Interazioni iniziali Radiaz. indirett. ionizzanti (raggi X, raggi γ)

Size: px

Start display at page:

Download "Interazioni iniziali Radiaz. indirett. ionizzanti (raggi X, raggi γ)"

Ann Montgomery
5 years ago
Views:

1 Radiobiologia delle particelle pesanti Angelica Facoetti Fondazione CNAO Corso teorico-pratico sull adroterapia: l alta tecnologia applicata alla clinica CNAO, Pavia, Maggio 2013

2 Radiobiologia studio degli effetti delle radiazioni ionizzanti sulla materia vivente Interazioni iniziali Radiaz. indirett. ionizzanti (raggi X, raggi γ) s Radiaz. dirett. ionizzanti (elettroni, protoni) s Stadio fisico-chimico s Danno chimico (radicali liberi) 10-7 s - ore Danno biomolecolare (proteine, acidi nucleici) ms - ore Effetti biologici precoci (morte cellulare) ore - settimane Effetti biologici tardivi (induzione di neoplasie, effetti genetici) anni, secoli

3 E. Fokas et al, 2009 X-ray Protons Carbon ions

4 RBE (Relative Biological Effectiveness) Schardt & Elsasser, 2010

5 BUT, RBE is a complicated radiobiological concept that depends on: Dose level Measured endpoint Particle charge and velocity Dose rate or fractionation Energy/LET of the particle Cell/tissue type Oxygen concentration Cell cycle phase Etc and it gives a greatly simplified picture of the high LET radiation effects!!!

6 RBE is greater for lower doses

7 Protons have radiobiological properties that are close to those of photons and electrons (RBE does not change very much with the depth and a significant increase appears only in the distal part of the Bragg peak) so that their main advatage relies on the superior dose distribution compared to low LET radiations Carbon ions offer an even larger efficacy for tumour treatments due to the enhanced biological effect at the end of their range in the tumor. 7

8 RBE of C ions changes along the SOBP Variation of RBE as a function of depth in the 290 MeV carbon-ion beam at HIMAC- Chiba (Japan). The RBE is given at the four depths in water that are indicated. The SOBP is 6 cm thick. IAEA-TECDOC-1560

9 RBE in vivo RBE values based on the dose for 50% complication probability for the radiation tolerance of the rat spinal cord after 1, 2, 6, and 18 fractions of carbon ions. Spread-out Bragg peak (125 kev/mm), plateau (13 kev/mm) Schardt & Elsasser, 2010

11 Aim to confirm the uniformity of biologic doses in PTV positions with in vitro and in vivo experiments to estimate biologic RBE values for in vitro and in vivo endpoints in order to evaluate whether the new carbon beam works in safe and optimal conditions for the clinic.

12 Radiother Oncol. 2004

13 Microscopic understanding of RBE

14 Belli et al.

postirradiation with 2 Gy of gamma rays or 0.

15 Low LET High LET ioni C (15 MeV/u) Formation of fluorescent γ-h2ax clusters in irradiated human fibroblasts at 10 min postirradiation with 2 Gy of gamma rays or 0.5 Gy of 176 kev/mm iron ions Modificato da: JAEA R&D, 2007; Cucinotta and Durante, 2006

Clustered DNA Damage It has been proposed that Carbon ions radiation produces multiple lesions within a few nm in DNA molecules, so-called clustered DNA damage.

16 Clustered DNA Damage It has been proposed that Carbon ions radiation produces multiple lesions within a few nm in DNA molecules, so-called clustered DNA damage. This densely localized damage might distort the tertiary structure of DNA and consequently interfere with the binding of repair enzymes to the damage site.

17 The optimal LET Diagram illustrating why radiation with a LET of 100 kev/µm has the greatest RBE for cell killing, mutagenesis, or oncogenic trasformation. Fot this LET, the average separation between ionizing events coincides with the diameter of the DNA double helix (i.e. about 2 nm). Radiation of this quality is most likely to produce a double strand break from one track for a given absorbed dose. Radiobiology for the radiologist, 7th edition

The larger size and the longer persistance of foci observed after C ions compared to γ-rays can be due to multiple and/or complex DSB which are difficult to repair 1.

18 The larger size and the longer persistance of foci observed after C ions compared to γ-rays can be due to multiple and/or complex DSB which are difficult to repair 1.7 Gy of iron ions fixed 5 h after irradiation. Comparison between H2AX phosphorylation-dephosphorylation kinetics after irradiation with 1 Gy of γ-rays (closed circles) or carbon ions (open circles). Antonelli F et al, 2005; Desai N et al, 2005

19 Chromosomal aberrations induced by Carbon ions Chromosomal damage (mfish) in first cycle cells after exposure to 0.2 Gy X-rays or 1 carbon ion per nucleus (0.2 Gy). Fraction of aberrant cells. Fournier C et al, 2012

20 1 hit C ions per nucleus Examples of karyotypes (mfish) with clonal complex aberrations occurring in the progeny of cells exposed to Carbon ions Fournier C et al, 2012

21 5 hits C ions per nucleus Fournier C et al, 2012

22 FACTORS THAT DETERMINE RBE (BASIC RADIOBIOLOGICAL PROPERTIES OF CHARGED HADRONS)

23 Cell cycle phase radiosensitivity

24 The oxygen effect The presence or absence of molecular oxygen dramatically influences the biologic effect of X-rays. Basic clinical radiobiology, Joiner & van der Kogel

25 The ratio of the dose required to kill the cells with the oxygen divided by the amount to kill cells without oxygen is referred to as the oxygen enhancement ratio (OER).

