Interaction of Radiation with Biological Matter:
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Interaction of Radiation with Biological Matter: (what is biological dose?) Bill McBride Division of Cellular and Molecular Oncology Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. [email protected] Room B3-109, x47051. Objectives:

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Objectives: Know the characteristics of ionizing radiation that make it useful for RT

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Objectives know the characteristics of ionizing radiation that make it useful for rt

Interaction of Radiation with Biological Matter: (what is biological dose?)Bill McBrideDivision of Cellular and Molecular OncologyDept. Radiation OncologyDavid Geffen School MedicineUCLA, Los Angeles, [email protected] B3-109, x47051


Objectives know the characteristics of ionizing radiation that make it useful for rt

Objectives:

  • Know the characteristics of ionizing radiation that make it useful for RT

  • Define LET and RBE and what is meant by quality of radiation

  • Know the difference between direct and indirect action of radiation and the role of free radicals

  • Recognize the impact of oxygen on initial radiation damage and of hypoxia in tumor RT

  • Understand how biological radiation dose and physical radiation dose differ


Radiation therapy

Radiation Therapy

  • Approximately 50% of cancer patients receive RT with curative intent

  • Approximately half of these are cured

Radiation Therapy has a long history!


Roentgen with his wife s hand 1895

Roentgen with his wife’s hand, 1895

X-rays were rapidly adapted for use as a clinical treatment, initially for non-cancerous conditions, but soon for cancer, as well.


First cure of cancer by x rays 1899 basal cell carcinoma

FIRST CURE OF CANCER BY X-RAYS 1899 - BASAL CELL CARCINOMA

X-rays were used to cure cancer very soon after their discovery


And rapidly became a standard treatment

And rapidly became a standard treatment

Hammersmith Hospital, London, 1905


Objectives know the characteristics of ionizing radiation that make it useful for rt

Although side-effects were encountered! This is a picture of a 70 year old person who was irradiated by Freund at the of age 5 in Austria 1896 for nevus pigmentosus piliferus. L. Freund, Ein mit Rontgenstrahlen behandelter fall von nevus pigmentosus piliferus. Wein. Med. Wochschr. 47, 428-434 (1987).


Epilepsy

Epilepsy

Initially more non-cancerous diseases were treated that cancer (still popular in Europe)

Lupus


Objectives know the characteristics of ionizing radiation that make it useful for rt

The Nobel Prize in Physiology or Medicine 1946

"for the discovery of the production of mutations by means of X-ray irradiation

However, its use for benign conditions has been limited in most countries for fear of radiation-induced cancer.

The carcinogenic effects of X-rays was discovered using fruit flies by Muller in 1946.

Hermann J. Muller


Objectives know the characteristics of ionizing radiation that make it useful for rt

Maltese cross

Natural radioactivity was discovered by Becquerel, who was awarded the Nobel Prize in Physics in 1903 along with Marie and Pierre Curie "in recognition of the extraordinary services they have rendered by their joint researches on the radiation phenomena"

Marie Curie

Henri Becquerel

“One wraps a Lumiere photographic plate with a bromide emulsion in two sheets of very thick black paper, such that the plate does not become clouded upon being exposed to the sun for a day. One places on the sheet of paper, on the outside, a slab of the phosphorescent substance, and one exposes the whole to the sun for several hours. When one then develops the photographic plate, one recognizes that the silhouette of the phosphorescent substance appears in black on the negative. If one places between the phosphorescent substance and the paper a piece of money or a metal screen pierced with a cut-out design, one sees the image of these objects appear on the negative. One must conclude from these experiments that the phosphorescent substance in question emits rays which pass through the opaque paper and reduces silver salts.” Paris 1896


Natural radioactivity

Natural Radioactivity

  •  particles

    • Positively charged, helium nucleus

  •  particles

    • Negatively charged, electrons

  • -rays

    • No charge, EMR


Radioisotopes also were soon being used to treat and cure cancer

Radioisotopes also were soon being used to treat and cure cancer.

First cure of cancer by radium plaque - 1922

Radioactive plaques and implants are still in common use, for example in prostate implant seeds.

Radium applicators were used for many other conditions!


Therapeutic benefit and r t

Therapeutic Benefit and R.T.

