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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5255_Библиотеки_им_академика_М_И_Перельмана
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472
(1 ( / )
M app M i Mi
( )
1000( )
LNAA M
M
PET Quantification
K K C K
( )
(10)
Where KM is the undisturbed affinity for leucine and Ci and KMi represent the
concentrations and affinities of all the other LNAAs in plasma. Moreover, consistent with
Michaelis-Menten kinetics, it was shown that the transport rate constant K1 for leucine is
inversely related to the sum of all LNAAs in plasma and largely independent from plasma
leucine concentration (22-24). In addition, Stout et al. presented data showing that the
unidirectional inflow parameter K1 correlates with the total sum of all LNAAs but does not
correlate with the K
data, which indicated similar K
weighted sum of all LNAAs. We confirmed this result with our
M(app)
values for leucine in both males and females despite
M(app)
significantly different total LNAA plasma levels. In order to account for the effect of varying
total LNAA plasma levels on the K1 transport parameter, the Kcplx was normalized to a
standard total LNAA level of 1000 µM. The value of 1000 µM approximates the mean
normal LNAA plasma concentration (our data indicates an overall mean value of 918 +
80µM). The normalized Kcplx is then defined as,
'
Kcplx Kcplx
(11)
Kcplx’ represents the unidirectional uptake rate constant for leucine normalized to a
standard total LNAA concentration. If the Kcplx’ is used in equation-5, we obtain the
protein synthesis rate normalized to a standard total sum of all LNAAs (PSR’). It should be
noted that whereas Kcplx can be derived either from compartmental modeling or noninvasively using a left ventricular input function and the Patlak graphical analysis, and
thus PSR can only be determined using compartmental modeling of the entire tissue time
activity curve.
We found that the mean plasma concentration of the sum of all LNAA was 13% higher
in males (981 + 86 µM) compared to females (850 + 76 µM, p = 0.012), whereas the plasma
leucine concentration was found to be similar in both sexes (males, 64 + 20 µM, females 58
+ 21 µM, p = 0.57). The whole brain value for was determined as 0.64 + 0.03 and did not
show a gender difference (p = 0.66). Whole brain Kcplx values were found to be significantly
higher in females (0.0162 + 0.0024) as compared to males (0.0121 + 0.0031; p = 0.011);
however, after normalization of the Kcplx to a standard plasma concentration of the sum of
all LNAAs (Kcplx’), the Kcplx’ was similar between the sexes (p = 0.21), as was the PSR’
(1.24 + 0.49 µM/min in males; 1.29 + 0.62 µM/min in females; p = 0.87). No relationship
between plasma leucine and Kcplx (r = 0.08, p = 0.75) was observed. We also found a
significant correlation between the PSR and the Kcplx derived using the Patlak graphical
analysis ( = 0.65, p < 0.001). On the basis of our findings, we concluded that both the
Kcplx macroparameter as well as the PSR are stable indices of brain protein synthesis and
are appropriate measures for testing altered protein synthesis in neurological disorders.
GSPant\Newbook\Final-2008\30-chp\472
PET Quantification
473
References
1. Sokoloff L, Reivich M, Kennedy C, et al. The [14C] deoxyglucose method for the measurement of
local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized
albino rat. J Neurochem 1977; 28: 897-916.
2. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to brain transfer constants
from multiple-time uptake data. Cereb Blood Flow Metab 1983; 3: 1–7.
3. Zasadny KR, Wahl RL. Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-
fluoro-2-deoxy-D-glucose: variations with body weight and a method for correction. Radiology 1993
Dec; 189(3): 847-50.
4. Kim CK, Gupta NC, Chandramouli B, Alavi A. Standardized uptake values of FDG: body surface
area correction is preferable to body weight correction. J Nucl Med 1994; 35: 164–167.
5. Freedman NM, Sundaram SK, Kurdziel K, et al. Comparison of SUV and Patlak slope for monitoring
of cancer therapy using serial PET scans. Eur J Nucl Med Mol Imaging 2003; 30: 46–53.
6. Hoekstra CJ, Paglianiti I, Hoekstra OS, et al. Monitoring response to therapy in cancer using (18F)-2-
fluoro-2-deoxy-D- glucose and positron emission tomography: an overview of different analytical
methods. Eur J Nucl Med 2000; 27: 731–743.
7. Hunter GJ, Hamberg LM, Alpert NM, Choi NC, Fischman AJ. Simplified measurement of deoxyglucose
utilization rate. J Nucl Med 1996; 37: 950–955.
8. Sundaram SK, Freedman NM, Carrasquillo JA, et al. Simplified kinetic analysis of tumor 18F-FDG
uptake: a dynamic approach. J Nucl Med 2004 Aug; 45(8): 1328-33.
