Introduction
Radiotherapy (RT) plays an important role in the treatment
of pelvic tumors. Up to 30% of all cancers originate
from the pelvis or have a significant pelvic component.
Tumors of the pelvic region are more common in men.
According to 2024 statistics, 43% of new patients in men
(bladder, rectum, colon, and prostate) and over 14% in
women (uterus, ovary, rectum, and vagina/vulva, etc.)
were diagnosed with tumors originating from the pelvic region in the United States.[] The aim of radiotherapy
is to deliver the desired dose homogeneously and completely
to the target volume while providing maximum
protection to the surrounding normal tissues. In radiotherapy
planning, normal tissues are protected by excluding
them from the radiation field as much as possible.
RT-induced changes in normal tissues depend on
many factors, such as beam type, RT parameters (dose,
fractionation, total duration, irradiation technique, etc.),
irradiated normal tissue volume, tissue and cell characteristics,
and whether radiosensitizing and radioprotective
agents or chemotherapeutic drugs are used together
with RT. Modern RT techniques (three-dimensional
conformal RT, intensity-modulated RT, etc.) allow preservation
of normal tissues as much as possible. In the
treatment of many tumors, it is inevitable that a certain
amount of normal tissue is included in the target volume.
Drugs that aim to protect normal tissues within the radiotherapy
field from radiation effects without reducing
tumor control are defined as "radioprotective agents".[]
The best-known group of radioprotectors are sulfhydryl
(SH) compounds. The protective effect of sulfhydryl
compounds is provided by the ability of the SH groups
they contain to capture free radicals. Amifostine is a
prodrug that is phosphorylated by alkaline phosphatase
of vascular endothelial cells and converted into its active
metabolite, free thiol. Free thiol acts by binding free
radicals produced by radiation.[] Studies have shown
that amifostine is effective in the prevention of normal
tissue damage due to RT and chemotherapy (CT) and
reduces the dose-limiting toxic effects of treatment.[]
The radioprotective effects of amifostine on the bladder
are mostly based on information obtained from clinical
studies. To the best of our knowledge, no preclinical
research has been conducted on this topic yet.
Carnitine is a natural substance that acts as a carrier
in the beta oxidation of fatty acids, transport to
the mitochondrial membrane, and removal of toxic
metabolites such as acyl-CoA and acylcarnitine from
the mitochondria. Carnitine and its short-chain esters,
propionyl-L-carnitine and acyl-L-carnitine, are
both endogenously synthesized in the human body
and found in the diet.[] Carnitine is an essential factor
of some enzymes required for the transformation
of long-chain fatty acids and acts as a scavenger of free
radicals. Carnitine may play a modulatory role against
ionizing radiation-induced free radicals in cells with
its antioxidant and free radical scavenging properties.
[] Although carnitine has been shown to have a radioprotective
impact on a variety of tissues, its protective
effect on the bladder has not yet been investigated.
The purpose of this study was to assess L-carnitine's
potential protective role against acute bladder toxicity
caused by radiation and, if it exists, to compare it to the
amifostine effect.
Methods
Animals
All animal experiments were conducted in accordance
with the guidelines of the Institutional Animal Ethics
Committee. In this study, 30 male Wistar Albino rats
with an average weight of 170?200 g, aged 3 months,
were used. All rats were housed in polypropylene cages
(containing sterile paddy husk, procured locally, as
bedding throughout the experiment) of 8 rats each in
an environment with 50-60% humidity, 22±1°C temperature,
and a 12-hour night and 12-hour daylight period
until the end of the experiment. All animals had
free access to sterile water and food.
Experimental Design
The 30 male rats were randomly divided into four groups:
1. Control group (n=6): Rats pretreated with 1 ml of
0.9% NaCl solution with a single-dose injection intraperitoneally
(i.p.) without radiation.
2. AMI + RT group (n=8): Rats pretreated with 1 ml
of AMI (200 mg/kg) (Ethyol; MedImmune Pharma
B.V., Nijmegen, the Netherlands) with a single-dose
injection i.p., 30 minutes prior to irradiation, and
then irradiated individually with a single dose of 20
Gy radiation.