There is always a need to derive a therapeutic benefit from RT. There are 2 main ways by which this is achieved:

1. Physical means

  • distributing dose by treatment planning

    2. Biological means

  • dose fractionation


Objectives know the characteristics of ionizing radiation that make it useful for rt

1-25 MeV

Megavoltage

500 KeV

Orthovoltage

150 KeV

Superficial Therapy

50 KeV

Contact Therapy

20 KeV

Grenz Rays

Major improvements in RT during the mid-1900s came from improved penumbra and decreased skin dose associated with higher energy x-rays, cobalt, and high energy photons.

More recently conformal RT, IMRT, IGRT, Gammaknife, Cyberknife, tomotherapy, SRS, SRT, protons, heavy ions, etc. have added considerable variety to the choices for physical radiation delivery and present radiobiological challenges.


History of fractionation

Freund - treated hairy nevus with fractionated doses

Stenbeck - cured skin cancer with single doses

Bergonie and Trubandeau introduced the “Law” that radiosensitivity is related to cell proliferation (NOT TRUE!) to explain why fractionated doses sterilized rams without skin reactions

Regaud - treated uterine cancer with fractionated doses

Schwartz

- Fractionation is superior because of cell cycle redistribution

1919Coutard cures deep-seated H&N tumors

1932Coutard shows fractionation superior to single dose

Strandquist - empirical laws for changing dose per fraction

Ellis - Nominal Standard Dose (NSD) formula

1980s Linear Quadratic formula gains favor

History of Fractionation


The first radiation dosimeter

The First Radiation Dosimeter!

Early x-ray machines took a long time to deliver effective dose and gave skin reactions that could be circumvented by dose fractionation.


Objectives know the characteristics of ionizing radiation that make it useful for rt

From Amaldi and Kraft, “Radiotherapy with beams of carbon ions, Reports on Progress in Physics, 68, (2005)


Objectives know the characteristics of ionizing radiation that make it useful for rt

History has repeatedly shown that dose fractionation results in a therapeutic advantage

“In order to save machine time, a 3-day-a-week schedule was initiated in 1962. This schedule was quickly abandoned in pre-operative irradiation because of increased wound healing problems. Although acute reactions in the 3-day-a-week schedule for protracted radical irradiation were not excessive, late radiation sequelae are probably more pronounced as observed 2 or more years later.”

Fletcher, 1966.

3 x 3.3 Gy

5 x 2 Gy


Clinical rt is changing which presents challenges and opportunities for radiobiology

Clinical RT is Changing, which PresentsChallenges and Opportunities for Radiobiology

Conventional treatment:

Tumors are irradiated to a specified dose with 2Gy fractions delivered, more or less homogeneously, in a 6 week time period

  • Varying this schedule impacts outcome

  • Radiobiological modeling attempts to provide guidelines for customization of RT using

    • Radiobiological principles derived from preclinical data

    • Radiobiological parameters derived from clinical altered fractionation protocols

      Modern treatment:

      IMRT etc allows optimized non-homogeneous dose distributions, concomitant boosts, dose painting - dose heterogeneity

      SRS, SRT, HDR, Protons, Heavy Ions - high dose/fx issues

      Molecular and chemical targeting - dose adjustment

      Molecular prognosis and diagnosis promise individualized treatment plans and biological treatment planning


Objectives know the characteristics of ionizing radiation that make it useful for rt

  • Radiobiology has derived means of understanding why dose fractionation gives a therapeutic benefit.

  • New physical delivery methods need to incorporate and/or modify these concepts.

  • In order to understand either conventional or newer treatment effects, one needs to know the differences between physical and biological radiation dose


What is radiation

What is Radiation?

  • Radiation is classified into two main categories:

    • Non-ionizing radiation

    • Ionizing radiation


Electromagnetic radiations

 (cms)

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

1

10

102

103

104

E (eV) 1.24x107

1.24x102

1.24x10-13

v

i

s

i

b

l

e

Radar

T.V.

Radio

Microwaves

Short Waves

rays

Infra Red

Radio Waves

X-rays

U.V.

