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Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 260-265

The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity

1 Department of Radiation Oncology, Trakya University, Edirne, Turkey
2 Department of Pathology, Trakya University, Edirne, Turkey

Date of Web Publication26-Jul-2012

Correspondence Address:
Murat Caloglu
Department of Radiation Oncology, Trakya University Hospital, Edirne 22030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.98982

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 > Abstract 

Background: The aim of the study was to compare the protective efficacy of l-carnitine (LC) to amifostine on radiation-induced acute small intestine damage.
Materials and Methods: Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia.
Results: Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group.
Conclusions: Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure.

Keywords: Acute toxicity, amifostine, irradiation, L-carnitine, radioprotection, small intestine

How to cite this article:
Caloglu M, Caloglu VY, Yalta T, Yalcin O, Uzal C. The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity. J Can Res Ther 2012;8:260-5

How to cite this URL:
Caloglu M, Caloglu VY, Yalta T, Yalcin O, Uzal C. The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity. J Can Res Ther [serial online] 2012 [cited 2022 Jul 4];8:260-5. Available from: https://www.cancerjournal.net/text.asp?2012/8/2/260/98982

 > Introduction Top

Radiotherapy is one of the choices of the multimodal treatment for neoplastic diseases in the pelvic region. However, rapidly dividing tissues as small bowel in the pelvic are potential targets for radiation induces injury. [1] While epithelial ulceration and mucosal and submucosal inflammation are characteristics of acute radiation enteritis, excessive extracellular matrix deposition, vascular sclerosis, and muscular dystrophy are the characteristics of transmural effects of chronic radiation enteritis. [2] An increasing number of experimental and clinical data have supported the role of acute radiation injury in the development of chronic radiation enteritis. [3] Therefore, reduction of the severity of acute mucosal injury during radiotherapy might be a potential therapeutic strategy to limit the consequential late adverse effects of radiation. [1] The effect of ionizing radiation is primarily mediated through the action of free radicals, which can cause damage to DNA, proteins, and lipids. [4] Hence, antioxidative defense mechanisms are responsible for much of the radiation damage. [5]

Amifostine (S-2-{3-aminopropylamino-ethylphosphorothioic acid; Ethyol; WR-2721) is a prodrug that is converted in vivo by alkaline phosphatase to an active sulfhydryl compound (WR-1065). This substance has a selective protective effect on normal cells from antineoplastic drug toxicity. It scavenges free radicals, donates hydrogen ions to free radicals, depletes oxygen, and binds to active derivatives of antineoplastic agents. [6],[7] Previous studies showed substantial radioprotective effects of amifostine on lung, kidney and growing bone tissues. [8],[9],[10] The effectiveness of amifostine as a radioprotective agent in irradiated small intestine has also been shown in earlier studies. However, use of amifostine has been reported to be accompanied by undesirable side-effects including nausea, vomiting, sneezing, hot flashes, mild somnolence, hypocalcemia, and hypotension. [11]

l-Carnitine (3-hydroxy-4-trimethylammoniumbutyric acid) (LC) is a small water-soluble molecule that facilitates the transfer of long-chain fatty acids into the mitochondria of skeletal muscle and cardiomyocytes, where they undergo β-oxidation. [12] LC prevents the formation of ROS produced by the xanthine-xanthine oxidase system and thus decreases damage to the cell membrane. LC is obtained mostly from the diet or can be given exogenously. It can also be synthesized endogenously by skeletal muscle, heart, liver, kidney, and brain. LC is also a relatively well-tolerated and safe compound. [13] The radioprotective effect of LC on several tissues including kidney, lens, retina, brain, cochlea, and salivary glands has been shown in earlier studies. [9],[14],[15],[16],[17] Additionally, it has been shown that LC has protective effects on small intestine against several injury models but radiotherapy.

