1. RADIOBIOLOGY
Agnieszka Żyromska

2. Role of radiobiology
Elaborate theoretical basis of RTH: identify mechanims of tumour and healthy tissues response to irradiation.
Develop new therapeutic strategies (hiperfractionation, hadron therapy, radiosensitizers).
Elaborate individual therapeutic protocols depending on tumour biology

3. Radiobiology – science on ionizing radiation influence on living organisms
Röentgen – discovery of X rays
Becquerel – discovery of natural radioactivity
first patient cured with X rays from the cancer of the nose skin

4. 1850 – Harting, first publication on cancer
epidemiology – lung lymphosarcoma in silver
mine workers
1896 – description of X rays effects in humans:
erythema, epilation, eyes irritation
1930 – discovery of the genetic risk of radiotherapy
1945 – Hiroshima & Nagasaki
Charnobyl

5. RADIOBIOLOGY - EXPERIMENTAL SCIENCE

7. DOGMA 1
“ The object of treating tumour by radiotherapy is to damage every single potentially malignant cell to such an extent that it cannot continue to proliferate.”
Munro & Gilbert BJR 1961; 34:246
P = e - m
P = e - 1
P = 37%

8. 0 Gy 2 Gy Puck & Markus J Exp Med 1956; 103: 653-66 • • • • • • • •
• • •
• • •
• • • •
• • •

9. 4R of fractionated radiotherapy (DOGMA 2)
Regaud & Ferroux
Compt Ren Soc Biol 1927; 97:431

10. 4R of fractionated radiotherapy (DOGMA 2)
Repair of sublethal damages (α/β, µ)
Repopulation (Tpot)
Redistribution
Reoxygenation (pO2)
Withers HR, 1975
+ Radiosensitivity (SF2)
Steel G, 1989
Geneticly conditioned

11. Irradiation effects depend on DNA damage (biological target).
DOGMA 3
Irradiation effects depend on DNA damage (biological target).
Erikson RL, 1963
Warters RL et al., 1977
Cole A, 1980
DSB (!), claster damage
SSB, BD, DNA-P X-links

12. REPAIR (1) – „α/β” – repair capacity
different repair capacity of early
and late reacting tissues
tk. późno
reagujące
tk. wcześnie
reagujące

13. REPOPULATION Beginning not precisely determined
* Withers et al.: 4th week of RTH for planoepithelial
carcinomas of head and neck
* Bentzen et al., Fowler et al.: 2nd-3rd week of
RTH
= loss of daily dose of radiation (Gy/day), which lethal effect is balanced by accelerated proliferation of clonogenic cells (about 1 Gy/day for OTT > 6 weeks)

14. REOXYGENTION
! Oxygen increases cell radiosensitivity (X rays) - about 3X !
! Tumour hypoxia is an important problem in RTH
Influences treatment efficacy
Independent unfavourable prognostic factor: breast ca, cervix ca, H&N ca, soft tissue sarcomas

15. REOXYGENATION
Important mechanism increasing the efficacy of RTH and enabling the cure in case of hypoxic tumours
Scant data on carcinomas in humans (intensity, time scale)

16. REOXYGENATION etc. Hypoxic fraction Czas Oxygenated cells

17. REDISTRIBUTION
Sinclair WK
Radiat Res 1968, 33:

18. CELL CYCLE DEPENDENT EFFECTS
FRTH, HDR BTH – sterilization of cells being in most radiosensitive cycle phases (G2/M); arrest of surviving cells in cycle phases, in which they were exposed to radiation; redistribution;

19. RADIATION EFFECTS – CLASSIC MODEL
DNA damage
DSB
Nieprawidłowa naprawa
Repair
Incorrect repair
No repair
Mutations
Carcinogenesis
Cell survival
Cell death

20. NON – (DNA) TARGETED EFFECTS
Adaptive response
Inverse dose-rate effect
Bystander effect
4. Genomic instability
5. Hyperradionsensitivity – HRS

21. NEW RADIOBIOLOGICAL ASPECTS
Bystander effect (< 1 Gy)
Cytokines, Ca+2, RNS, ROS
Reactive nitrogen species
Nagasawa &Little, 1992
Mothersill & Seymour, 1997

22. BYSTANDER EFFECT - DETECTION
Microbeams (protons, α particles)
Introduction of non-irradiated cells into irradiated cell cultures
Exposition of cell cultures to the serum of irradiated animals/humans
partial blocks of irradiated tissues

23. BYSTANDER EFFECT
in vitro (different cell lines, incl. glioblastoma) and in vivo evidence
importance: protective mechanism - removes potentially damaged functional group of cells in order to decrease the risk of post-radiation carcionogenesis (Belyakov i wsp. 2002)

24. NEW RADIOBIOLOGICAL ASPECTS
hypersensitivity to low doses of radiation (< Gy)
100 80 60
Increased
radio
resistance SF
Hyper
sensitivity
D (Gy)
Joiner et al., 2001

25. HRS
Proven for 26 cell lines (glioblastoma, melanoma, prostate ca, colon ca, cervix ca, lung adenoca)
in vivo evidence
Probably decreases the risk of carcinogenesis <– eliminates demaged cells

26. DZIĘKUJĘ ZA UWAGĘ