IONIZING

RADIATION

NON-IONIZING RADIATION

ELECTROMAGNETIC RADIATIONS

Photon E = h(energy = Planck’s const x frequency)

= hc/ (c = speed of light,  = wave length)


Objectives know the characteristics of ionizing radiation that make it useful for rt

excitation

and ionization

particle

excitation

ionization

-ray

’-ray

  • Non-ionizing radiation

    • Is a particle or wave that has enough kinetic energy to raise the

      thermal energy of an outer shell electron and cause excitation

      with emission of low energy EMR (infrared)

  • Ionizing radiation

    • Ionizing radiation has enough kinetic energy to detach at least one electron from an atom or molecule, creating ions

    • Charged particles such as electrons, protons, heavy ions, alpha and beta particles are directly ionizing because they can interact directly with atomic electrons through coulombic forces and transfer a major part of their kinetic energy directly

    • In contrast, photons (x rays,  rays) and neutrons are chargeless and therefore more penetrating. They areindirectlyionizing. They have sufficient kinetic energy to free an orbital electron producing a ‘fast’ recoil or Compton electron that is, in turn, directly ionizing

      • Energy is deposited in “packets”, which is why, when it is deposited in DNA, ionizing radiation is an efficient cytotoxic agent

      • Ionizing radiation has an energy in excess of 124 eV, which corresponds to a l < about 10-6 cm.


Interaction of photons with matter

e+

h

N

e-

e- recoil (Compton) electron

N

h

Scattered Photon

0.51MeV photon

Electron-positron pair

1.02MeV

0.51MeV photon

Characteristic X-rays

e- Auger electrons

N

N

L

K

M

e- photoelectron

Interaction of Photons with Matter

  • In general, the interaction can result in

    • Photoelectric effect, which predominates at low photon energies.

    • Compton (incoherent) scattering effect, which predominates at intermediate energies.

    • Pair production, which predominates at high photon energies.

  • The probability for a photon to undergo any one of the various interaction phenomena with an atom of the absorber depends on

    • the atomic number Z of the absorber as well as the energy of the photon

  • In the Compton Effect

    • photon interacts with aloosely bound “free” orbital electron which is emitted from the atom as a Compton (recoil) electron and the photon is scattered

Arthur H. Compton

Nobel Prize in Physics 1927

  • Inpair production

    • The threshold energy for pair production is1.02 MeV

    • The photon disappears

    • An electron-positron pair is produced

  • In the Photoelectric Effect

    • photon interacts with atightly bound electron it is absorbed losing all its energy to the electron


Objectives know the characteristics of ionizing radiation that make it useful for rt

Ionization produces ions, ion radicals, and free radicals concentrated along tracks and especially at Bragg peak of primary and secondary electrons. They are highly reactive and cause damage to biological matter

SECS

Absorption of energy

Physical effects

Chemical lesions

Chemical repair

Enzyme repair/lesion

Cellular effects

Tissue effects

Systemic effects

Ion formation – H2O+ and e-

Excitation and H and OH radical formation

ION RADICAL LIFETIME

FREE RADICAL LIFETIME

BREAKAGE OF BONDS

CHEMICAL REPAIR / MISREPAIR

ENZYMIC REPAIR / MISREPAIR

EARLY BIOLOGICAL EFFECTS

LATE BIOLOGICAL EFFECTS

10-18

10-16

10-14

10-12

10-6

100

Mins-Hrs

Hrs-Days

Days-Years

106

  • Ion - atom or molecule that has lost an electron and is charged.

  • Free radical - atom or group of atoms that contains an unpaired electron and is highly reactive

  • Aqueous electron - has lost kinetic energy and has been captured by water - a powerful reducing agent.


The gray is the physical unit of radiation

The Gray is the Physical Unit of Radiation

  • 1 GRAY, the unit of absorbed dose (1 joule / Kg),

    • Causes 1-2 x 105 ionization events / cell

    • 1% in DNA

    • A single cobalt 60 ray will deposit about 1mGy in a cell

  • Rad (Radiation Absorbed Dose) is the old unit = cGy


Direct and indirect action of radiation

Direct and Indirect Action of Radiation

  • Indirectly ionizing radiation can act directly or indirectly on biological targets

  • If the ion pairs and free radicals are produced in a biologic target (DNA) then this is direct action

  • If water or other atoms or molecules are ionized, diffusible free radicals can act as intermediaries to cause damage - this is indirect action


Direct and indirect action of ionizing radiation on dna

H2O

OH.

e-

R.