To date, to the best of our knowledge, no study has yet investigated the efficacy of LC in prevention of radiation-induced acute small intestine damage. On the basis of the abovementioned studies, we hypothesized that LC might have protective effects against radiation-induced acute small intestine damage as well as amifostine. The aim of this study was therefore to evaluate the radioprotective effect of LC in irradiated small intestine and to compare it to the radioprotection afforded by amifostine, histopathologically.

 > Materials and Methods Top

Animals and experimental design

All animal experiments adhered to the guidelines of the Institutional Animal Ethics Committee. Infant rats were housed with their mothers until 4 weeks-old, and then were housed in rat cages with ad libitum access to a standard rodent diet and tap water, with a 12:12-h artificial light cycle, mean temperature 21 ± 2°C, and mean humidity 55 ± 2%. When they had reached 3 months of age, all animals were randomly assigned into four groups, for the following treatments:

Group 1: Control (CONT), n = 6, normal saline alone, injected with normal saline (200 mg/kg) by intraperitoneal injection (i.p.) 30 min before a sham irradiation.

Group 2: Irradiation alone (RT), n = 8, injected with normal saline (200 mg/kg) by i.p. 30 min before irradiation.

Group 3: Amifostine before irradiation (AMI+RT), n = 8, injected with amifostine (200 mg/kg) (Ethyol, MedImmune Pharma B.V., Nijmegen, the Netherlands) by i.p. 30 min before irradiation, [9]

Group 4: LC before irradiation (LC+RT), n = 8, injected with LC (300 mg/kg) (Santa Pharma Co., Istanbul, Turkey) by i.p. 30 min before irradiation. The selection of the 30-min interval between LC administration and exposure to radiation was based on our previous study on animals. [9]

All experimental procedures were performed on anesthetized rats. Anesthesia was maintained with ketamine and xylazine (50 mg/kg BW and 5 mg/kg BW, i.m.) during irradiation and Euthanasia. The follow-up period was 5 days. During the follow-up, all rats were monitored by the veterinary care staff.


The rats in AMI+RT, LC+RT and RT groups were irradiated individually with a single dose of 20 Gy. Doses of irradiation were given with Co-60 photon at a depth of 1 cm through an anterior 5 × 5 cm single portal (with a 0.5 cm bolus) covering total abdomen, using a Co-60 treatment unit (Cirus, cis-Bio Int., Gif Sur Yvette, France) at a source skin distance of 80 cm. The rats were anesthetized and then fixed onto a 20 × 30 cm blue Styrofoam treatment couch (Med-Tec, Orange City, IA) in a prone position. Correct positioning of the fields was controlled for each individual rat using a therapy simulator (Mecaserto-Simics, Paris, France). Special dosimetry was done for the irregular fields. The dose homogeneity across the field was ±5%. After irradiation, the animals were closely observed until recovery from anesthesia. The animals in the CONT group received an equal field sham irradiation.


The rats were euthanized 5 days after the radiation therapy. Prior to euthanasia, the rats received anesthesia using ketamine and xylazine combination. Euthanasia was performed by decapitation.

Histopathological analysis

In order to estimate the radioprotective effects of LC and amifostine on rat small intestine, the tissue were taken after they were killed, and the tissue slices were fixed in 10% neutral-buffered formaldehyde, embedded in paraffin. Five micrometer thick sections were cut and stained with hematoxylin-eosin. A certified pathologist, who was unaware of the experimental protocol, examined each slide under a light microscope (Nikon E400, Japan) according to the 5-point semiquantitative scale, i.e. tissue damage score for degenerative [Table 1] and vascular changes [Table 2], three times in a blinded manner. The histologic parameter above was scored on a 4-point scale as follows: 0, none; 1, low (grade 1); 2, moderate (grades 2-3); 3, high (grades 4-5).
Table 1: Tissue damage score for degenerative changes

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Table 2: Tissue damage score for vascular changes

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Statistical analysis

The data were analyzed using standard statistical methods (Statistica version 7 program). All data were expressed as mean ± SD. One-way analysis of variance (ANOVA) was used for statistical comparisons between the groups. The differences were considered significant when probability was less than 0.05.