3. LC + RT group (n=8): Rats pretreated with 1 ml of
LC (300 mg/kg) (Santa Pharma Co., Istanbul, Türkiye)
with a single-dose injection i.p., 30 minutes
prior to irradiation, and then irradiated individually
with a single dose of 20 Gy radiation.
4. RT group (n=8): Rats pretreated with 1 ml of 0.9%
NaCl solution i.p., 30 minutes prior to irradiation,
and then irradiated individually with a single dose
of 20 Gy radiation.
All experimental procedures were performed on anesthetized
rats. During irradiation, anesthesia was maintained
with a mixture of 100 mg/kg i.p. ketamine (Ketalar;
Pfizer Ilaçlari, Istanbul, Türkiye) and 3.9 mg/kg
i.p. xylazine (Rompun; Bayer Türk Kimya Sanayi, Istanbul,
Türkiye).
Bladder Irradiation
The rats in the AMI + RT, LC + RT, and RT groups were
irradiated individually with a single dose of 20 Gy. The
rats were anesthetized and then fixed onto a 20×30 cm
blue Styrofoam treatment couch (Med-Tec, Orange City, IA, USA) in a supine position. Correct positioning of irradiation
fields was controlled for each rat using a therapy
simulator (Mecaserto-Simics, Paris, France). Irradiation
was delivered by a cobalt-60 teletherapy unit (Cirus;
cis-Bio Int., Gif Sur Yvette, France) at a source?surface
distance of 65 cm. A single dose of 20 Gy radiation was
given at a depth of 1.5 cm (half thickness) with a dose
rate of 129.13 cGy/min to the 4×3 cm pelvic area including
the bladder. Special dosimetry was used for the
irregular fields. The dose homogeneity across the field
was ±5%. After the irradiation, the animals were closely
observed until recovery from anesthesia. The animals in
the control group received equal-field sham irradiation.
Euthanasia
The rats were euthanized 5 days after the radiation
therapy. Prior to euthanasia, the rats received anesthesia
using a combination of ketamine and xylazine.
Euthanasia was performed by decapitation. The bladder
was removed and placed in 10% formaldehyde for
histopathologic examination.
Histopathological Evaluation
After 24 hours of formaldehyde fixation, the tissues
were sliced with 1 transverse incision in the middle and
placed in tissue tracking. After tissue tracking, paraffin
embedding was performed, and 4-micron thick sections
were taken. The sections were stained with hematoxylin-
eosin stain and examined under a light microscope.
Vascular wall thicknesses were measured with a
Zeiss Axioplan 2 imaging light microscope (KS 300 Imaging
System). Epithelial desquamation, epithelial regeneration,
stromal edema, stromal fibrosis, stromal inflammation,
increased vascularization, and vessel wall
thickness were also evaluated as present or absent. All
histopathological evaluations were made by a pathologist
who was blinded to the study group allocations.
Statistical Analysis
A normal distribution test was performed for the measurable
data, and Kruskal-Wallis analysis of variance
was used for intergroup comparisons. The Mann-Whitney
U test was used for pairwise comparisons. Differences
in vessel wall thickness between groups were evaluated
by an ANOVA test. If the p-value was less than
0.05, it was judged as "significant." The STATISTICA
AXA 7.1 statistical program was used for this analysis.
Results
Among the evaluated parameters, epithelial desquamation
(p=0.001), stromal edema (p=0.003), and vessel wall thickness (p=0.003) showed statistically significant
differences between the groups.
Epithelial desquamation was observed in 14 out
of 30 animals across all experimental groups. Within
the RT group and the LC+RT group, epithelial desquamation
occurred in 6 out of 8 animals. Only 1 out
of 6 animals in the control group exhibited epithelial
desquamation. Statistical analysis revealed no significant
difference in epithelial desquamation between the
LC+RT and RT groups (p>0.05). However, both the
RT group (p=0.001) and the LC+RT group (p=0.001)
showed statistically significant exacerbation of epithelial
desquamation compared to the control group
(Table 1). Furthermore, epithelial desquamation was
observed in 1 out of 8 animals in the AMI+RT group,
with no significant difference compared to the control
group. Notably, the addition of amifostine to radiotherapy
resulted in a significant reduction in epithelial desquamation
compared to radiotherapy alone (p=0.003).