Direct and Indirect Action of Ionizing Radiation on DNA

4 nm

photon

e-

p+

INDIRECT ACTION

photon

p+

2 nm

DIRECT ACTION


Reactive oxygen species ros

Reactive Oxygen Species (ROS)

  • Since H2O is the major component in cells, the most common ionization event is radiolysis of water, producing reactive oxygen species (ROS)

    • The most relevant water is within 2nm of the DNA and tightly bound

  • ROS produced include: H. - reducing; OH. - oxidizing; HO2.- oxidizing (O2 + H.); H2O2 - oxidizing

    • The net effect is oxidation of cellular constituents

  • About 60% of DNA damage caused by x-rays is due to ROS

  • About 75% of the indirect action of radiation is due to hydroxyl radicals (OH.)


Objectives know the characteristics of ionizing radiation that make it useful for rt

Free OH. radicals generateorganic radicals by:

  • Addition R + OH..ROH

  • Hydrogen abstractionRH + OH. R. + H2O

  • Electron transferR + OH. R. + OH -

Where R is the organic moiety


Free radicals and their scavengers matter

Free Radicals and their Scavengers Matter

  • Biological effects of ionizing radiation are determined in large part by free radicals

  • Free radicals are involved in many biological processes, including cellular respiration

  • We have defenses against free radicals

    • Endogenous free radical scavengers - most relevant within 2nm of the DNA

    • Anti-oxidants

      • eg superoxide dismutase, especially in mitochondria, and catalase

  • Free radical scavengers can protect normal tissue from radiation

    • eg Amifostine

  • Depleting free radical scavengers will radiosensitize

  • What interacts with free radicals, in particular radicals in biological materials will be important in determining outcome at this level

  • Oxygen interacts with free radicals


Oxygen matters

Oxygen Matters

  • Binds H radicals forming hydrogen peroxide

    H. + O2 HO2. (+HO2. ) H2O2 (+O2)

  • Binds electrons to give superoxide

    e- + O2 O2- + (H2O) HO2. + OH-

  • Binds organic radicals to form peroxides

    R. + O2 RO2. (radical peroxide)

    RO2. + R’ H ROOH + R’ (hydroperoxide)

    RO2. + R’. ROOR’ (peroxide)

  • Oxygen “fixes” the radical lesions in DNA in a form that can not be easily chemically repaired and therefore is a very powerful radiosensitizer.


Oxygen enhancement ratio oer

.

.

.

.

.

.

.

.

1.0

0.1

0.01

S.F.

hypoxic

oxic

0 2 4 6 8 10

Dose (Gy)

Oxygen Enhancement Ratio (OER)

=

Dose required to produce a specific biological effect in the absence of oxygen

Dose required for the same effect in its presence

OER varies with level of effect but can be 2.5 - 3 fold

1) Culture Cells

4) irradiate under oxic or hypoxic conditions

5) Plate cells and

grow for about 12 days

0 Gy 2Gy 4Gy 6Gy

2) Suspend Cells

trysinization)

6) Count colonies

(

3) Count cells in hemocytometer

Physical Dose = Biological Dose


Clinical relevance of hypoxia

Hypoxic areas occur almost solely in tumors and are more radioresistant than oxic areas.

Hypoxia contributes to treatment failure

Reoxygenation occurs between radiation dose fractions giving a rationale for dose fractionation

The oxygen effect is greater for low LET than high LET radiation

Clinical Relevance of Hypoxia

The effects of hypoxia were first discovered in 1909 by Schwarz who showed that strapping a radium source on the arm gave less of a skin reaction than just placing it there. This was used to give higher doses to deep seated tumors.

Giacca and Brown

Pimonizadole (oxygen mimetic) staining colorectal carcinoma


Radiation quality and biological effectiveness

RADIATION QUALITY AND BIOLOGICAL EFFECTIVENESS


Objectives know the characteristics of ionizing radiation that make it useful for rt

LINEAR ENERGY TRANSFER

LOW LET

Radiation

Separation of ion clusters in relation to

size of biological target

gamma rays

deep therapy

X-rays

soft X-rays

alpha-particle

LET is average energy (dE) imparted by excitation

and Ionization events caused by a charged particle

traveling a set distance (dl) - LET = dE/dl (keV/ m)

HIGH LET

Radiation


Objectives know the characteristics of ionizing radiation that make it useful for rt

excitation and ionization

particle

excitation

ionization

-ray

’-ray

  • A dose of 1 Gy will give 2x103 ionization events in 10-10 g (the size of a cell nucleus). This can be achieved by:

    • 1MeV electrons

      • 700 electrons which give 6 ionization events per m.

