Out of target dose in radiotherapy of cancer: the radiobiology phenomena that may influence late effects in healthy tissue Massimo Pinto post-doctoral fellow January 22, 2009, CERRO 24

Massimo Pinto

post-doctoral fellow

Yet another one

What you will be hearing in this talk A brief outline of low dose radiation biology phenomena, their inter-relations , and how they could impact on both radiation therapy of cancer and radiation protection .

A brief outline of low dose radiation biology phenomena, their inter-relations , and how they could impact on both radiation therapy of cancer and radiation protection .

In other words… … based on what you will hear on the bystander effect , this may well be my last attendance at CERRO!

Key points Classical paradigm of radiation biology The events of the last 20 years Speculations over the potential impact of these “new” phenomena on clinical practice .

Classical paradigm of radiation biology

The events of the last 20 years

Speculations over the potential impact of these “new” phenomena on clinical practice .

Classical paradigm I am your target The critical target for I.R.-induced damage is the DNA You shall have no other targets before me If you miss the DNA, you have no effects. High LET (i.e.  -particles) Low LET (i.e.  -rays)

I am your target

The critical target for I.R.-induced damage is the DNA

You shall have no other targets before me

If you miss the DNA, you have no effects.

Support for the classical paradigm Po needle Munro (1970) DNA-incorporated radioisotopes deliver higher effectiveness than when incorporated in the RNA or in proteins 125 I near DNA less effective than when incorporated in the DNA Cell lines with defects in genes involved in DNA repair are more radiosensitive. Microbeam experiments (from 1995)

Po needle Munro (1970)

DNA-incorporated radioisotopes deliver higher effectiveness than when incorporated in the RNA or in proteins

125 I near DNA less effective than when incorporated in the DNA

Cell lines with defects in genes involved in DNA repair are more radiosensitive.

Microbeam experiments (from 1995)

Classical Paradigm Based on a DNA-centric perspective of IR-induced biological effects, it has indoctrinated more than one generation of radiation biologists, and has shaped both radiation protection and radiation therapy… however…

Based on a DNA-centric perspective of IR-induced biological effects, it has indoctrinated more than one generation of radiation biologists, and has shaped both radiation protection and radiation therapy… however…

… violations appeared Genomic instability (1992) Time Violation Space Violation Bystander effect (1992) time

I. Bystander effect: cells do talk to each other (1992) gap junctions -mediated signals Medium-mediated signals Influenced by both phenotype and micro-environment

I. Bystander effects - implications Target for biological effects larger than cell size Most relevant at low doses Much like abscopal effects, but at the cellular rather than organ level

Target for biological effects larger than cell size

Most relevant at low doses

Much like abscopal effects, but at the cellular rather than organ level

Radiation-induced genetic damage. Old Paradigm An IR-induced mutation is carried on to the entire progeny

Non-targeted Effects of Radiation: II. Genomic Instability IR does not induce a mutation in irradiated cells, but rather enhances the frequency with which mutations arise in the descendants of these cells Little JB, Health Physics 2006 IR can induce a type of genomic instability in cells that is transmitted to their progeny A Mutator phenotype.

IR does not induce a mutation in irradiated cells, but rather enhances the frequency with which mutations arise in the descendants of these cells

Little JB, Health Physics 2006

IR can induce a type of genomic instability in cells that is transmitted to their progeny

II. Genomic Instability Gene mutation Chromosomal aberration Cell death Mitotic failure-aneuploidy Micronuclei

Genomic Instability and 2 nd cancers? … As nearly one in 10 cancer diagnoses are second (or higher) malignancies, it is important to understand the contribution of radiotherapy to second cancer induction and pursue well-coordinated efforts to determine the role of induced genomic instability

Phenomenological Inter-relations HRS/IRR (‘91) Adaptive Response (‘84) Genomic Instability (‘92) Bystander effect (‘92)

Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect Oxidative metabolism

Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect

Bystander as Adaptive Ed Azzam Roger Howell Pinto, Azzam & Howell, Radiat Prot Dosim 2006 Howell et al, Radiat Prot Dosim 2006 Pinto & Howell, Biotechniques 2007 Pinto, Azzam & Howell, in prep .

Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect

Bystander-mediated Genomic instability ... 35 y.o. Male. Nuclear power plant accident. Total body neutron dose of 5.4 Gy, plus 8.5–13 Gy γ rays. B lood stem cell transplant from his sister ( HLA identity ). Good initial recovery. Chromosomal damage was then observed in the offspring of the donor (sister) cells, hinting at a bystander effect . Decesased 82 days after the accident due to multi-organ failure .

To control for bystander-mediated genomic instability... may have saved this radiation accident patient? In the context of radiation therapy, may reduce the risk of late effects in healthy tissue, exposed to bystander signals coming from irradiated tumor tissue.

may have saved this radiation accident patient?

In the context of radiation therapy, may reduce the risk of late effects in healthy tissue, exposed to bystander signals coming from irradiated tumor tissue.

Waiting for some convincing evidence

In vivo oncogenic bystander

Even if…how relevant? Age at first radiotherapy treatment Late Adulthood Pediatric / Young Adult not so relevant Time to develop a secondary cancer

So what remains to be done to convince you? In order to exploit these phenomena in the clinical practice, one should aim at : A complete phenomenological picture, in experimental models that mimic the tissue environment. Notably, it is not clear whether these effects are necessarily harmful or beneficial . Molecular Mechanisms . Molecular Mechanisms. And again: molecular Mechanisms

In order to exploit these phenomena in the clinical practice, one should aim at :

A complete phenomenological picture, in experimental models that mimic the tissue environment. Notably, it is not clear whether these effects are necessarily harmful or beneficial .

Molecular Mechanisms . Molecular Mechanisms. And again: molecular Mechanisms

Thank you