Evaluation of the radiationsensitizerprotector andor antioxidant efficiencies using Fricke and PAG d

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Evaluation of the radiation-sensitizer/protector
and/or antioxidant efficiencies using Fricke and
PAG dosimeters

• Ridthee Meesat,
• Jean-Paul Jay-Gerin,
• Abdelouahed Khalil, Martin Lepage

29th Sept. 3rd Oct. 2008
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What are radiosensitizers, radioprotectors and
antioxidants?

• Radiosensitizers are used to increase radiation
  dose in radiation treatment.
• Radioprotectors are used to protect normal tissue
  during radiotherapy.
• Antioxidants can delay or prevent oxidative
  damage from oxidizing agents.

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H2O
Ionization
H2O -? eaq-, HO., H., H2, H2O2, H
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Primary yields (G-value) of radiolytic products
of water by low-LET radiation
C. Ferradini and J.-P. Jay-Gerin., Res. Chem.
Intermed. 26,549-565, (2000).
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Fricke dosimeter (presence of O2)

• Fe2 HO ? Fe3 OH-
• O2 H ? HO2
• Fe2 HO2 ? Fe3 H2O2
• Fe2 H2O2 ? Fe3 OH- HO

H
G(Fe3) 2.9 3(3.7) 2(0.8)3(0.02) G(Fe3)
15.60.3
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Fricke solution
Fe2
Fe2
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The effect of radiosensitizers, radioprotectors
and antioxidants on G(Fe3)
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Acrylamide gel dosimeter
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Acrylamide polymerization
Radiolysis
Initiation
Propagation
Termination
Martin Lepage et al, Phys. Med. Biol. 46,
1061-1074 (2001).
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The measurement of PAG by MRI

• Gamma irradiation of an acrylamide gel dosimeter

T2 Spin-spin relaxation time (s)
R2 relaxation rate (s-1)
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The effect of radiosensitizers, radioprotectors
and/or antioxidants on R2
SEN R2-dose sensitivity
DER Dose-enhancement ratio
PF Protector factor
RELATIVE R2 (s-1)
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Computer simulations

• Monte-Carlo technique
• The important information needed
• Reactions
• Rate constant of the reactions
• Diffusion coefficient
• Reaction radius

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Computer simulations
Physical stage (lt10-15 s)
Physico- chemical stage (10-15 -10-12 s)
radiolysis of water
Chemical non- homogeneous stage (10-12 -10-6 s)
...
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The results

• Radioprotectors
• Cystamine
• Thiourea
• Antioxidant
• Trolox
• Radiosensitizers
• NaI
• Iodine contrast agent (ICA)

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Cystamine

• Cystamine is a radioprotector that can be
  dissolved in water.
• Cystamine can delay CNS disorder in animals.1,2

1A. Dedeoglu et al, J. Neurosci. 15, 8942-8950
(2002) 2D. C. Craig et al, Neurobiol. Aging. 27,
871-879 (2006).
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The results of a radioprotector in the Fricke
system

• Effect of cystamine on G(Fe3)

Presence O2
Absence O2
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Results of antioxidant and radioprotector in an
acrylamide gel dosimeter
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The result of an antioxidant and radioprotector
in an acrylamide gel dosimeter
The effect of Trolox and Thiourea on the gel
dosimeter irradiated by Gamma ray
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Results of radiation-sensitizers in an acrylamide
gel dosimeter
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The result of a radiosensitizer in an acrylamide
gel dosimeter
The effect of NaI on an acrylamide gel dosimeter
irradiated by Co-60 (mean energy 1.25 MeV)
Kedge of I 33 keV
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The result of a radiosensitizer in an acrylamide
gel dosimeter
The effect of NaI on an acrylamide gel dosimeter
irradiated by Therapax (filter no. 6, 100 kVp,
10.4 mA, mean energy 40 keV)
Dose-enhancement ratio of Iodine
Kedge of I 33 keV
1C. Boudou et al Phys. Med. Biol. 52, 4881-4892
(2007).
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Iodine contrast agent (ICA)
Conray 30 (141.1 mg/ml of Iodine) Iothalamate
meglumine (ITA)
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The result of an Iodinated contrast agent (ICA)
in an acrylamide gel dosimeter
The effect of ICA on an acrylamide gel dosimeter
irradiated by Therapax (filter no. 6, 100 kVp,
10.4 mA, mean energy 40 keV)
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The result of an ICA in a clonogenic assay
The effect of ICA on cancerous cells (MC7-L1)
irradiated by Therapax (filter no. 6, 100 kVp,
10.4 mA, mean energy 40 keV)
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Conclusion

• Fricke and Acrylamide gel dosimeter have been
  used to measure the efficiency of
  radiation-sensitizers/protectors and
  antioxidants.
• In the Fricke dosimeter, radioprotectors and
  antioxidants compete with Fe2 for the reaction
  with water free radicals.
• In the acrylamide gel dosimeter, radioprotectors
  and antioxidants compete with the monomers for
  the reaction with water free radicals.
• The effect of a radiosensitizer in the Fricke
  dosimeter and the acrylamide gel dosimeter is to
  cause a dose enhancement.

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Acknowledgement

• The Royal Thai Government
• Prof. Martin Lepage (Ph.D.)
• Prof. Jean-Paul Jay-Gerin (Ph.D.)
• Prof. Abdelouahed Khalil (Ph.D.)
• Prof. Johan E. Van Lier (Ph.D.)
• Jitana Meesungnoen (Ph.D.)
• Mahbod Sedaghat (M.Sc.)
• Colleagues of the department
• .

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The cell survival by clonogenic assay
Principle of the clonogenic assay1
Irradiation
Transfer appropriate number of cells to dishes,
allow time for cells to attach
Prepare single-cell suspension
Prepare dilutions
Prepare survival curve
This technique can be difficult and time
consuming.2,3
1S. Lehnert, Biomolecular Action of Ionizing
Radiation, (2008), p53 2A. Slavitinek et al, Eur.
J Cancer 30A, 1376-1382 (1994). 3J. Kiefer,
Biological Radiation Effects, (1990), pp138-139
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Comparison between Fricke and acrylamide systems
PAG
Fricke dosimeter
Computer simulation
Acidity condition pH 0.46
pH 5.5
G(Fe3)
UV spectrophotometer
Polymerization
MRI
Radioprotectors
Radioprotectors
Indirect effect
Competition between Fe2 and compounds react with
radiolytic species (HO?, H?, HO2? and H2O2
Competition between monomer and compounds react
with radiolytic species (e-aq, H? and HO?)
Radiosensitizers
Radiosensitizers
Direct effect
Dose increase
Dose increase
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Objectives

• To use chemical systems to identify compounds
  having radiation-sensitizer/ protector and
  antioxidant properties.
• To use Monte Carlo simulations to help finding
  the mechanism of the action of these compounds.