    • 30 keV electrons

      • 140 electrons which give 30 ionization events per m.

    • 4 MeV protons

      • 14 protons which give 300 ionization events per m.

  • The biological effectiveness of these different radiations vary!


Relative biological effectiveness rbe of the radiation matters

1.0

0.1

0.01

0.001

S.F.

Low LET, HDR

High LET

DOSE Gy

Physical Dose = Biological Dose

Relative Biological Effectiveness (RBE) of the Radiation Matters

Dose of 250 kVp x-rays required to produce an effect

Dose of test radiation required for the same effect

=


Rbe and oer as a function of let

8

4

6

3

4

2

2

1

0

0

1

10

100

1000

RBE and OER as a function of LET

Fast

Neutrons

Alpha

Particles

RBE

(for cell kill)

OER

overkill

RBE

Co-60

gamma rays

Diagnostic

X-rays

OER

0.1

Linear Energy Transfer (LET keV/m)

OER is the inverse of RBE because OER depends considerably on the indirect action of ionizing radiation

RBE is maximal when the average distance between ionization events = distance between DNA strands = 2nm


Objectives know the characteristics of ionizing radiation that make it useful for rt

DNA is the Primary, but not the only, Cellular Target for Radiation

  • Microbeam irradiation of cell cytoplasm does not generally cause cell death, but irradiation of the nucleus does

  • Tritiated thymidine incorporated into cells can kill them

  • Radiation-induced chromosomal abnormalities correlate with cell death and carcinogenesis

  • However, irradiation of the cytoplasm is not without biological consequences


Objectives know the characteristics of ionizing radiation that make it useful for rt

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaquv

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

OH . eaqu

The lesions in DNA that are associated with cell death and carcinogenesis after radiation exposure are large

Spur

4 nm diam

3 ion pairs

100 eV energy

95% of energy deposition events

Lesion size

about 15-20

nucleotides

Blob

7 nm diam.

12 ion pairs

The high cytotoxic efficiency of ionizing radiation can be ascribed to the deposition of low levels of energy in small packets within the DNA that cause lesions large enough to be fatal


Objectives know the characteristics of ionizing radiation that make it useful for rt

DOUBLE STRAND BREAK

30/ CELL / GRAY

SINGLE STRAND BREAK

1000 / CELL / GRAY

BASE CHANGE (eg C - U)

BASE LOSS

1000 / CELL / GRAY

BASE MODIFICATION

(eg thymine/cytosine glycol)

SUGAR DAMAGE

(abstraction of hydrogen atom)

INTRASTRAND

CROSSLINK

0.5 / CELL / GRAY

INTERSTRAND

CROSSLINK

*

DNA-PROTEIN

CROSSLINK

1 / CELL / GRAY


Objectives know the characteristics of ionizing radiation that make it useful for rt

  • Not all ionization events are lethal!!

  • As a rough guide the fraction of cells surviving 2Gy (SF2Gy) is about 0.5

  • If the S.F. 2Gy is 0.5, what is the S.F. after 60Gy?

    = 0.530 = 0.9x10-9

  • If the S.F. 2Gy is 0.7, what is the S.F. after 60Gy?

    = 0.730 = 2.2x10-5


Objectives know the characteristics of ionizing radiation that make it useful for rt

What is the Lethal Lesion?


X or radiation is sparsely ionizing most damage can be repaired

X- or -radiation is sparsely ionizing; most damage can be repaired

4 nm

Repairable Sublethal Damage

2 nm


Objectives know the characteristics of ionizing radiation that make it useful for rt

It is hypothesized that the lethal lesions are large double strand breaks with Multiply Damaged Sites (MDS) that can not be repaired. They are more likely to occur at the end of a track

4 nm

Unrepairable Multiply Damaged Site

Single lethal hit

Also known as  - type killing

2 nm


Objectives know the characteristics of ionizing radiation that make it useful for rt

At high dose, intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS

Also known as  - type killing


Dose rate matters

Physical Dose = Biological Dose

Dose Rate Matters

1.0

0.1

0.01

0.001

Low Dose Rate

allows continuous SLDR

S.F.

