NORWAY 2013
Lecture 2
The Cell Cycle
Mitosis & Beyond…
THINK:
Of how many cells are you composed?
When an organism grows bigger do you get
more cells or just bigger cells or both?
When do your cells divide the fastest?
Slowest?
Do cells ever stop dividing?
Are all cells capable of division and
replacement?
Why does a cell divide?
-As a cell absorbs nutrients and gets larger, the
volume of the cell increases faster than the
surface area.
-Therefore, the demands of the cell (the volume)
exceed the ability of the cell to bring in nutrients
and export wastes. Solution? Divide into two
smaller cells
When is cell division occurring?
GROWTH -increase number of cells
REPAIR -replace lost cells due to injury, disease
CANCER – Abnormally high rates of cell division
due to mutation
Different kinds of cells divide at different rates:
E. coli – 20 minutes
(What domain?)
Yeast cell – 2 hours (What domain? What kingdom?)
Amoeba – a few days (What domain? What kingdom?)
Human embryo cell – 15-20 minutes
Human adult cell – 8 hours to 100 days
Aging
All cells die after a certain number of divisions
(programmed cell death-”apoptosis”). At any
given time some cells are dividing and some
cells are dying.
Childhood
Adulthood
Aging
Cell division > cell death
Cell division = cell death
Cell division < cell death
Control of the Cell CycleCell proliferation
Interphase
Interphase ~ 90% of the time.
G1: Little new cell absorbs nutrients and
grows larger. Does protein synthesis, its job.
S phase: Synthesis of new DNA (DNA
replication) for daughter cells in preparation
for mitosis.
G2: Cell continues to grow, do protein
synthesis, do its job. Gets too large, needs to
divide.
Chromosomes exist in 2
different states, before and
after they replicate their
DNA. Before replication,
chromosomes have one
chromatid. After
replication, chromosomes
have 2 sister chromatids,
held together at the
centromere. Each chromatid
is one piece of DNA with its
supporting proteins.
Remember that diploid cells
have two copies of each
chromosome, one from each
parent. These pairs of
chromosomes are NOT
attached together.
Structure of a eukaryotic chromosome
• unreplicated chromosome
arm
arm
centromere
Prior to cell division:
• chromosomes (DNA) are replicated
(duplicated)
• duplicated chromosome
– attached at their centromeres
– as long as attached, known as
sister chromatids
duplicated
chromosome
sister
chromatids
daughter
chromosomes
How long is one cell cycle?
Depends. Eg. Skin cells every 24
hours. Some bacteria every 2 hours.
Some cells every 3 months. Nerve
cells, never. Cancer cells very short.
Programmed cell death: Each cell
type will only do so many cell cycles
then die. (Apoptosis)
MITOSIS
Equal distribution of the 2 sets of DNA
amongst the 2 daughter cells.
4 Stages: “PMAT”
1. Prophase
2. Metaphase
3. Anaphase
4. Telophase
How the Cell Cycle Works
Mitosis Animation
Cell Cycle
What is Mitotic Cell Division?
• Division of somatic cells (body cells)
(non reproductive cells) in
eukaryotic organisms
• A single cell divides into two
identical daughter cells
(cellular reproduction)
=> Maintains chromosome ploidy of cell
Ploidy – refers to the number of pairs of
chromosomes in cells
• haploid – one copy of each
chromosome
– designated as “n”
• diploid – two copies (= pair) of each
chromosome
– designated as “2n”
As a cell enters
mitosis from
interphase it has 2
complete sets of
chromosomes because
of replication in the S
phase.
Each set must be rearranged and
distributed into the 2
new daughter nuclei.
This is mitosis.
Prophase…
-Chromatin condenses
(coils) into chromosomes.
Sister chromatids joined
by centromere.
-Nuclear membrane
dissolves.
-Centrioles divide and
move to opposite poles
forming spindle between
them.
chromatin
nucleus
nucleolus
centrioles
condensing
chromosomes
Metaphase
-
Sister chromatids line up on metaphase plate.
-Centromeres lock on to spindle fibre
Anaphase
Centromeres divide.
-Spindle fibres contract
pulling sister chromatids
apart to poles.
-
Telophase:
-New nuclear membranes form
around new nuclei
Mitosis Movie
CYTO KINESIS – Cytoplasm splits
into 2 cells.
-Animal cells: Cleavage furrow forms from outside
in.
