Photon Activation Therapy

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This talk is dedicated to all of you young
scientists who will fulfill the goals of the
SESAME project by using the facility as an
instrument for peace and for the betterment of
the human condition.
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Photon Activation Therapy
Brenda Laster Dabney Dixon Sara Novick Zvi
Goldbart Itzhak Orion Peter Hambright Geraldine
LeDuc
Veronique Seror Jon Feldman Ron
Goldvasser Udi Sheleg

• Medical Applications of Synchrotron Radiation

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PROBLEMS In CANCER RADIOTHERAPY
DOSE is LIMITED BY THE TOLERANCE of NORMAL
TISSUES SURROUNDING the TUMOR.
THE DNA IS THE VITAL STRUCTURE WITHIN THE TUMOR
CELL THAT MUST BE DAMAGED in ORDER to KILL THE
CELL.
THE MASS of the DNA is 0.25 THE MASS OF THE
ENTIRE CELL.
The white spot in the brain region above
represents the tumor. The colored regions
represent surrounding normal tissues.
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The DNA Target
X - ray
0.25 of the cell mass
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Photoabsorption in the K or L shell of a high Z
atom ultimately leads to the emission of Auger
electrons.
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Because of their low energy (and short range),
Auger electrons densely ionize the DNA frequently
rendering the repair enzymes incapable of reading
the template.
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THE SIMULTANEOUS PRESENCE OF THESE TWO AGENTS IS
NEEDED TO INDUCE AN AUGER EFFECT IN THE HIGH Z
ATOM.
RADIATION SOURCE
THE AUGER ELECTRONS ARE RELEASED FROM THE
ATOM AND DEPOSIT THEIR ENERGY AT THE SPOT WHERE
THEY WERE EMITTED.
TARGET ATOM in DNA
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AUGER ELECTRONS

• When released from the indium atom the low energy
  Auger electrons will deposit their energy
  directly at the site of their emission.
• If the indium atom is situated in or close to
  tumor cell DNA, Auger electrons will densely
  ionize the DNA over a sphere of 25 nm.
• The Auger electrons act like an energy sink. The
  DNA is damaged so severely that the DNA repair
  mechanisms are ineffective.

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Radiation Source Requirements for Inducing Auger
Emission for Cancer Radiotherapy

• Monochromatic photons with a high cross section
  for interacting with the target atom

• Photons with sufficient energy to penetrate to
  the tumor at depth

PHOTONS With energies suitable for activating the
K or L absorption edge of the high Z atom
TUMOR With high Z atom, In or Pt, bound to DNA
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Where high energy photons can be used to
stimulate photoabsorption in an atom, such as
with platinum or gadolinium, Synchrotron
Radiation can be used independently as a
treatment facility. Where low energy photons are
required for stimulating photoabsorption in an
atom, such as the K absorption edges of In, Pt,
I, or Br, Synchrotron Radiation is a valuable
TOOL for predicting the therapeutic advantage of
a particular drug/radiation combination.
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Iodine-125 (E28 keV) and palladium-103 (E21
keV) brachytherapy seeds have suitable energies
for activating either the K or L absorption edges
of a number of different high Z atoms.
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Brachytherapy Implantation Technique
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Elemental Requirements for Inducing Auger
Emission in Cancer Radiotherapy

• The carrier molecule must be capable of
  transporting the high Z atom to tumor cell DNA

• The high Z atom must remain bound to cellular
  DNA throughout the irradiation interval

• A sufficient number of high Z atoms must be
  bound to DNA to be therapeutically effective

• The molecule must show minimal to no toxicity

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The mesotetrakis porphine sulfonate, TMPyP(4),
was shown to have met these criteria in a host of
different assays.
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X-ray Microscopy using Synchrotron Radiation is a
Valuable Tool for
Browsing the
Intracellular Network
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After digital subtraction of the above and below
edges..we can see
In collaboration with Janos Kirz
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This infra-red micrograph of a porphyrin entering
a cell was obtained by using infra-red light
obtained at the NSLS to fingerprint the carboxyl
terminus (COOH) of the porphyrin (yellow).
In collaboration with Gwynn Williams
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Platinum can be a very useful atom for PAT, when
incorporated in DNA, both for synchrotron and
brachytherapy radiations. Synchrotron-Biston et
al showed cure of brain tumors after injecting
Cisplatin and irradiating above the K absorption
of Pt (78.2 keV) at the medical beamline of the
ESRF Brachytherapy-Laster et al showed a delay in
tumor growth of breast tumors after injecting a
platinum-labeled porphyrin and irradiating above
the L absorption edge of Pt (14 keV) using
palladium-103 brachytherapy seeds
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Std. Err.
103Pd Tumor volume, mm3
Std. Err.
AET Tumor volume, mm3
Days, post seed implantation
27.5
155.9
18.6
117.5
0
12.9
150.9
15.3
112.8
3
26.0
228.3
25.7
110.6
5
44.1
223.0
29.4
121.5
7
58.6
221.8
26.9
123.1
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100.4
486.2
31.5
150.7
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52.6
312.2
44.9
116.5
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103.0
666.5
69.2
175.6
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170.9
746.1
81.9
200.1
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172.1
1093.1
91.2
232.6
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225.8
1233.6
90.6
280.2
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318.1
1759.2
133.9
356.2
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The mean tumor volumes on day 32 for PAT mice
compared to 103Pd-only indicates a potential
therapeutic gain factor of 5 for the AET
treatment compared to radiation alone.
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Data Analysis The term VVo expat adequately
describes an exponentially growing tumor. Log V
b at is the same term when expressing the
log of the tumor volume. This equation was used
to plot the growth rate of each tumor in all
experimental groups. Linear regression was
applied to obtain the best fit slope of the
line for each phase. Radiation-treated tumors
showed a biphasic component on each curve.
Curves of irradiated tumors were separated into
two phases, Phase 1 and 2. The log of tumor
volume was plotted as a function of time for each
phase.
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Treatment efficiency factors were calculated
according to the equation eff1-(a(treat)/a(con
trol) 100
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Survival of V-79 Chinese hamster cells irradiated
at the ESRF
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Repair of V-79 Chinese hamster cells after split
dose experiment carried out at the ESRF
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THANK YOU FOR YOUR ATTENTION!