9. Hamberg LM, Hunter GJ, Alpert NM, et al. The dose uptake ratio as an index of glucose metabolism:
useful parameter or oversimplification? J Nucl Med 1994; 35:1308–1312.
10. Barrio JR, Keen RE, Ropchan JR, et al. L-[1-11C]Leucine: Routine synthesis by enzymatic resolution.
J Nucl Med 1983; 24: 515-521.
11. Phelps ME, Barrio JR, Huang SC, Keen RE, Chugani H, Mazziotta JC. Criteria for the tracer kinetic
measurement of cerebral protein synthesis in humans with positron emission tomography. Ann Neurol
1984; 15 Suppl: S192-202.
12. Hawkins RA, Huang SC, Barrio JR, et al. Estimation of local cerebral protein synthesis rates with
L-[1-11C]leucine and PET: methods, model, and results in animals and humans. J Cereb Blood Flow
Metab 1989; 9(4): 446-60.
13. Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L. Measurement of local cerebral protein
synthesis in vivo: influence of recycling of amino acid derived from protein degradation. Proc Natl
Acad Sci USA 1988; 85: 9341-5.
14. Mu F, Mangner TJ, Chugani HT. Facile synthesis of L-[11C]leucine as a PET radiotracer for the
measurement of cerebral protein synthesis. J Label Compd Radiopharm 2005; 48: S1-S341.
15. Schmidt KC, Cook MP, Qin M, Kang J, Burlin TV, Smith CB. Measurement of regional rates of
cerebral protein synthesis with L-[1-11C]leucine and PET with correction for recycling of tissue
amino acids: I. Kinetic modeling approach. J Cereb Blood Flow Metab 2005; 25(5): 617-28.
16. Smith CB, Schmidt KC, Qin M, et al. Measurement of regional rates of cerebral protein synthesis
with L-[1-11C]leucine and PET with correction for recycling of tissue amino acids: II. Validation in
rhesus monkeys. J Cereb Blood Flow Metab 2005; 25(5): 629-40.
17. Sundaram SK, Muzik O, Chugani DC, Mu F, Mangner TJ and Chugani HT. Quantification of Protein
Synthesis in the Human Brain Using L-[1-11C]-Leucine PET: Incorporation of Factors for Large
GSPant\Newbook\Final 2008\30-chp\473
474
PET Quantification
Neutral Amino Acids in Plasma and for Amino Acids Recycled from Tissue. J Nucl Med 2006;
47(11): 1787-1795.
18. Keen RE, Barrio JR, Huang SC, Hawkins RA, Phelps ME. In vivo cerebral protein synthesis rates
with leucyl-transfer RNA used as a precursor pool: determination of biochemical parameters to
structure tracer kinetic models for positron emission tomography. J Cereb Blood Flow Metab 1989;
9(4): 429-45
19. Abrams RM, Burchfield DJ, Sun Y, et al. Rates of local cerebral protein synthesis in fetal and
neonatal sheep. Am J Physiol 1997; 272: R1235-44.
20. Sun Y, Deibler GE, Jehle J, et al. Rates of local cerebral protein synthesis in the rat during normal
postnatal development. Am J Physiol 1995; 268: R549 – 61.
21. Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the
blood-brain barrier. J Neurochem. 1987; 49(5): 1651-8.
22. Shulkin B, Betz A, Koeppe R, Agranoff B. Inhibition of neutral amino acid transport across the
blood-brain-barrier. J Neurochem 1995; 64: 1252-57.
23. Koeppe RA, Shulkin BL, Rosenspire KC, et al. Effect of aspartame derived phenylalanine on neutral
amino acid uptake in human brain: A PET study. J Neurochem 1991; 56: 1526-35.
24. Stout D, Huang S, Melega W, Raleigh M, Phelps M, Barrio J. Effects of large neutral amino acid
concentrations on 6-[18F] Fluoro-L-Dopa kinetics. J Cereb Blood Flow Metab 1998; 18: 43-51.
GSPant\Newbook\Final-2008\30-chp\474
Part – V
Health Physics & Radiation Safety
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Basics Concepts in Radiobiology
G. S Pant, S. Senthamizhchelvan and O. Nair
Radiobiology is the study of the action of ionising radiation on living system (1). The
main focus of radiobiology is the mechanisms of action and effects of radiation on biological
systems, i.e. on sub-cellular and cellular levels. Radiation causes ionizations of atoms,
which may affect molecules, cells, tissues, organs, and the whole body. Although we tend to
think of biological effects in terms of the effect of radiation on living cells, in actuality,
ionizing radiation, by definition, interacts only with atoms/molecules by a process called
ionization. Thus, the biological damage begins with the consequence of radiation interactions
with the atoms/molecules forming the cells.