Plant cells: Division/cell plate forms from inside
out.
Cell now returns to interphase . The
chromosomes uncoil back into
chromatin. The whole cell cycle starts
over again…..
http://www.cells
alive.com/mitosi
s.htm
At any point
in time the
cells in a
tissue will be
at different
stages in the
cell cycle.
The Guarantee of Mitosis…
The 2 daughter cells formed are
identical to each other and
identical to the mother cell.
Why is this so important?
In Mitosis, each daughter cell is exactly the
same as the original mother cell.
Cell Differentiation
Mitosis is also an ASEXUAL
form of reproduction. These are
other examples of the uses of
mitosis to create new organisms
asexually:
Propogation of
plants by cuttings
Runners from
plants like
strawberries
Budding of Yeast
Homologous pairs of
chromosomes:
Each chromosome has a certain gene sequence
on it. Eg. Chrom #1 Has insulin, foot size, and
lactase on it.
You have a chromosome one from your mom
and one from your dad. So you have 2 genes for
each trait. One from your mom – one from your
dad.
A homologous pair is a pair with the same gene
sequence – one from mom, one from dad.
APOPTOSIS
What is it?
Why is it important?
How is it controlled?
What is its role in age-related disease?
APOPTOSIS
Programmed cell death
Orderly cellular self destruction
Process: as crucial for survival of multi-cellular
organisms as cell division
MULTIPLE FORMS???
Forms of cell death
Necrosis
"Classic"
Apoptosis
Passive
Pathological
Mitotic catastrophe
Active
Physiological or
pathological
Swelling, lysis
Condensation,
cross-linking
Passive
Pathological
Swelling, lysis
Dissipates
Phagocytosed
Dissipates
Inflammation
No inflammation
Inflammation
Externally induced Internally or
externally induced
Internally induced
APOPTOSIS
Evolutionarily conserved
•Occurs in all multicellular animals studies (plants too!)
•Stages and genes conserved from nematodes (worms)
and flies to mice and humans
STAGES OF CLASSIC APOPTOSIS
Healthy cell
DEATH SIGNAL (extrinsic or intrinsic)
Commitment to die (reversible)
EXECUTION (irreversible)
Dead cell (condensed, crosslinked)
ENGULFMENT (macrophages, neighboring cells)
DEGRADATION
STAGES OF CLASSIC APOPTOSIS
Genetically controlled: Caenorhabditis elegans
soil nematode (worm)
ces2
Healthy cell
ced9
ces1
ced3,4
Dead cell
Committed cell
BCL2
Caspases
(proteases)
C. elegans genes == mammalian genes
Cells are balanced between life and death
DAMAGE
Physiological death signals
DEATH SIGNAL
ANTIAPOPTOTIC
PROTEINS
(dozens!)
PROAPOPTOTIC
PROTEINS
(dozens!)
DEATH
APOPTOSIS: important in embryogenesis
Morphogenesis (eliminates excess cells):
Selection (eliminates non-functional cells):
APOPTOSIS: important in embryogenesis
Immunity (eliminates dangerous cells):
Self antigen
recognizing cell
Organ size (eliminates excess cells):
APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):
Apoptosis
Virgin mammary gland
Late pregnancy, lactation
- Testosterone
Apoptosis
Prostate gland
Involution
(non-pregnant, non-lactating)
APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):
Apoptosis
Resting lymphocytes
+ antigen (e.g. infection)
- antigen (e.g. recovery)
Steroid immunosuppressants: kill
lymphocytes by apoptosis
Lymphocytes poised to die by apoptosis
APOPTOSIS: important in adults
Maintains organ size and function:
Apoptosis
X
+ cell division
Cells lost by apoptosis are replaced by cell division
(remember limited replicative potential of normal cells
restricts how many times this can occur before
tissue renewal declines)
APOPTOSIS: control
Receptor pathway (physiological):
FAS ligand
Death receptors:
(FAS, TNF-R, etc)
TNF
Death
domains
Adaptor proteins
Pro-caspase 8 (inactive)
Pro-execution caspase (inactive)
MITOCHONDRIA
Caspase 8 (active)
Execution caspase (active)
Death
APOPTOSIS: control
Intrinsic pathway (damage):
Mitochondria
BAX
BAK
BOK
BCL-Xs
BAD
BID
B IK
BIM
NIP3
BNIP3
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
BCL-2
BCL-XL
BCL-W
MCL1
BFL1
DIVA
NR-13
Several
viral
proteins
Caspase (3) cleavage of cellular proteins,
nuclease activation,
etc.
