either cell death or survival depending on the extent of given damage and the repair
capability of the cells. Generally, the main target for the biologic effects by ionizing
radiation in the cells is DNA. According to the physical properties of ionizing
radiation, several DNA damages are induced by deposition of radioactivity;
single-strand and double-strand DNA breaks, DNA base damage, and DNA-protein
crosslinks [6]. Second, ionizing radiation that has a long range in tissues allows
killing tumor cells located adjacent to the cells harnessing the target. So, even cells
that lack targets can be affected by ionizing radiation, when they are placed within
the particles’ range. This collateral damage caused by ionizing radiation is as
known as ‘cross-fire effect’, and it is helpful to overcome heterogeneity of
expression of targets within a cancer [7]. Next, there is another mechanism that
ionizing radiation can render damage to cells located far from the target cells. Often
cells receive damages that are not directly traversed by ionizing radiation. This is
defined as ‘bystander effect’, and it occurs when damaged cells release cytokines
and free radicals [8]. In addition, radiation can activate various cell death pathways,
since radiation causes damage not only to DNA but also to cell membranes and
organelles including mitochondria that could initiate signaling of apoptosis [8, 9].
Internal radiation therapy generates heterogeneous, low-dose rate and continuous
irradiation over hours and days. Irradiation at low-dose rate provides a window of
opportunity for the cells to repair radiation-induced sub-lethal damages and to
proliferate after recovery from the damage. In addition, the physical characteristics
of particle-emitting radionuclides can affect biological effect of internal radiation
therapy. For example, linear energy transfer (LET) means the energy that is released
by ionizing radiation over a certain distance, and it depends on the nature of the
emitted radiation from the radionuclides. Low LET radiation mainly causes
sub-lethal damage that can be easily repaired, such as sparse ionization and individual DNA lesions, and high LET radiation are more cytotoxic than low LET
radiation at the equivalent absorbed doses [7].
The most commonly used radionuclides in the clinical trials are beta-particle
emitters such as lutetium-177 (
177 Lu), yttrium-90 (
90
Y), rhenium-188 (
188 Re),
copper-64 (
64 Cu) and iodine-131 (
131
I). They emit low LET radiation (*0.2 keV/l
m) in the form of beta particles, internal conversion electrons, as well as
gamma-rays or x-rays [10]. It might be undesirable since low LET radiation causes
sub-lethal damages to cancer cells. However, beta emitters are often considered
ideal for treating large tumors because of their long range and relatively long
physical half-life. Beta emitter with a long range enables to deliver radiation
damage not only tumor cells harboring targets but also neighboring cells without
targets on their cell surfaces, thus it helps overcoming heterogeneous target
expression within a tumor. So called ‘cross-fire irradiation’ is particularly advantageous, when not all the tumor cells can be reached by radiopharmaceuticals owing
to the heterogeneous distribution of targets in the tumor tissues. Alpha emitters such
as
213 Bi,
212 Bi,
211 At, and
225 Ac that produce high LET radiation (50–230 keV/lm)
have desirable characteristics as cancer therapeutics, since they produce clusters of
DNA damage that are difficult to repair. Moreover, the high cytotoxicity of high
434
S. W. Oh and D. S. Lee
capability of the cells. Generally, the main target for the biologic effects by ionizing
radiation in the cells is DNA. According to the physical properties of ionizing
radiation, several DNA damages are induced by deposition of radioactivity;
single-strand and double-strand DNA breaks, DNA base damage, and DNA-protein
crosslinks [6]. Second, ionizing radiation that has a long range in tissues allows
killing tumor cells located adjacent to the cells harnessing the target. So, even cells
that lack targets can be affected by ionizing radiation, when they are placed within
the particles’ range. This collateral damage caused by ionizing radiation is as
known as ‘cross-fire effect’, and it is helpful to overcome heterogeneity of
expression of targets within a cancer [7]. Next, there is another mechanism that
ionizing radiation can render damage to cells located far from the target cells. Often
cells receive damages that are not directly traversed by ionizing radiation. This is
defined as ‘bystander effect’, and it occurs when damaged cells release cytokines
and free radicals [8]. In addition, radiation can activate various cell death pathways,
since radiation causes damage not only to DNA but also to cell membranes and
organelles including mitochondria that could initiate signaling of apoptosis [8, 9].
Internal radiation therapy generates heterogeneous, low-dose rate and continuous
irradiation over hours and days. Irradiation at low-dose rate provides a window of
opportunity for the cells to repair radiation-induced sub-lethal damages and to
proliferate after recovery from the damage. In addition, the physical characteristics
of particle-emitting radionuclides can affect biological effect of internal radiation
therapy. For example, linear energy transfer (LET) means the energy that is released
by ionizing radiation over a certain distance, and it depends on the nature of the
emitted radiation from the radionuclides. Low LET radiation mainly causes
sub-lethal damage that can be easily repaired, such as sparse ionization and individual DNA lesions, and high LET radiation are more cytotoxic than low LET
radiation at the equivalent absorbed doses [7].
The most commonly used radionuclides in the clinical trials are beta-particle
emitters such as lutetium-177 (
177 Lu), yttrium-90 (
90
Y), rhenium-188 (
188 Re),
copper-64 (
64 Cu) and iodine-131 (
131
I). They emit low LET radiation (*0.2 keV/l
m) in the form of beta particles, internal conversion electrons, as well as
gamma-rays or x-rays [10]. It might be undesirable since low LET radiation causes
sub-lethal damages to cancer cells. However, beta emitters are often considered
ideal for treating large tumors because of their long range and relatively long
physical half-life. Beta emitter with a long range enables to deliver radiation
damage not only tumor cells harboring targets but also neighboring cells without
targets on their cell surfaces, thus it helps overcoming heterogeneous target
expression within a tumor. So called ‘cross-fire irradiation’ is particularly advantageous, when not all the tumor cells can be reached by radiopharmaceuticals owing
to the heterogeneous distribution of targets in the tumor tissues. Alpha emitters such
as
213 Bi,
212 Bi,
211 At, and
225 Ac that produce high LET radiation (50–230 keV/lm)
have desirable characteristics as cancer therapeutics, since they produce clusters of
DNA damage that are difficult to repair. Moreover, the high cytotoxicity of high
434
S. W. Oh and D. S. Lee