Radiation interaction with cells
The initial physical effects of radiation are ionisation and excitation of the atoms/molecules
of the medium through which they pass. These events result in physicochemical reactions.
The excited and ionised molecules also form diffusible free radicals, which bring about
chemical changes in the molecules of the system. The chemical changes in biologically
important molecules lead to the biological effects in the system. Irradiation results in damage
of all the intracellular structure with nucleus being the most sensitive site. The nucleus
consists of an important structure in the form of chromosomes, which contain DNA
(deoxyribose nucleic acid) molecules. Radiation can break the DNA strand (single or double),
alter the base, destruct the sugar molecules or produce cross links and form dimers. The
damage to DNA molecules may lead to cell death, loss of reproductive capacity or mutation.
Time scale of radiation damage
The timescale involved between the breakage of chemical bonds and the biological effect
may vary from hours to years, depending upon the type of damage. If cell kill is the result,
it may happen in hours to days, when the damaged cell attempts to divide (early effects of
radiation). This can result in early tissue reactions (deterministic effects), if many cells are
killed. If the damage is associated with cancer induction, then its expression may be delayed
47 7
478
H
H
Basics Concepts in Radiobiology
for years (late effects of radiation). Ionizing radiation is known to cause leukaemia and
some of the solid tumours in tissues such as lung, skin, thyroid and breast. In addition to
carcinogenesis, the late effects of radiation include: delayed tissue reactions (deterministic
effects) such as fibrosis and other reactions mediated by vascular deficiencies; life span
shortening (due largely to cancer lethality); genetic damage, where the effects may be
expressed in subsequent generations; and potential effects to the foetus.
Reactive free radicals
It has long been recognized that the damaging effects of ionizing radiation are brought about
by both direct and indirect mechanisms. The direct action produces disruption of sensitive
molecules in the cells whereas the indirect action is through the production of highly reactive
free radicals, such as
OH
,
, and
an unpaired orbital electron in its outer shell. This unpaired electron in the outer shell makes
the atom/molecule chemically highly reactive. High energy radiation breaks chemical bonds
and this creates free radicals in the body. The free radicals can induce chemical alteration in
the body. The half life of these free radicals is extremely short (10
they immediately react with any bio-molecules in the vicinity and produce highly sitespecific oxidative damage. These changes can disrupt cell function and may even kill them.
An estimated 60% - 70% of tissue damage induced by ionising radiation is believed to be by
radicals formed from the radiolysis of water (2).
OH
e
. Free radical is a free atom or molecule carrying
aq
-6
-10
– 10
second); however,
Radiolysis of water
The radiation action on water plays a vital role since the biological systems contain more
than 80% of water. Radiation decomposes water and forms free radicals. The water molecule
needs very small energy for excitation (5 eV to break the bond) and about 13 eV of energy
to get ionised.
Excitation of water molecule
22
Where
radicals. These radicals are chemically reactive. There is great possibility of their
OH
is an excited water molecule possessing excess energy and forms
*2OH
recombination if they lie very close to each other.
Ionisation of water molecule
eOHRadiationOH
22
The water ion decomposes and forms a free radical as follows:
HOHOHRadiationOH *
and
Basics Concepts in Radiobiology
479
2
OHHOH
The hydroxyl radical (
) so formed is a powerful oxidising agent and exceedingly
OH
reactive. The electron loses its kinetic energy by collisions on its path in the medium and is
finally captured by a water molecule or a hydrogen ion as shown below:
22
HHe
eOHe
2
aq
OHHOHOHe
The hydrated or aqueous electron so formed is a powerful reducing agent and readily
reacts with radiolysis products and reduced products such as disulphide groups.
The contribution of the indirect action is significant in case of low LET radiation such as xrays, gamma rays and electrons whereas, direct action plays a vital role with high LET
radiation. In a biological system the contribution of indirect action is more pronounced than
the direct effect. Among the DNA damage produced by free radicals; oxidized bases, DNA
single and double strand breaks, and DNA- protein cross links are the most significant.
These occur primarily by interaction of free radicals with DNA bases and to a lesser extent,
with DNA sugar. DNA damage caused by radiation exhibit multiple damaged sites and
clustered legions.
Radiation can kill cells by two distinct mechanisms known as apoptosis and necrosis.
The apoptosis, also termed as programmed cell death, takes place in interphase within few
hours of irradiation. It shrinks its nuclear and cytoplasmic materials, condenses and then
breaks into membrane bound fragments (apoptic bodies) that are finally phagocytosed.
Radiation induced apoptosis depends on the functional activity of the p53 gene and is a
protective mechanism by which the body gets rid of radiation damaged cells. It is believed
to be the significant cause of death of a cell exposed to high radiation dose. Another kind of
cell death known as necrosis is morphologically distinct from apoptosis. It is the pathological
cell death caused by cellular metabolic collapse, when a cell can no longer maintain ionic
homeostasis, in response to the injury.