Death
APOPTOSIS: control
Physiological
receptor pathway
Intrinsic
damage pathway
MITOCHONDRIAL SIGNALS
Caspase cleavage cascade
Orderly cleavage of proteins and DNA
CROSSLINKING OF CELL CORPSES; ENGULFMENT
(no inflammation)
APOPTOSIS: Role in Disease
TOO MUCH: Tissue atrophy
Neurodegeneration
Thin skin
etc
TOO LITTLE: Hyperplasia
Cancer
Athersclerosis
etc
APOPTOSIS: Role in Disease
Neurodegeneration
Neurons are post-mitotic (cannot replace themselves;
neuronal stem cell replacement is inefficient)
Neuronal death caused by loss of proper connections,
loss of proper growth factors (e.g. NGF), and/or
damage (especially oxidative damage)
Neuronal dysfunction or damage results in loss of synapses
or loss of cell bodies
(synaptosis, can be reversible; apopsosis, irreversible)
PARKINSON'S DISEASE
ALZHEIMER'S DISEASE
HUNTINGTON'S DISEASE etc.
APOPTOSIS: Role in Disease
Cancer
Apoptosis eliminates damaged cells
(damage => mutations => cancer
Tumor suppressor p53 controls senescence
and apoptosis responses to damage
Most cancer cells are defective in apoptotic response
(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins
===> CANCER
APOPTOSIS: Role in Disease
AGING
Aging --> both too much and too little apoptosis
(evidence for both)
Too much (accumulated oxidative damage?)
---> tissue degeneration
Too little (defective sensors, signals?
---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
OPTIMAL FUNCTION (HEALTH)
APOPTOSIS
AGING
APOPTOSIS
Neurodegeneration, cancer, …..
Discovery of Oxygen Effect
•
The oxygen effect was observed in 1912 by Swartz in Germany,
who noted that the skin reaction to a radium applicator
wasreduced if the applicator was pressed hard onto the skin.
•
1921 - Holthusen: Ascaris eggs were resistant to radiation in the
absence of oxygen; wrongly attributed to the absence of cell
division under these conditions.
•
1923 - Petry: correlation between radiosensitivity and the
presence of oxygen based on the study of the effects of radiation
on vegetable seeds.
•
1930s - Crabtree and Cramer: survival of tumor slices irradiated
in the presence or absence of oxygen.
•
1930s - Mottram, Gray and Read: quantitative measurement of
the oxygen effect
The nature of the oxygen effect
Survival curves for mammalian cells exposed to X-rays in the
presence (lower curve) and absence (top curve) of oxygen.
The ratio of hypoxic to aerated doses needed to achieve the
same biological effect is called oxygen enhancement ratio (OER)
Effect of dose, dose rate, cell type
•
There is some evidence that for rapidly growing cells cultured in
vitro the OER has a smaller value of about 2 at lower doses.
•
This results from the variation of OER with the phase of the cell
cycle:
Cells in G1 have a lower OER than those in S. Because G1 cells
are more radiosensitive they dominate the low-dose region of the
survival curve. For this reason the OER of an asynchronous
population is slightly smaller at low doses than at high doses.
Effect of dose
OER has a value close
to 3 at high doses but
may have a lower value
of about 2 at X-ray
doses below about 2 Gy
The OER for various types of radiation
The OER for alpha particles is unity. X-rays exhibit a larger OER
of 2.5. Neutrons are between these extremes, with an OER of 1.6.
Cell-survival curves for Chinese hamster cells at
various stages of the cell cycle
From Sinclair W.K., Radiat Res. 33:620-643, 1968. The broken line is
a calculated curve expected to apply to mitotic cells under hypoxia.
OER as a function of LET
The oxygen effect and LET
At low LET, the OER is
between 2.5 and 3.
As LET increases, the OER
falls until the LET reaches 60
keV/µm.
When LET exceeds 60
keV/µm, the OER falls rapidly
and reaches unity by the time
the LET has reached about
200 keV/µm.
The oxygen effect and LET
Measurements were made with cultured cells of
human origin. Closed circles refer to monoenergetic
charged particles, the open triangle to 250 kVp X-rays
with an assumed LET of 1.3 keV/µm.
The oxygen effect and LET
Variation of the OER and the relative biologic effectiveness as
a function of the linear energy transfer of the radiation involved.