26 Oxygen-fixation hypothesis E. Hall, Radiobiology for the Radiologist

27 OER is significantly reduced for ion irradiation Hirayama E et al, 2005

28 The OER decreases with increasing LET Basic clinical radiobiology, Joiner & van der Kogel

29 CARBON IONS AND TUMOUR CELLS GENETIC BACKGROUND

30 x p53 The p53 tumor suppressor limits cellular proliferation by inducing cell cycle arrest and apoptosis in response to cellular stresses such as DNA damage About 50% of cancers harbor mutation in the TP53 gene, which result in a decreased propensity to undergo apoptosis. These tumurs are more resistant to treatment, both by X-rays or chemotherapy P53-dependent apoptotic pathway

33 Bcl-2 is an anti-apoptotic protein Bcl-2 overexpression has been associated with the resistance to conventional photons and chemotherapeutic agents

34 High LET radiations render Bcl-2 cells more vulnerable Hamada N et al, 2008

35 Taking into consideration that Bcl-2 overexpression and p53 mutations occur in more than half of tumors, high-let heavy ions appear to effectively kill a wide variety of radioresistant tumors.!

37 Human lung adenocarcinoma (A549) Human lung squamous cell carcinoma(ebc-1) Cell migratory activity Invasive activity Akino Y et al, 2009

38 Particle Irradiation Suppresses Metastatic Potential of Cancer Cells X- rays C ions LM8 osteosarcoma cells Ogata et al, 2005

39 X- rays C ions Therapeutic effects of cells irradiated with X-ray or carbon ion on experimental pulmonary metastasis from mice inoculated intravenously Ogata et al, 2005

On the other hand, sublethal X-ray irradiation promoted migration of

40 About 90% of the cells irradiated even at 0.1 Gy could be destroyed compared with unirradiated cells. On the other hand, sublethal X-ray irradiation promoted migration of endothelial cells, and the capillary- like tube structure in three dimensional culture progressed even after 16 Gy irradiation.

41 BYSTANDER EFFECTS AND HADRONTHERAPY

42 Morgan WF & Sowa MB, 2005

43 Radiation-induced bystander effect represents a paradigm shift in the understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the final biological consequences of exposure to low doses of radiation. There is evidence that cells that are not directly hit by radiation, whether nuclear or cytoplasm, but in the vicinity of one that does, contribute to the biological response of the cell population The progeny of non-targeted cells shows an increase in genomic instability as evidenced by an increase in delayed mutations and chromosomal aberrations many generations afterwards

irradiation signal substance, which induces

44 Irradiated cells communicate to neighboring non-irradiated bystander cells by transmitting an irradiation signal substance, which induces radiation effect on bystander cells as well. Iwakawa, M et al, 2008

45 The expression profile of the bystander cells was completely different from that of the irradiated cells. Iwakawa, M et al, 2008

46 CANCER STEM CELLS AND HADRONTHERAPY

47 Cancer stem cells A small subset of cancer cells within the tumor mass, which constitutes a reservoir of self-sustaining cells with exclusive ability of self-renewal and tumor maintenance (from the Cancer Stem Cell Workshop of the American Association for Cancer Research in 2006) An anticancertherapycan cure a tumouronlyifallcancerstemcellsare killed(withoutproducingseriousside effects in surrounding normal tissues) In the radiotherapy context, a cancer stemcellisa cell which, when left after irradiation to its natural environment, has the capacity to cause a tumour recurrence. BaumannM etal, 2008

48 Since cancer stem cells appear to be responsible for driving and maintaining tumor growth in many tumors, it is critical to understand the mechanisms by which these cells resist commonly used therapies such as chemotherapy and radiotherapy

49 CSC: known (???) mechanisms of radioresistance X A high frequency of CSCs are believed to be quiescent, and this would make them more resistant to cycle active agents, including radiation. Their residence in a microenvironmental niche may provide them with both direct physical X contacts (eg, cell-cell or cell- stroma) and growth factor/cytokine signaling that may provide additional survival signals in response to the stresses induced by radiation X Increased potential of defense against ROS mediated by high levels of free-radical scavengers X The capacity to recover and repair sublethal damage between irradiation fractions

50 Summary Durante M & Loeffler JS, 2010

Peak temperature ratio of TLD glow curves to investigate the spatial variation of LET in a clinical proton beam

Peak temperature ratio of TLD glow curves to investigate the spatial variation of LET in a clinical proton beam University of Chicago CDH Proton Center LET study C. Reft 1, H. Ramirez 2 and M. Pankuch