Low LET, HDR

DOSE Gy


Chromatin structure matters

840nm

Chromatin Structure Matters

  • Each cell contains about 2m of DNA

  • The basic structure is the nucleosome, which is 146 base pairs of DNA wrapped around 2 copies of histones H2A, H2B, H3, and H4

  • Nucleosomes are in turn wrapped around other proteins to form compacted chromatin

  • Chromatin is maximally compacted during mitosis

  • Transcription requires decompaction to facilitate initiation (binding of transcription factors and RNAP II) and elongation

miniband

- 30nm


Chromatin structure and radiation responses

1

.1

S.F.

LATE S

.01

EARLY S

Physical Dose = Biological Dose

G1 PHASE

G2/M PHASE

0

0

4

8

12

16

20

Dose (Gy)

Chromatin Structure and Radiation Responses

  • Compact chromatin is more radiosensitive than non-compacted

    • Mitotic cells

      • are 2.8 times more sensitive to DNA breaks than interphase cells

      • have a lower OER (eg 2.0 compared with 2.8)

      • do not have much of a “shoulder” on their survival curve

    • Actively transcribing genes are less sensitive to damage

  • Decompaction and compaction require acetylation and deacetylation of histones by acetyltransferases (HAT) and deacetylases (HDAC)

    • HDAC inhibitors are entering the clinic as anti-cancer agents and can radiosensitize

  • Radiation Damage to DNA is not randomly distributed.

  • It varies with cell cycle phase and level of gene expression


  • Objectives know the characteristics of ionizing radiation that make it useful for rt

    700R

    1500R

    Repopulation

    Redistribution

    12.5Gy

    14.0Gy

    Repair

    15.5Gy

    17.0Gy

    Withers, H. R. and Elkind, M. M. Radiology 91:998, 1968

    Used the macrocolony assay in mouse jejunum to assessed the effects of 2 radiation doses given varying times apart to measure the time to and extent of repair, redistribution, and repopulation (regeneration) between dose fractions.

    Colony derived from a single surviving clonogen


    Tissue type matters

    ACUTE RESPONDING TISSUES

    (responses seen during standard therapy)

    Gut

    Skin

    Bone Marrow

    Mucosa

    LATE RESPONDING TISSUES

    (responses seen after end of therapy)

    Brain

    Spinal Cord

    Kidney

    Lung

    Bladder

    1

    .1

    Physical Dose = Biological Dose

    .01

    Tissue Type Matters

    Surviving

    Fraction

    Acute Responding

    Tissues and

    Many Tumors

    Late Responding

    Tissues

    0

    0

    4

    8

    12

    16

    20

    Dose (Gy)


    Dose fractionation

    1

    .1

    .01

    Dose Fractionation

    Surviving

    Fraction

    Fractionated dose

    Late responding tissues

    Fractionated dose

    Acute responding tissues

    Single dose

    Late responding tissues

    Single dose

    Acute responding tissues

    0

    4

    8

    12

    16

    20

    24

    0

    Dose (Gy)

    Dose fractionation spares late responding tissues more than acute responding tissues and many tumors


    The aim is to increase therapeutic benefit

    1.0

    Probability

    of tumor

    control/

    of normal

    tissue

    damage

    therapeutic benefit

    0

    A B C

    Dose (Gy)

    The Aim is to Increase Therapeutic Benefit!

    Normal tissue complication dose-response curves are steep!


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Biological effectiveness of RT varies with

    Size of Dose (D) - (alpha and beta)

    Size of Dose Per Fraction (d) - (alpha and beta)

    Time over which it is delivered (T)- (alpha and beta)

    Time between fractions (t)

    Volume irradiated (V)

    Quality of Radiation (Q) - RBE

    Presence/Absence of Oxygen - OER

    DNA Repair efficiency and completeness

    Cell cycle phase and level of gene activation

    Tissue/Tumor Type

    Physical Dose = Biological Dose


    4rs of radiobiology relevant to clinical dose fractionation

    4Rs OF RADIOBIOLOGY RELEVANT TO CLINICAL DOSE FRACTIONATION

    • Repair of sublethal damage

      • spares late responding normal tissue preferentially

    • Reassortment/Redistribution of cells in the cell cycle

      • increases acute effects

      • no influence on late effects

      • increases damage to tumor

    • Repopulation/Regeneration

      • spares acute responding normal tissue preferentially

      • no influence on late effects,

      • danger of tumor repopulation

    • Reoxygenation

      • no influence on normal tissue responses

      • increases tumor damage


    Questions on interaction of radiation with biological matter what is biological dose

    Questions onInteraction of Radiation with Biological Matter: what is biological dose?