The data were obtained by using T1 kidney cells of human origin,
irradiated with alpha particles or deuterons.
Impact of O2 concentration
Variation of radiosensitivity with
O2 concentration
Impact of O2 concentration
Very small amounts of oxygen are necessary to produce the
dramatic and important oxygen effect observed with X-rays.
Oxygen tension between different tissues may vary over a wide
range from 1 to 100 mm Hg. Many tissues are bordering
hypoxic and contain a small proportion of cells that are
radiobiologically hypoxic. This is particularly true of, for
example, the liver and skeletal muscles. That shows up as a
change of slope if the survival curve is pushed to low
survival levels.
Time scale of oxygen effect
For the oxygen effect to be observed, oxygen must
bepresent during the radiation exposure or, to be
precise, during or within microseconds after the
radiation exposure.
In a number of experiments it has been shown that
oxygen need not be present during the irradiation
to sensitize but could be added afterward, provided
the delay was not too long.
Some sensitization occurred with oxygen added as
lateas 5 ms after irradiation.
Mechanisms of oxygen effect
There is general agreement that oxygen acts at the levels of
the free radicals.
The chain of events from absorption of
radiation to the final expression of biologic damage is as
follows:
Absorption of radiation
Production of fast charged particles
Production of ion pairs
Production of free radicals
Breakage of chemical bonds, chemical changes,
initiation of the chain of events that result in
biological damage
The oxygen fixation hypothesis
The damage produced by free radicals in DNA can be repaired
under hypoxia, but may be “fixed” if oxygen is present
Nature of the Oxygen Effect
Surviving Fraction
High Dose Assay,
OER = 3.5
Low Dose Assay,
OER = 2.5
1.0
1.0
0.9
Hypoxic
Hypoxic
0.1
0.8
0.0
1
0
Aerated
5
10
15
Aerated
0.7
20
25
30
0
0.5 1.0 1.5 2.0 2.5 3.0
Dose (Gy)
Dose (Gy)
Low-LET radiation
70
Other Radiations and the
OER
15 MeV Neutrons
α particles
1.0
1.0
OER = 1.6
OER = 1.0
0.1
0.1
Hypoxic
0.0
1
0.01
Aerated
0.001
0.001
0
2
4
6
0
1.0
Dose, Gy
2.0
3.0
Dose, Gy
High-LET radiation
71
Mechanism of Oxygen
Enhancement
• Radiochemistry of rad. effect:
– radiation absorption --> energetic (i.e.
fast) charged particle --> ion pair
created
– T1/2 of ion pair is short (10-10 sec)
– ion pair produces free radical: OH•
– T1/2 of free radical is short (10-5 sec)
– ion pair --> indirect effect --> break
bonds --> chemical changes
72
O2 Concentration Effects
100
Surviving Fraction
• Bacteria and
mammalian
systems show
similar effects
• A: 210,000 ppm
(air)
• B: 2200 ppm O2
• C: 355 ppm O2
• D: 100 ppm O2
• E: 10 ppm O2
Chinese hamster cells
10
1
0.1
0.01
A
0.001
0
B
C
D
E
6
4
2
Dose (krad)
Photons
73
Two Conditions of Hypoxia
• Chronic hypoxia
– limited diffusion distance of O2 through
respiring tissues
– tumors may outgrow blood supply, have O2
starved regions
• Acute hypoxia
– blood vessels can be temporarily shut down
– rapidly re-open to supply tissues with O2
74
Acute and Chronic Hypoxia in
Tissue
75
Solid Tumors
• As tumor grows, necrotic center expands
• Thickness of healthy sheath remains
constant
• Estimated diffusion distance of O2 in
respiring tissue is 70µm
• In 1950s, radiobiologists focused on
– O2 and effect of tumor cell killing
– alternative treatments with high-LET particles
• no O2 effect
76
Thomlinson & Gray (1955)
77
Hypoxia and Radiosensitivity
Diffusion of oxygen through a capillary in tumor tissue
78
Solid Subcutaneous
Lymphosarcoma
• Two-component
curve
• Extrapolating back:
normoxic
component
hypoxic
component
– SF ~ 1%; implies 99% of
cells were well
oxygenated
– low-dose response:
killing of aerated cells
– begin killing hypoxic
cells > 9 Gy
• Solid tumor has
protected hypoxic
cells (i.e., clonogenic)
79
Hypoxic Cell Fraction in
Tumors
• Paired survival
curves
• Distance between
indicates % of
hypoxia
• Theoretical; what
does real data look
like?
