Paradigm Shifts in Radiation Biology: Impact on Intervention and Radiation Protection Dr' Antone L'

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Paradigm Shifts in Radiation Biology Impact on
Intervention and Radiation Protection Dr.
Antone L. Brooks Washington State University
Tri-Cities, 2710 University Drive, Richland,
Washington 99352Brookhaven Health Science,
Long Island, NY
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Self sufficiency in growth signals
Insensitivity to anti-growth signals
Evading apoptosis
Sustained angiogenesis
Tissue invasion and metastasis
Limitless replicative potential
Hanahan and Weinberg 2000
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Gene Mutation and Expression in Cancer
Mutation Theory
Tissue Theory
Single cell origin of cancer
ROS status Matrix interactions Gene activation
Normal
Normal
Gene Activation
Down Regulation
Initiation
Promotion
Progression
Progression
Gene Mutation- a rare event
Tissue response- a frequent event
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Mechanisms for Radiation-induced Cancer

• High Doses
• Cancer
• Changes in gene expression
• Mutations
• Chromosome aberrations
• Genomic instability
• Cell killing
• Stimulate cell proliferation
• Tissue and matrix disruption
• Inflammation

• Low Doses
• Cancer?
• Changes in gene expression
• Mutations
• Chromosome aberrations
• Adaptive response

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Influence of radiation on mechanisms of cancer

• The complex biology of cancer induction plays an
  important role in the shape of dose-response
  relationships.
• There are both linear and non-linear biological
  processes involved
• It is important to consider all of these
  processes in making risk estimates.

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Cell Transformation
Proliferation
X-Irradiation
300 Cells
13 cell divisions
Confluence
1/10
1/100
1/1000
Proliferation
1/10,000
Anne Kennedy 1985
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Mechanisms involved in new paradigms

• Altered gene expression
• Impact of oxidative status of the cell
• Radiation-induced changes in differentiation
  pathways
• Cell/cell, cell/matrix interactions
• Nutrition and radioprotectants

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Cellular Changes

• Adaptive Response
• Small dose alters response to large dose
• Small dose decreases spontaneous damage
• Bystander Effects
• Cells respond without energy deposition
• Cell-cell communication
• Materials into the media
• Genomic Instability
• Loss of genetic control many cell generations
  after the radiation exposure

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Relationship between biological responses to
radiation
Adaptive Response
Genomic Instability
Bystander Effects
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Bystander EffectAll-or-none dose response
Fraction of cells damaged
One cell targeted per dish Four cells
targeted per dish
Numbers of particles per targeted cell
Belyakov et al. 2001
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Adaptive ResponseSub-linear dose response
Transformation Frequency
0
10
20
30
40
50
60
70
80
90
100
Dose (cGy)
Redpath et al. 2001
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Genomic Instability
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DIFFERENCES IN TRANSCRIPTION PROFILES
BETWEEN LOW AND HIGH DOSE IRRADIATION IN
MURINE BRAIN CELLS







0.1 Gy
2Gy



191
299
213







Total gene set contains nearly 10,000 genes
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Protective Response

• It was found that low-dose IR exposures
  modulated genes involved in stress response,
  synaptic signaling, cell-cycle control and DNA
  synthesis/repair, suggesting that low-dose IR may
  activate protective and reparative mechanisms as
  well as depressing signaling activity.

Yin 2003
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Radiation-induced changes in gene expression
Low Dose Genes
High Dose Genes
0 10 100
1000
Dose (cGy)
Wyrobek
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Radiation and the redox status of cells

• Radiation produces free radical and reactive
  oxygen species (ROS)
• Radiation triggers signals that alter the level
  of ROS and RNS for long periods of time (frequent
  event)
• Redox status regulates cell cycle,
  differentiation, and apoptosis
• Physiological factors can be used to modify redox
  signaling pathways induced by radiation
• These represent potential methods for
  intervention to modify radiation-induced damage
  and risk

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Inhibition of gamma ray -induced (50 cGy)
oxidative stress by ascorbic acid
Radiation only
No radiation, no ascorbic acid
Wan, et al 2004
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Radiation-induced changes in cellular switches
?
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Signaling from Microenvironment
Differentiation
Apoptosis
Proliferation
Microenvironment
Park et al. 2000
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Cell/Matrix Interactions

• Cell/Matrix communication and signaling
• Cell/matrix tension
• Signaling molecules and pathways
• Exposed matrix can produce transformation in
  non-exposed cells
• Change phenotype with matrix
• Frequent non-mutagenic event

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Dietary InterventionSupplements reduce Oxidative
Stress Levels after Radiation
Guan, et al 2004
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Observations suggesting major paradigm shifts

• Hit theory vs. bystander effects
• Adaptive response vs additive or synergistic
  effects
• Mutation vs. gene induction and genomic
  instability
• Single cell vs tissue responses
• Intervention vs non-intervention

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Why dont biological observations agree with old
radiation paradigms?

• Lack of information in the low dose region
• Need for simple risk estimates
• Problems with thresholds

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Why suggest the presence of radiation related
thresholds?

• They have been demonstrated in many biological
  systems, including human cancer
• They represent a biological reality
• If defined, they make it possible to make well
  defined regulatory decisions
• Biology is based on repair and restoration of a
  normal homeostatic state for any insult

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Why dont we use thresholds in radiation
protection?

• Energy deposition increases linear with no
  barriers.
• Mutations in fruit flies increased linearly with
  dose.
• Thresholds suggest a level below which no
  biological damage is induced
• Threshold levels are variable for each biological
  system.
• They have been declared to not be present for
  radiation- induced solid cancers in human. (NCRP
  136)

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Barriers in dose-response

• Biological
• Practical
• Energy barriers

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Biological Barriers
Bone sarcoma in Radium dial painters
Evans 1981
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Practical Life-span Barriers
100000
tL20,000 Radium dial painters
10000
tL4865 for Davis dogs
Time to death (days)
tL655 for mice
1000
10-2 10-1 1
10 100
Average dose rate to skeleton, rads/day
Raabe et al. 1980
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Energy Barriers
Nq/NH
Nq
A
B
A
B
Baseline Rate
B
Baseline Rate
Absorbed Dose (Gy)
Imparted Energy (J)
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Biological paradigm for dose-response
relationships
Chromosome Aberrations
Background
0 20 40
60 80 Dose (cGy)
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Predicted shapes and consequences of low-dose
radiation

• The initial energy deposition events and the
  initial molecular changes are linear.
• The repair and processing of the damage has some
  very non-linear components.
• The adaptive response suggests that cells
  recognize low doses of radiation and change in
  gene and protein gene expression, which may
  protect against late effects of ionizing
  radiation.
• New paradigms suggest possibility of intervention
  to modify dose-response relationships

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How will this research impact standards?
Genetic Susceptibility
Adaptive Response
Genomic Instability
Bystander Effects
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Summary

• Mechanisms for radiation action are not linearly
  dose dependent.
• Bystander effects, adaptive responses, and
  genomic instability are interrelated.
• The observations suggest the need for paradigm
  shifts in radiation biology.
• New biology provides additional information
  suggesting the presence of barriers.
• The observations suggest the need for paradigm
  shifts in radiation biology
• Understanding the role of these biological
  changes in cancer risk may or may not impact
  radiation protection standards, but will help
  ensure that the standards are based on scientific
  data and are both adequate and appropriate.