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    The lifetime of radicals in target molecules is about

    • 10-3 secs

    • 10-6 secs

    • 10-9 secs

    • 10-12 secs


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Electromagnetic radiation is considered ionizing if it has a photon energy greater than

    • 1.24 eV

    • 12.4 eV

    • 124 eV

    • 1.24 keV


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    The S.I. unit of absorbed dose is

    • Becquerel

    • Sievert

    • Gray

    • Roentgen


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following are not charged particles?

    • Electrons

    • Neutrons

    • Protons

    • Heavy ions

    • Alpha particles


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following is NOT a characteristic of the indirect action of ionizing radiation

    • Production of diffusible free radicals

    • Production of reactive oxygen species

    • Involvement of anti-oxidant defenses

    • A change in redox within a cell favoring reduction of constituents


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following is true about the oxygen enhancement ratio

    • Is the same at all levels of cell survival

    • Can be measured by the dog-leg in a cell survival curve after single high dose irradiation of tumors

    • Is the ratio of doses needed for an isoeffect in the absence to the presence of oxygen

    • Is low for cells in S cell cycle phase compared to cells in G2/M phase


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following is true about Linear Energy Transfer

    • It is a measure of the biological effectiveness of ionizing radiation

    • Correlates directly with the oxygen enhancement ratio

    • Is maximal at a relative biological effectiveness of 150 keV/micrometer

    • Is measured in keV/micrometer


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    The Relative Biological Effectiveness of a radiation is

    • Assessed by the dose required for to produce the same effect as 250kVp X-rays

    • The ratio of the dose required of 250 kVp X-rays to that of the test radiation for a given isoeffect

    • Directly related to Linear Energy Transfer

    • About 1 for alpha particle radiation


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    The lethal lesion caused in DNA by low LET ionizing radiation is

    • 15-20 nucleotides in size

    • Caused by alpha-type events

    • Does not correlate with chromosomal aberrations

    • Due to oxygen fixation


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Approximately how many DNA double strand breaks are caused per cell per Gray?

    • 1-10

    • 15-25

    • 30-40

    • 45-60

    • 60-75


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    If the fraction of cells surviving 2Gy irradiation is 0.5, what is a reasonable estimate of the percent of DNA double strand breaks that are effectively repaired?

    • 99%

    • 95%

    • 75%

    • 50%


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    If the fraction of cells surviving 2Gy is 0.4, what is the surviving fraction after 50 Gy given in 2Gy fractions?

    • 10-8

    • 10-9

    • 10-10

    • 10-11


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Sublethal DNA damage is most likely to accumulate

    • At high total doses given at high dose rate

    • At high total doses under hypoxia

    • After high LET radiation

    • After low fractionated doses of radiation


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Sublethal DNA damage is most likely to be repaired

    • After high total doses given at high dose rate

    • If cells are held in a non-proliferative state

    • After high LET radiation

    • Between low fractionated doses of radiation


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following is true about chromatin structure in cells

    • Compacted chromatin is more radiosensitive than non-compacted chromation

    • During mitosis cells decompact their chromatin and become radiosensitive

    • Compact chromatin in S phase mediates radioresistancy

    • Compaction facilitates gene transcription


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following is correct about alpha-type cell killing following radiation exposure

    • It represents single lethal hits

    • It is due to accumulated damage

    • It requires intertrack interactions

    • It is not oxygen dependent


    Objectives know the characteristics of ionizing radiation that make it useful for rt

    Which of the following radiobiological phenomena occurring between dose fractions has little or no effect on normal tissue radiation responses?

    • Repair

    • Redistribution of cells in the cell cycle

    • Repopulation

    • Reoxygenation


    Answers

    Answers

    1.NA

    2.2

    3.3

    4.3

    5.2

    6.4

    7.3

    8.4

    9.2

    10.1

    11.3

    12.1

    13.3

    14.4

    15.4

    16.1

    17.1

    18.4


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