80
Hypoxic Cell Fraction in
Mouse Tumor
• Air curve
– mice breathing air
– mixture of hypoxic
and aerated cells
• Hypoxic curve
– mice asphyxiated
by breathing N2 or
cells irradiated in
vitro in N2
• Oxic curve
– cells in vitro in O2
81
Reoxygenation
• During fractionated treatments,
oxygen status varies in cells and is
dynamic
• As cells die, hypoxic cells within the
tumor obtain more oxygen to improve
their oxygen status
– these cells have an increased OER which
makes the next dose fraction more
effective
82
Reoxygenation
• Mouse sarcoma:
– 14% hypoxic cells, initially
– 5 dose fractions, 1.9 Gy/day
– 3 days later, 18% hypoxic cells
• Similar experiment:
– 4 fractions over 4 days
– next day, 14% hypoxic cells
• Fraction of hypoxic cells essentially
unchanged by therapy
83
Reoxygenation
•
•
•
•
What’s going on?
Treatment kills oxygenated tumor cells
Hypoxic ones become oxygenated
This is good for therapy!
– oxygenated cells are more radiosensitive
• Reoxygenation:
– hypoxic cells reoxygenate after radiation
therapy
84
Process of Reoxygenation
• If reoxygenation
occurs, the
presence of
hypoxic cells does
not significantly
impact the
outcome of the
multi-fraction dose
regime
85
Percentage of Hypoxic
Cells
• Transplantable
mouse sarcoma
• Initially, all aerated
cells are killed
• Rapid reoxygenation
• 6 hours, back to near
pre-irradiation levels
• Similar results in
other tumor systems
86
Hypoxic Cells PostIrradiation
• Sequence for
reoxygenation
varies with the
tumor type
–
–
–
–
mouse osteosarcoma
mouse fibrosarcoma
mouse fibrosarcoma
mouse mammary
carcinoma
– rat sarcoma (2 waves)
• Extent & rapidity
of reoxygenation is
extremely variable
87
Significance for
Radiotherapy
• The presence of O2 enhances cell killing
• Tumors (animal) include both aerated and
hypoxic cells
• Hypoxia confers protection from
– x-rays (low/moderate LET radiations) and
certain chemotherapeutic agents
– i.e., agents involving free radical mechanisms
88
Radioprotectors/Radiosensitizers
89
Radioprotectors
• Compounds which reduce the effect of
radiation on the cell or organism
– Sodium cyanide, carbon monoxide, etc. act by
reducing oxygen concentration in organs, which lowers
the effect of x-rays; they’re also toxic
• The first compounds discovered (1948)
are cysteine and cysteamine
– Experiments showed these drugs could protect animal
subjects with a dose reduction factor of 1.8 (DRF = ratio
of radiation doses with and without drug, when
measuring the same level of lethality)
90
Making a better radiation
trap
• Cysteine and cysteamine are toxic - drug dose
levels necessary for protection produce nausea
and vomiting
• Here comes the army - program initiated in 1959;
first discovery was that a phosphate cover on
the sulfhydryl group greatly reduced toxicity;
larger drug doses meant larger radiation doses
could be tolerated
• Over 4000 compounds tested - these three are
prominent:
– WR-638, or cystaphos: DRF=1.6 over 7 d, 2.1 over 30 d
– WR-2721, or amifostine: DRF=1.8 over 7 d, 2.7 over 30 d
– WR-1607, or d-CON. Marketed as rat poison.
91
How do they work?
