyces cere-visiae. Radiat. Res., 1983, vol. 96, no. 1, pp. 95-99.

12. Barbe M.F., Tytell M., Gower D.J., Welch WJ. Hyperthermia protects against light damage in the rat retina. Science, 1988, vol. 241, no. 4874, pp. 1817-1820.

13. Petin V.G., Zhurakovskaya G.P., Komarova L.N. Fluence rate as a determinant of synergistic interaction of simultaneous action of UV-light and mild heat in Saccharomyces cerevisiae. J. Photochem. Photobiol. B: Biol., 1997, vol. 38, no. 2-3, pp. 123-128.

14. Calkins J., Ballard R., Gillespie M. Ultraviolet light-induced reactivation of alpha-irradiated yeast cells. Radiat. Res., 1978, vol. 73, no. 3, pp. 440-451.

15. Petin V.G. Geneticheskij kontrol' modifikatsii radiochuvstvitel'nosti kletok [Synergetics of environmental fac-tors]. Moscow, Energoatomizdat, 1987. 208 p.

16. Petin V.G., Morozov I.I. Sinergetika faktorov okruzhayushchej sredy [Influence of the intensity of acting agents on the manifestation of synergistic interaction]. Moscow, GEOS, 2015. 249 p.

17. Petin V.G., Zhurakovskaya G.P. Influence of the intensity of acting agents on the manifestation of synergistic interaction. Radiatsionnaya Biologiya. Radioekologiya – Radiation Biology. Radioecology, 2015, vol. 55, no. 6, pp. 598-606. (In Russian).

18. Petin V.G., Belkina S.V., Zhurakovskaya G.P. Matematicheskie modeli i reaktsii kletok na obluchenie ioniziruyushchimi izlucheniyami raznogo kachestva [Mathematical models and cell responses to exposure to ionizing radiation of different quality]. Moscow, GEOS, 2020. 263 p.

19. Petin V.G., Zhurakovskaya G.P. The peculiarities of the interaction of radiation and hyperthermia in Saccha-romyces cerevisiae irradiated with various dose rates. Yeast, 1995, vol. 11, no. 6, pp. 549-554.

20. Ben-Hur E. Mechanisms of the synergistic interaction between hyperthermia and radiation in cultured mam-malian cells. J. Radiat. Res., 1976, vol. 17, no. 2, pp. 92-98.

21. Ben-Hur E., Elkind M.M. DNA damage and repair in hyperthermic mammalian cells: relation to enhanced cell killing. In: Radiation Research: Biomedical, Chemical and Physical Perspectives. New York, Academ Press, 1975, pp. 703-717.

22. Urano M., Kahn J., Majima H., Gerweck L.E. The cytotoxic effect of cis-diamminedichloro-platinum (II) on cultured Chinese hamster ovary cells at elevated temperatures: arrhenius plot analysis. Int. J. Hyperthermia, 1990, vol. 6, no. 3, pp. 581-590.

23. Panin L.E. Systemic ideas about homeostasis. Byulleten' SO RAMN – Bulletin SD RAMS, 2007, vol. 127, no. 5, pp. 10-16. (In Russian).

Full-text article (in Russian)