Table 1 Epithelial desquamation seen in the groups
Stromal edema was observed in 18 out of 30 animals
included in the study. Within the RT group, stromal
edema was present in 7 out of 8 animals, while
none of the 6 animals in the CONT group exhibited
this condition. Consistent with expectations, the incidence
of stromal edema was significantly higher in the
RT group compared to the CONT group (p<0.0001)
(Table 2). Additionally, stromal edema was observed
in 5 out of 8 animals in the AMI+RT group and 6 out
of 8 animals in the LC+RT group. Notably, both the
AMI+RT (p=0.008) and LC+RT (p=0.002) groups demonstrated statistically significant elevations in stromal
edema compared to the CONT group. Importantly,
no significant difference in stromal edema was observed
between the AMI+RT and LC+RT groups when
compared to the RT group.
Table 2 Stromal edema seen in the groups
Vascular wall thickness was markedly increased
in animals that received radiation therapy (RT) alone
compared to the CONT group (p<0.0001) (Table 3). In
the RT group, the highest recorded wall thickness was
27.4 µm, the lowest was 16.78 µm, with a mean of 21.92
?m. Similarly, in the LC+RT group, the highest wall
thickness was 23.02 µm, the lowest was 12.55 µm, with
a mean of 19.15 µm. In the AMI+RT group, the highest
wall thickness measured was 23.3 µm, the lowest was
10.05 µm, with a mean of 17.36 µm. Conversely, in the
CONT group, the highest wall thickness was 20.31 µm,
the lowest was 10.05 µm, with a mean of 15.72 µm.
Table 3 Vascular wall thickness in the groups
The co-administration of amifostine with RT resulted
in a statistically significant reduction in vessel
wall thickness (p=0.009). However, no similar effect
was observed with carnitine in combination with RT.
Notably, the CAR+RT group exhibited a significantly
increased vessel wall thickness compared to the CONT
group (p=0.005). Nevertheless, no significant difference
in vessel wall thickness was detected between the
AMI+RT and CONT groups. Examples of histopathological
findings are given in Figures 1-4.
Fig. 1. Amifostine+radiotherapy group. In addition to
regeneration in the surface epithelium, scattered
and mildly inflammatory cells, edema, and connective
tissue increase are observed in the stroma.
The thickest vessel wall thickness that can be
observed is 17.62 µm (Hematoxylin- eosin, X50).
Fig. 2. Control group. The surface epithelium appears
normal, with mild edema and fibrosis in the stroma.
The thickest vessel wall thickness that can be
observed is 14.91 (Hematoxylin- eosin, X50).
Fig. 3. Carnitine+radiotherapy group. In addition to
desquamation and regeneration in the surface
epithelium, scattered and mildly inflammatory
cells, edema, and connective tissue increase are
observed in the stroma. The thickest vessel wall
thickness that can be observed is 17.99 µm (Hematoxylin-
eosin, X50).
Fig. 4. Radiotherapy group. In addition to desquamation
of the surface epithelium, there is marked
edema and connective tissue increase in the stroma.
The thickest vessel wall thickness that can be
observed is 19.37 µm (Hematoxylin- eosin, X50).
Discussion
The use of advanced RT techniques has led to significant
improvements in cancer treatment. By using
modern treatment techniques, the goal is to achieve
maximum tumor control and minimum normal tissue toxicity. However, despite all technological advances,
it is not possible to eliminate both acute and late side
effects related to RT. Therefore, the role of radioprotectors
used during irradiation becomes more important
to minimize normal tissue toxicity.
In our study, epithelial desquamation, epithelial
regeneration, stromal edema, stromal fibrosis, stromal
inflammation, increased vascularization, and vessel
wall thickness were evaluated as histopathologic
changes caused acutely by 20 Gy RT applied in a single
fraction. Among the above histopathologic changes,
statistically significant differences were found in epithelial
desquamation, stromal edema, and vessel wall
thickness. Amifostine significantly decreased epithelial desquamation and vessel wall thickness changes but
had no effect on stromal edema. Carnitine administered
before radiotherapy had no statistically significant
protective effect on epithelial desquamation, vessel
wall thickness, or stromal edema.
