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RADIOBIOLOG Y

Explore the theoretical basis of radiation therapy and its effects on tumor and healthy tissues. Develop new therapeutic strategies such as hyperfractionation, hadron therapy, and radiosensitizers. Elaborate individual therapeutic protocols based on tumor biology.

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RADIOBIOLOG Y

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  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 • 1895 - Röentgen – discovery of X rays • 1896 - Becquerel – discovery of natural radioactivity • 1899 - 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 • 1986 - Charnobyl

  5. RADIOBIOLOGY -EXPERIMENTAL SCIENCE

  6. 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%

  7. 0 Gy 2 Gy Puck & Markus J Exp Med 1956; 103: 653-66 ••• ••• ••• • •• •• •

  8. 4R of fractionated radiotherapy(DOGMA 2) Regaud & Ferroux Compt Ren Soc Biol 1927; 97:431

  9. 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

  10. 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

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

  12. 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)

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

  14. 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)

  15. REOXYGENATION Oxygenated cells Reoxygenation Hypoxic cells Hypoxic fraction Czas etc.

  16. REDISTRIBUTION Sinclair WK Radiat Res 1968, 33: 620-643

  17. CELL CYCLE DEPENDENTEFFECTS 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;

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

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

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

  21. 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

  22. 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)

  23. NEW RADIOBIOLOGICAL ASPECTS hypersensitivity to low doses of radiation (< 0.2 - 0.5 Gy) 100 80 60 Increased radio resistance SF Hyper sensitivity 0 1 2 D (Gy) Joiner et al., 2001

  24. 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

  25. DZIĘKUJĘ ZA UWAGĘ

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