Recovery of radiation damage
Radiation induced damage may be lethal, potentially lethal or sub-lethal. Recovery of cells
from radiation damage is considered in terms of their proliferation capacity.
(a) Recovery from potentially lethal damage : The radiation induced cell death can be
avoided under certain definite conditions. These injuries, generally called potentially lethal,
are either repaired and the cells survive or materialise and the cells die. Potentially lethal
damage can be revealed by change in the survival curve by changing the conditions of the
480
environment of the cells during first hour post irradiation. If a cell is damaged in G1 phase
of the cell cycle, there is a chance for its repair provided it does not undergo DNA synthesis.
During DNA synthesis the cell may die. If some how the G1 phase is artificially prolonged,
so that the cell remains in this phase, the cell may survive due to some enzymatic repair.
There are other such conditions, which inhibit the cell to proceed further (in terms of
protein synthesis etc) and provide sufficient chance for the cell to repair from radiation
injury.
(b) Recovery from sublethal damage : This type of damage or injury is complete
within few hours of the exposure. Thus the slowly responding cells (connective tissues,
CNS, kidney etc) get better chance of repair than acutely responding normal and most of the
malignant tissues. This type of damage was revealed by split-dose (fractionated) irradiation.
Because of the slow repair mechanism in some of the cells the time spacing between the
fractionations should be at least 6 h but commonly it is kept as 24 h in practice.
Basics Concepts in Radiobiology
Molecular mechanism of repair
With respect to the time of occurrence there are three types of repair processes:
a) Pre-replicative repair occurs before the phase of DNA replication. The DNA breaks
may rejoin and the damaged bases may be removed (excised). In a simple situation
the breaks may be rejoined by ligase but in other situations several enzymes (such
as endonucleases, exonucleases, DNA-polymerase, DNA-ligase) participate in the
recovery. Some recovery processes are fast and some are slow and take 1-2 h. The
base damage is recognised by specific gamma-endonuclease, then incised and replaced
with the help of complementary section of undamaged DNA chain as a template.
b) Post-replicative repair is a process in which a cell retains its viability notwithstanding
the presence of defects in the DNA. In true sense it is rather ability of overcoming
the injury and not a recovery. The altered DNA may be retained and passes through
cell generations and manifest as late effect of radiation exposure.
c) Replicative repair is the DNA repair during its replication process. This is
accomplished by removing the injuries during replication in the area of chain growth
or by continuing elongation bypassing the injury.
The difference in the functional ability between original DNA molecule and the repaired
one is not exactly known. The recovery of cells is recorded in terms of survival curves. It is,
therefore, difficult to know their functional activity and also the fate of their descendants.
Factors influencing the radiation effect
Quality of radiation
The biological damage also depends upon the type of radiation to which the system is
Basics Concepts in Radiobiology
dl
481
exposed. All radiations are not alike. The effectiveness of radiation may be expressed in
terms of the following two parameters (LET and RBE).
a) Linear Energy Transfer (LET) : The radiation type is better explained in terms of
its linear energy transfer. The LET is defined as the energy transferred per unit length of the
track and mathematically expressed as:
LET
dE
Where dEis the average energy locally deposited in the medium by a charged particle
of given energy in traversing a distance dl. It is usually expressed in keV/micron (m).
Since most of the radiation have wide spectrum of energies and/or change their ionisation
density along the track, the LET cannot have a single value. It is therefore, expressed as an
average quantity. The average may be either track average or energy average. The track
average is obtained by dividing the track into equal lengths and find the mean of energy
deposited in each length whereas the energy average is obtained by dividing the track into
equal energy increments and then averaging the track length over which these increments
are deposited. These two methods of LET calculations yield different values. The LET is
commonly used to express the quality of different types of radiation. The typical values of
track average for 60Co-gamma rays and 250 kV x-rays have LET values of about 0.3 and 2
keV/m respectively whereas the corresponding value for 14 MeV neutrons is 12 keV/m
and for heavy charged particles is 100 to 2000 keV/m.
b) Relative Biological Effectiveness (RBE) : Equal doses of different radiations do not
produce the same biological effect in a biological system (organ or tissue) due to variation
in their biological effectiveness. RBE is defined as the ratio of the amount of standard
radiation (250 kV x-rays) to produce a given biological effect in a system to the amount of
test radiation to produce the same biological effect in the same system.
RBE
RBE depends on following factors:
LET of radiation
Radiation dose
Mode of radiation exposure (continuous/fractionation)
Dose rate and
The biological system exposed
log)250(tan
log
systemaineffecticalbiogivenaproducetoraysxkVradiationdardsofAmount
systemsametheineffecticalbiosametheproducetoradiationtestofAmount
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