In most preclinical studies, doses between 10?30
Gy were used. In studies using rats, lower doses were
preferred compared to studies using mice. The most
preferred doses are 10 Gy and above.[-] In a study
by Jaal and Dörr, early and late side effects of radiation
were evaluated in mouse bladder. In the study, changes
in the number of bladder superficial urothelial cells
were measured after a 20 Gy dose was applied in a single
fraction. According to the LQ model and α/β ratio
of 5 Gy, the selected dose corresponds to approximately
70 Gy from a fraction of 2 Gy as a rough biological
equivalent dose.[] In our study, rats were irradiated
with a single dose of 20 Gy, similar to the literature.
In preclinical studies, acute and late side effects of
radiotherapy on bladder tissue were frequently evaluated
by functional methods. One functional method
used is the measurement of intravesical pressure, which
is a marker of organ capacity, by cystometry. Another
frequently used method is measuring the frequency of
urination. In a study by Stewart et al.[] evaluating
radiation-induced acute and late damage in the mouse
bladder by urinary frequency and cystometry, a transient
wave of damage was observed in mice 1-3 weeks
after 10-30 Gy single-dose bladder irradiation. During
this period, urinary frequency increased twice or more
in the RT group compared to the control group, depending on the dose. Again, during this period, compared
to the control group, 20-40% of the mice receiving
20 Gy doses showed a decrease in bladder volume
below approximately 50%. Early damage terminated in
approximately one week. Lundbeck et al.[] evaluated
bladder function using the cystometric method within
30 days after irradiating the mouse bladder with a single
dose of 5-30 Gy and found that bladder wall compliance
decreased dose-dependently during this period.
However, they observed that the resulting damage
recovered in the second month.
In the literature, there are animal studies investigating
the acute and late side effects of radiotherapy on
the bladder, examining histopathological changes as
well as functional studies. Several animal models, employing
both mouse and rat, have been developed with
the aim of investigating the pathological modifications
that occur in the bladder after irradiation, but a "standard"
universally recognized radiation cystitis model
is still lacking. To standardize the evaluation of histologic
patterns, which are meant to be surrogates of the
functional status of the bladder, morphological scores
have been used. To date, hematoxylin and eosin (H&E)
indisputably remain the most informative staining employed,
allowing the recognition of macroscopic signs
of both early acute and late histological changes.[]
In a study investigating early and late morphological
changes in the rat bladder with a single dose of 20
Gy, the urothelium, bladder wall, and nerve cells were
evaluated.[] One month post-irradiation, the urothelium
appeared normal except for more-than-usual
numbers of lysosomes in the basal layer. By 1 month, some basal cells were necrotic, and macrophages had
invaded the epithelium. The smooth muscle of the
bladder wall proved surprisingly sensitive to radiation
damage. One week after irradiation, the marginal pinocytotic
vesicles were very conspicuous, and by 1 month
many cells were edematous. Morphological changes
were detected in nerve cells by electron microscopy in
the first month. In another study by Jaal and Dörr, a
7% loss of superficial umbrella cells was found in the
RT group with a single 20 Gy dose two to three days
after irradiation compared to the control group.[]
Similarly, Schreiber et al.[] found a loss of urothelial
cells eight days after 20 Gy RT to the bladder in rats.
In the study conducted by Sener et al.,[] whole-body
irradiation was performed in rats with a single dose of
8 Gy, and the protective effect of melatonin was investigated.
Epithelial desquamation or the vacuolation of
epithelial cells was observed in the urinary bladders
of the subjects in this study 12 and 72 hours after irradiation.
The presence of interstitial edema suggested
prominent tissue injury. In our study, with a single dose
of 20 Gy RT to the pelvic region, acute side effects of
RT such as epithelial desquamation and stromal edema
were observed on the fifth day.