• These and other compounds have
chemical characteristics which
allow them to protect against the
adverse effects of sparsely ionizing
x and gamma rays:
– Primarily free-radical scavenging
• These compounds become less
effective as LET increases
• Protective effect tends to parallel
the oxygen enhancement ratio
• Not the whole story, since these
compounds also have some effect
against densely ionizing neutrons
92
Radiosensitizers
• Chemical or pharmacological agents that
increase the lethal effects of radiation
• Must be present when the irradiation occurs
• Key to effectiveness in tumor control is the
presence of a differential - tumor gets sensitized
more than normal tissue
• Two categories found effective- halogenated
pyrimidines and hypoxic sensitizers
• Both work to change tumor control percentages
93
94
Radiosensitizing Hypoxic Cells
• Hypoxic cells are resistant to x-rays; efforts have been
made to induce higher oxygen levels in tumors prior to
treatment
– hyperbaric oxygen chambers
– blood transfusions, artificial blood, patient can’t smoke
• In the 60’s, the search began for drugs that mimic
oxygen’s effect on tumors; drugs must have these traits to
be effective:
– must sensitize tumor cells without undo toxicity to
normal cells
– must be chemically stable and not readily metabolized
– must be highly soluble in water and fat and able to
diffuse large (200µm) distances
– must be effective at low doses (several Gray) for
fractionated treatments
• First satisfactory candidate was misonidazole
95
96
Hypoxic Cytotoxins
• Change in philosophy: kill hypoxic cells
instead of sensitize them
• Used alone, they are chemotherapeutic
agents
• Used in conjunction with radiation, is cellkilling more effective?
• Leading compound of interest is
tirapazamine (TPZ)
97
Genetic Susceptibility
Genetic Susceptibility
Can we identify cells, individuals or subpopulations
that are genetically susceptible to radiation?
Some individuals are more
sensitive than others to a
variety of things
•
•
•
•
•
•
•
Dust
Animal hair
Chemicals
Sun
Drugs, medicines
Foods
Radiation
We know that radiation is one
of the things that has a wide
range of sensitivities
Resistant
Individuals
Sensitive
Individuals
Radiation Dose
Radiosensitive cells have been
developed. After the same amount of
radiation, they have more changes
than normal cells.
Normal Cells
Sensitive Cells
Sensitive and Insensitive Mice
Hybrid Mouse
Models
Some strains of mice such as BALBc are
more sensitive to radiation than others.
For example, C57BL/6 mice are
particularly resistance to radiation-induced
mammary cancer.
Survivors of radiation exposure have
demonstrated that some people are less sensitive
to radiation exposure than others.
LD50 for radiation for humans is about 300,000 mrem.
This means that at this high dose, half of all people will
die- but half of all people will still survive.
A-BOMB
Some survivors received more than 300,000
mrem, 60 years after the exposure, 40% of the
population of A-bomb survivors are still alive.
CHORNOBYL
One survivor in control room received 550,000 mrem
Why are these people apparently unaffected
by the effects of radiation?
Genetic susceptibility can be passed on
from one generation to the next,
therefore it probably involves genes.
• Strains of mice have been developed that are more
sensitive to radiation than others.
• Cell lines have been developed that are more
sensitive to radiation than others.
• People with some genetic diseases, such as Ataxia,
are radiation sensitive.
Multiple genes contribute to
radiosensitivity
• Different genes respond to high radiation and low
radiation. The types of genes vary.
• Most biological systems have back ups or require
homologous chromosomes, so that one mutation or
irregularity does not automatically cause a problem.
• Most sensitivity to radiation involves disruptions of
multiple genes.
Genes which may effect
Genetic Susceptibility
• Radiation-induced genes
– Some genes are activated or deactivated by radiation- these genes
may make people more sensitive or more resistant to radiation
damage.
• Stress response genes
– If these genes cannot deal appropriately with oxidative stress caused by
radiation, the function of the cell can be disrupted.
• DNA repair genes
–
Most radiation damage to DNA is repaired. If DNA repair genes are defective
then cells cannot fix even minor damage caused by radiation.
• Apoptosis genes
–
Genes which trigger the normal death of cells may malfunction, resulting in
inappropriate death or survival of altered cells.
Researchers have developed
methods to identify radiation
sensitive and resistant individuals
• Changes in gene expression are being used to predict
sensitivity in individuals.
• It has been found that people with increased
radiation-induced aberrations at the G2 stage of the
cell cycle are more sensitive to radiation therapy.
• Dose response for cells taken from patients can help
predict their radiation sensitivity.
The impact of genetic
susceptibility
• Identification of sensitive subpopulations may suggest
an increased risk at low doses for that unique
subpopulation.
• It might then be possible to control environmental
exposure to these sensitive subpopulations.
• Resistant individuals would have lower than
average risk.
Summary
•
Radiation does not effect individuals to the same
degree.
•
Some people may be radiosensitive, while others
may be more resistant to the effects of radiation.
•
Scientists are trying to find better ways to
determine if someone is particularly sensitive to
radiation.
•
Understanding genetic susceptibility will help
predict and control risk in clinical and occupational
settings.