Clinical radiobiology -

tumour/normal tissue

Oslo universitetssykehus - Radiumhospitalet Universitetet i Oslo

Why does radiation work?• The dose is given in Gy = Joule/Kg• 1 Joule = 0.24 cal

• 1 cal is the amount of energy that is needed to increase one gram of water by1°C

• 1 Gy = 0.24 cal / 1000 g = 0.00024 cal/g

• ⇒ 1Gy to 1 gram, will increase the temperature with 0.00024 °C

• The energy that is deposited in a breast by delivering 2 Gy is equvalnet to a tourch turned on for one second!

tid~ 10-12s ~103s ~ 107s ~ 109s

Interaction Production of free radicals,

DNA-damage

Secondary cancer

Repair,

cell death

Tissue damage

~ 10-3s

Micro seconds Seconds Hours Days - year year

PHYSICALC H E M I C A L B I O L O G I C A L

Phases after radiation

• Radiation has a ionization and/or excitation effect.

• The cells contain a lot of water. When the water molecule is excited free radicals will be created.

• The creation of the ions, excited molecules and free radicals is called the physical phase. This phase takes place in a fraction of a second.

The physical phase

The chemical phase• The creation of the ions, excited molecules

and free radicals will be followed by chemical changes on the molecule and the cell structure.

• This phase is called the chemical phase and takes place within seconds after the delivery of the radiation.

The biological phase• The consequences of the two previous

phases are cell death, mutations, cancer and genetic damage. This phase is called the biological phase.

• The biological phase can last from days to years, depending of the type of cells that have been irradiated

Cell survival Cell death

DNA damage

Cell response

Cell cycles arrest DNA repair

Cancer therapy: clinical response Recidiv Cure

Biological phase – response of cells and tissue

Cell death at irradiation• All the components in the cell can be damaged

by the free radicals: the proteins, the enzyms, components in the cell membrane etc.

• A large amounts of such molecules exits in the cells and damage on these molecuules will not kill the cell.

• However, damage on the DNA will be letal or give mutations (the prescription for the cell division is coded in the DNA).

• Two types of celle death:– Mitotic death– Apopotic death (programmed celle deadth)

Molecular radiobiology

Basically three types of damage can occur in the DNA-molecule:

1.Single-strand breaks2.Double-strand breaks

3.Base damage

Direct effect:

Ionization of atoms thatare apart of the DNAmolecule.

Indirect effect:

DNA damage due tofree radicals producedin water.

Direct and indirect effects of the radiation

Radiation damage on the level of the cell

Classified by using three categories:

- Lethal damage: irreversible, unreperable and will lead to cell death.

- Sublethal damage: Not lethal if the damge is repaired, but may beome lethal if it is reacts with another lethal damage.

- Potential lethal damage: The damage is lethal if it is not repaired on time.

Stem cells and differentiation• Stem cells are cells with the ability to form a

colony within some growth environments.• When a cell is well-differentiated it is highly

specialized.

Models:

Radiobiological studies have created the basis for our knowledge

Cell culture (cell lines) Spheroid

In vitro studies

Growing tumor in a animalPrimary animal tumorsHumane tumor xenografts

In vivo studies

Clinical studies

Survival curve

Local tumor controlA tumor at presentation will contain approx. 109 cells

• Assume every fraction of 2 Gy will result in a survival fraction of 0.5

• Then 30 fractions are required to reduce the number of clonogenic cells to 10

The 5 Rs of radiotherapy

• Repair• Re-assortment• Re-population• Re-oxygenation• Radiosensitivity

Repair

• The damage can be repaired in such way that the DNA is intact and the cell can divide

• The damage can be wrongly repaired and the cell can survive – mutation

• The damage can be wrongly repaired in such way that the DNA is not intact and the cell will die

• Repair plays an important role during fractionated radiotherapy

Repair

Repair

Re-assortmentThe radiosensitivity varies through the cell

cycle. M

G1

S

G2

Re-population

• The tumor volume will be dependent on the re-growth

• Can be different for different tumors

• If re-growth after radiotherapy occurs, often accelerated repopulation can be seen

Accelerated repopulation

Hypoxia

Two types of hypoxia: chronicand transient

Effect of hypoxia

Hypoxic cell are

more radiorestance

that well

oxygenated cells

Effect of hypoxia

Effect of hypoxia

Re-oxygenation

Mechanisms and time scale

Recirculation through temporarily closed vessels minutes

Reduced oxygen consumption in damaged tumor cells minutes – hours

Longer diffusion of oxygen due to cell death close to the vessels hours

Shorter distance to blood vessels due to absorption of dead cells days

Re-oxygenation will not always solve the problem with hypoxia

Re-oxygenation

•Repair of DNA damage

• Re-distribution in the cell cycle

• Re-population

• Re-oxygenation

The first 4 Rs of radiotherapy, consequences for the treatment

Radiosensitivity

A: lymphoma, myeloma, neuroblastoma

B: medullablastoma, small cell lung cancerC: breast, bladder, cervix

D: pancreas, colo-rectal, squamous lung cancerE: melanoma, sarcoma, glioblastoma, renal carcinoma

Radiosensitivity

High and low LET

High and low LET

Relative biological effect

OER and LET