Vascular changes due to radiotherapy are also
among the side effects reported in preclinical studies.
In the study in which Costa et al.[] investigated the
effects of nutritional supplementation with L-arginine,
10 Gy was given to the pelvic regions of rats in a single
fraction. The researchers found that the density of
blood vessels and the thickness of the arterial wall decreased
on the fifteenth day with this single dose. On
the contrary, in our study, on the fifth day, radiationinduced
vessel wall thickness was found significantly
higher compared to the control group. This difference
between the two studies is due to the fact that the days
on which acute effects were investigated were different
(day 5 vs. day 15). However, the decrease in vessel
density and arterial wall thickness is one of the side effects
that will be seen in the late period rather than the
acute period. The researchers explain this unexpected
finding as, "Because the part of the arterial wall that
was included in our measurements was basically the
tunica media, it can be inferred that this reduction in
thickness was due mainly to atrophy or loss of smooth
muscle cells, either as a direct effect of ionizing radiation
or through activation of apoptosis cascades."
Amifostine, a classic example of a radioprotective
agent, scavenges ROS and protects cells from radiation
damage. Amifostine has been used to reduce acute and
chronic toxicities, as shown in several studies.[] Its radioprotective effect on bladder tissue has also been
shown in some studies.[,] Interestingly, these
studies are in the form of phase II or phase III clinical
studies rather than preclinical studies. Athanassiou et
al.[] conducted a phase III study in which they investigated
the protective effect of amifostine in patients receiving
fractionated radiotherapy for pelvic carcinoma.
In this study, significantly less acute grade 2-3 bladder
toxicity was detected in the group given amifostine.
Similarly, in the study of Koukourakis et al.,[]
a significant reduction in rectal mucositis and acute
perineal skin and bladder toxicity was noted in the
amifostine arm in 40 patients with pelvic malignancies
undergoing RT. To the best of our knowledge, there is
no preclinical study investigating the radioprotective
effect of amifostine on bladder tissue in the literature.
Our study is the first to investigate the radioprotective
effect on acute side effects and to show that it is histopathologically
protective.
LC is a significant additional radioprotective agent.
It can be obtained through food, or the skeletal muscle,
heart, liver, kidney, and brain can synthesize it internally.
It can also be taken as a dietary supplement. It's
a safe and reasonably well-tolerated compound as well.
In addition to its ability to regulate the metabolism of
carbohydrates, LC is a necessary cofactor in the oxidation
of long-chain fatty acids and preserves the integrity
of cell membranes.[] Several important enzymes
involved in the metabolism of lipids and proteins are
also impacted. Furthermore, LC is a material that can
scavenge free radicals and function as an antioxidant.
[] Moreover, it increased endogenous antioxidant
defense mechanisms, which might have protected the
animals from radiation-induced organ toxicity.
According to Altas et al.,[] LC can help guinea
pigs with radiation-induced cochlear damage. In another
study, Kocer et al.[] demonstrated that LC also
functions as a protective agent against irradiation-induced
lens damage in rats. Other animal studies have
also documented the radioprotective qualities of LC in
postponing the onset and lessening the severity of radiation-
induced damage to the kidney, bone, testicles,
ovaries, and oral mucosa.[,] However, there have
been no studies investigating its radioprotective effect
on the bladder so far.
In our study, we investigated both whether Lcarnitine
has a protective effect and, if so, its efficacy
compared to amifostine. We could not determine the
protection conferred by L-carnitine. This could be attributed
to several factors. Firstly, L-carnitine has a low
bioavailability (14-18%), and it cannot be stored in the body, which, coupled with its short half-life (30-60
minutes), necessitates frequent dosing to achieve therapeutic
efficacy.[] However, its radioprotective effect
was observed at a single dose in multiple investigations.
[r16>,,] A plausible rationale would be that, as Lcarnitine
is predominantly excreted by the kidneys and
extensively reabsorbed by the renal tubules, there may
not have been much transfer of the compound from
the kidneys to the bladder during our investigation.
