lecture 7 2009

8/7/2019 lecture 7 2009

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RTE 2385Radiation Biology

8/7/2019 lecture 7 2009


Interactions with radiation

Although it is impossible to determinewhether ionizations of molecules occur

through direct vs. indirect effects, asthe human body is ~75% water it istheorized that most radiation actionswith humans are indirect.

The dose to cell irradiation is alsodetermined by dose in rads.

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Radiolysis of water

With the human body being ~75%water, it follows that the irradiation of

water is involved in the majority ofinteractions involving

DNA is the most critical target ofradiation and it is the irradiation of

water that causes indirect effects If water is irradiated, the water is

ionzied and separates into other

molecular products

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Water cont’d…

When at atom of water is irradiatedthis ionizes the water and produces afree radical, this makes it chemically

unstable & highly reactive The end result of radiolysis of water is

the development of an ion pair and twofree radicals

These ions can recombine & form anormal water molecule or they can reactchemically & damage other cellmacromolecules

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Irradiation of macromolecules

Solution: a suspension of particles ormolecules in a fluid; when you mix fluidsyou get a solution

When macromolecules are irradiated in vitro, three things happen: main chainscission, crosslinking and point lesions

Definition of scission: dividing, splittingor cutting

Definition of macromolecule: a largemolecule

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Main chain scission

The breakage of the backbone of thelong-chain macromolecule

When this happens, the long, singlemolecule becomes many molecules

What would happen if this was amacromolecule that was not in

abundance?

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Crosslinking

Some molecules have small, spur-likestructures extending off the main chain

Others produce these spurs due toirradiation

Sometimes these side structuresbehave as if there was a sticky

substance on their end, they attach toanother macromolcule or to anothersegment of their macromolcule

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Point lesions

A disruption of single, chemical bonds inthe macromolecule as a result ofirradiation

This type of lesion can cause the cell tonot function correctly

At low doses of radiation, these lesions

are regarded to be the cellular radiationdamage responsible for late effectradiation damage observed at the whole-body level

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The major effect of all ofthese is:

Genetic code being incorrectlytransferred to daughter cells

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Single-hit aberrations

When chromosomes are irradiated, theinteraction can be direct or indirect

The result of either interaction is called a “hit”

These chromosomal hits are the cause ofvisible chromosome change

Such a hit would mean that numerous molecularbonds had been interfered with and that

several chains of DNA had been severed Chromosome hits represent critical DNA

damage

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Single-hit aberrations

Figure 3-9

If there is a breakage of the chromatid, thisis termed a chromatid deletion

There is low probability that ionizing radiationwill pass through sister chromatids to produceisochromatids

The radiation normally causes a chromatid

deletion in just one arm of the chromosomeresulting in a chromosome that is missingchromatid fragment and subsequently ismissing genetic material

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Multi-hit chromosomeaberrations

It is theorized that human chromosomes havemore than a single target

It is feasible for a single chromosome to

receive more than one hit These multi-hit aberrations are not that

unusual

Multi-hit aberrations are rare, they require

that the same chromosome be hit two or moretimes or that neighboring chromosomes are hitand join together

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Multi-hit aberrations

Multi-hit aberrations arerepresentative of major cell damage

The results of this aberrations is thatone or both daughter cells is missingsignificant genetic information

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Reciprocal translocations

Multi-hit aberrations

If chromosomes experience this, they

do not lose genetic material The genes become rearranged

Results in all genetic codes beingavailable but sequenced incorrectly

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At the doses received in diagnosticradiology, only single-hit types ofchromosome aberrations are seen

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Dose-response relationships

Also called dose-response curves

Graphic relationship between observedeffects (response) from radiation anddose of radiation received

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Dose-response curves differ in two ways: They are either linear or nonlinear

They are either threshold or nonthreshold

Linear means that the observed response isdirectly proportional to the dose

Nonlinear means that an observed response isnot directly proportional to the dose

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Threshold assumes that there is noradiation level reached below whichthere would be no effects observed

Nonthreshold assumes that anyradiation dose causes an effect

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Linear dose response relationships

All linear dose response relationshipsexhibit an effect regardless of thedose

Leukemia, breast cancer and geneticdamage are believed to follow the

linear dose response relationship

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Linear, quadratic dose responsecurves

At low doses, the curve is linear and at highdoses the curve becomes curvilinear

The portion where the curve increases indose shows little to no increase is called the“toe” and the “shoulder” is considered thearea of the curve in which the leveling off

occurs (demonstrating little to no increase ineffect)

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Nonlinear dose responserelationships

The sigmoid dose response curve is

applied predominantly for use in thehigh dose effects observed inradiotherapy

There is normally a threshold belowwhich no observable effects occur

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Danger of this model:

it underestimates the low dose effect ofradiation, as the linear part of the curveis somewhat leveled off or flattened

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Using high LET radiation, ionizationdistances are so close together that

there is a high probability that a directhit will take place

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Target theory

Some molecules do not have a lot of“back-up” which could cause seriousproblems if the radiation damage wereto occur on those molecules

According to target theory, for a cellto die after radiation exposure, its

target molecule must be inactivated DNA is the target molecule

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According to target theory, there willbe cell death only if the cell’s targetmolecule is inactivated

The going theory is that DNA is thecritical molecular taget

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Cell survival curves

Cellular sensitivity studies began in themiddle 1950’s with Puck and Marcus

They performed in vitro studies using HeLa

cells Cell survival curves deal with the percentage

of cells not killed by various doses ofradiation

In complex cells like those found in humans,it is thought that at least one hit to at leasttwo targets is needed to kill the cell

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Because humans have two of eachchromosome, it is believed that both ofthese chromosomes or target must bedamaged for the damage to kill the cell

The cell survival curve for humans has

a shoulder at low doses if you were tograph it

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As the amount of radiation increases,the number of cells with no targets hitwill decrease until for all practicalpurposes, all cells have at least onetarget hit.

Up until that point, the response curve

would be quadratic or flattened, fromthat point on the curve would be linear

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The shoulder of the cell survival curveshows that some damage must accruebefore there can be cell death

The accumulated damage is calledsublethal damage

The wider the shoulder the more

sublethal damage the cell can endure

lecture 7 2009

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