While our study has yielded valuable insights into
the subject matter, it is essential to acknowledge its
inherent limitations and caveats. Firstly, in this study,
we investigated the protective effects of amifostine
and L-carnitine against radiation-induced toxicity in
bladder tissue only by histopathological methods. In
addition to histopathological methods, functional and
biochemical assessments could have been performed
to provide a more comprehensive evaluation of tissue
damage. Another limitation of our study might
be that L-carnitine was administered as a single dose.
Further research is needed to explore the effects of
repeated administration of L-carnitine on radiationinduced
bladder toxicity.
In conclusion, this study is the first to demonstrate
the protective effect of amifostine against radiationinduced
bladder toxicity in a preclinical setting and to
compare its efficacy with that of L-carnitine. Furthermore,
our findings suggest that, unlike amifostine, Lcarnitine,
administered as a single dose, may not confer
similar protection against radiation-induced bladder
damage. Further research is warranted to explore the
potential benefits of amifostine in mitigating radiationinduced
bladder injury and to investigate alternative
strategies for enhancing bladder radioprotection.
Ethics Committee Approval: The study was approved by
the Trakya University Animal Experiments Local Ethics
Committee (no: 2010/04.10, date: 07/06/2010).
Authorship contributions: Concept - V.Y.Ç., H.M.Ç.,
D.N., T.A.; Design - V.Y.Ç., H.M.Ç., D.N., O.İ.; Supervision
- V.Y.Ç., H.M.Ç., O.İ., Ö.Y., T.A.; Data collection and/or processing
- D.N., T.A., E.A., Ö.Y.; Data analysis and/or interpretation
- V.Y.Ç., H.M.Ç., O.İ.; Literature search ? V.Y.Ç.,
H.M.Ç., D.N., E.A.; Writing - V.Y.Ç., H.M.Ç., D.N., T.A.;
Critical review - H.M.Ç., V.Y.Ç.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: No AI technologies utilized.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
References
American Cancer Society. Cancer Facts & Figures
2024. Atlanta: American Cancer Society; 2024.
Sminia P, Guipaud O, Viktorsson K, Ahire V, Baatout
S, Boterberg, et al. Clinical radiobiology for radiation
oncology. In: Baatout S, editor. Radiobiology Textbook.
Cham: Springer International Publishing; 2023.
p. 237-309.
Utley JF, Phillips TL, Kane LJ. Protection of normal tissues
by WR2721 during fractionated irradiation. Int J
Radiat Oncol Biol Phys 1976;1(7-8):699-703.
Aktoz T, Caloglu M, Yurut-Caloglu V, Yalcin O, Aydogdu
N, Nurlu D, et al. Histopathological and biochemical
comparisons of the protective effects of
amifostine and L-carnitine against radiation-induced
acute testicular toxicity in rats. Andrologia
2017;49(9):12754.
Goa KL, Brogden RN. L-Carnitine: A preliminary review
of its pharmacokinetics, and its therapeutic use in
ischemic cardiac disease and primary and secondary
carnitine deficiencies in relationship to its role in fatty
acid metabolism. Drugs 1987;34(1):1-24.
Dokmeci D, Akpolat M, Aydogdu N, Doganay L,
Turan FN, et al. L-carnitine inhibits ethanol-induced
gastric mucosal injury in rats. Pharmacol Rep
2005;57(4):481-8.
Dörr W, Beck-Bornholdt HP. Radiation-induced impairment
of urinary bladder function in mice: Fine
structure of the acute response and consequences on
late effects. Radiat Res 1999;151(4):461-7.
Antonakopoulos GN, Hicks RM, Hamilton E, Berry
RJ. Early and late morphological changes (including
carcinoma of the urothelium) induced by irradiation
of the rat urinary bladder. Br J Cancer 1982;46(3):403-16.
Jaal J, Dörr W. Radiation-induced damage to mouse
urothelial barrier. Radiother Oncol 2006;80(2):250-6.
Stewart FA, Lundbeck F, Oussoren Y, Luts A. Acute
and late radiation damage in mouse bladder: A comparison
of urination frequency and cystometry. Int J
Radiat Oncol Biol Phys 1991;21(5):1211-9.
Lundbeck F, Ulsø N, Overgaard J. Cystometric evaluation
of early and late irradiation damage to the mouse
urinary bladder. Radiother Oncol 1989;15(4):383-92.
Zuppone S, Bresolin A, Spinelli AE, Fallara G, Lucianò
R, Scarfò F. Pre-clinical research on bladder toxicity
after radiotherapy for pelvic cancers: State-of-the-art
and challenges. Front Oncol 2020;10:527121.
Schreiber H, Oehlert W, Kugler K. Regeneration and
proliferation kinetics of normal and x-irradiated transitional
epithelium in the rat. Virchows Arch B Cell
Pathol [Article in German] 1969;4(1):30-44.
Sener G, Atasoy BM, Ersoy Y, Arbak S, Sengöz M,
Yeğen BC. Melatonin protects against ionizing radiation-
induced oxidative damage in corpus cavernosum
and urinary bladder in rats. J Pineal Res
2004;37(4):241-6.
Costa WS, Ribeiro MN, Cardoso LE, Dornas MC,
Ramos CF, Gallo CB, et al. Nutritional supplementation
with L-arginine prevents pelvic radiation-induced
changes in morphology, density, and regulating factors
of blood vessels in the wall of rat bladder. World J Urol
2013;31(3):653-8.
Caloglu M, Yurut-Caloglu V, Durmus-Altun G, Oz-
Puyan F, Ustun F, Cosar-Alas R, et al. Histopathological
and scintigraphic comparisons of the protective
effects of L-carnitine and amifostine against radiationinduced
late renal toxicity in rats. Clin Exp Pharmacol
Physiol 2009;36(5?6):523-30.
Athanassiou H, Antonadou D, Coliarakis N, Kouveli A,
Synodinou M, Paraskevaidis M, et al. Protective effect
of amifostine during fractionated radiotherapy in patients
with pelvic carcinomas: Results of a randomized
trial. Int J Radiat Oncol Biol Phys 2003;56(4):1154-60.
Koukourakis MI, Kyrias G, Kakolyris S, Kouroussis C,
Frangiadaki C, Giatromanolaki A, et al. Subcutaneous
administration of amifostine during fractionated radiotherapy:
A randomized phase II study. J Clin Oncol
2000;18(11):2226-33.
Bertelli A, Conte A, Ronca G. L-Propionyl carnitine protects
erythrocytes and low-density lipoproteins against
peroxidation. Drugs Exp Clin Res 1994;20(5):191-7.
Fritz IB, Arrigoni-Martelli E. Sites of action of carnitine
and its derivatives on the cardiovascular system:
Interactions with membranes. Trends Pharmacol Sci
1993;14(10):355-60.
Altas E, Ertekin MV, Gundogdu C, Demirci E. L-Carnitine
reduces cochlear damage induced by gamma irradiation
in guinea pigs. Ann Clin Lab Sci 2006;36(3):312-8.
Kocer I, Taysi S, Ertekin MV, Karslioglu I, Gepdiremen
A, Sezen O, et al. The effect of L-carnitine in the prevention
of ionizing radiation-induced cataracts: A rat model.
Graefes Arch Clin Exp Ophthalmol 2007;245(4):588-94.
Yurut-Caloglu V, Caloglu M, Eskiocak S, Tastekin E, Ozen
A, Kurkcu N, et al. Comparison of the protective roles
of L-carnitine and amifostine against radiation-induced
acute ovarian damage by histopathological and biochemical
methods. J Cancer Res Ther 2015;11(2):447-53.
Savitha S, Tamilselvan J, Anusuyadevi M, Panneerselvam
C. Oxidative stress on mitochondrial antioxidant defense
system in the aging process: Role of DL-alpha-lipoic acid
and L-carnitine. Clin Chim Acta 2005;355(1-2):173-80.
Tas S, Ozkan OF, Cikman O, Kiraz A, Akgun Y,
Karaayvaz M, et al. L-Carnitine has a protective effect
on the colonic mucosa during abdominopelvic radiotherapy
in rats. Acta Cir Bras 2016;31(9):615-20.