 > Results Top

Histopathologic analyses were made on 30 rats. The degenerative and vascular damages are summarized for each group in [Table 1]. The CONT group was normal for both histopathologic parameters. All histopathologic findings such as degenerative damage (P < 0.0001), vascular damage (P < 0.0001), and overall damage score (P < 0.0001) were significantly different between the groups.

Radiation-induced degenerative damage was significantly higher in the RT group than in the CONT group (P < 0.0001) [Figure 1] and [Figure 2]. Pretreatment with amifostine reduced the radiation-induced acute damage (P = 0.009) compared to the RT group [Figure 3]. Pretreatment with LC did not obtain any significant difference compared to the RT group [Figure 4]. The protective effect of amifostine was higher to LC in the small intestine (P = 0.026). However, there was significant difference between the CONT group and the AMI+RT (P < 0.0001) group.
Figure 1: CONT group, normal mucosal epithelium of the small intestine (H&E, ×50)

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Figure 2: RT group, diffuse infiltration of polymorphonuclear cells, diffuse hemorrhagic infi ltration, cells with pronounced vacoulization and pycnotic nuclei, plasmalysis and caryolysis of the cells, focal necrosis (H&E, ×50)

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Figure 3: AMI+RT group, single cells with small cytoplasmic granules, mild dilatation of small blood vessels (H&E, ×50)

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Figure 4: LC+RT group, diffuse infi ltration of polymorphonuclear cells, cells with vacoulization and pycnotic nuclei, caryolysis and plasmalysis (H&E, ×50)

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The vascular damage significantly increased in the RT (P < 0.0001), LC+RT (P < 0.0001) and AMI+RT (P < 0.0001) groups compared with the CONT group. This damage significantly reduced in both the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. There was no significant difference between AMI+RT and LC+RT groups.

The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). Unfortunately, it was higher than in the CONT group level (P < 0.0001). We did not find any significant difference between the LC+RT group and the RT group [Table 3] and [Table 4].
Table 3: The frequency of pathological scores for each group according to grade of intestinal damage

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Table 4: The frequency of overall intestinal damage scores for each group

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 > Discussion Top

The main findings of our study were as follows: (1) a marked radiation-induced acute toxicity was seen 5 days after with a single dose of 20 Gy; (2) amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue; (3) LC has limited radioprotective effects which are mainly against vascular damage.

The application of radiotherapy for abdomino-pelvic malignancies increases, thus radiation-induced gastrointestinal complications becomes even more important. After the irradiation of intestinal tissues, acute and chronic radiation enteritis occurs. In brief, the acute phase persists for hours to several days following exposure and is characterized by nausea, vomiting, and diarrhea. The chronic phase can occur months to several years following exposure and is associated with inflammation, stricture formation, and obstruction. [18] The direct cytotoxic acute effect of radiation may lead to the late effects arising as a result of progressive, occlusive vasculitis, collagen deposition, and fibrosis. [19] Additionally, the severity of acute symptoms can be proportionally related to the incidence of adverse chronic effects. It is thought that the early response to ionizing radiation can alter the physiology of the intestine and makes it more susceptible to triggers of inflammation. [20]

The acute morphological changes can be comprised from structural changes in the villus-crypt architecture and epithelial changes related to radiation-induced apoptosis. [18] Carr et al. described the effects of radiation on mucosal structure in their morphometric study. [21] They observed villous shortening in the mouse proximal small intestine, 3 days following a high dose (15 Gy) of radiation. Moreover, a significant reduction in enterocytes and in lamina propria cells was seen after c-radiation of 5 Gy, in another study. [22] In the present study, a marked radiation-induced acute toxicity that was composed from degenerative and vascular changes was seen 5 days after with a single dose of 20 Gy.

Amifostine has a selective radioprotection property, since the active metabolite of the drug (WR-1065) is absorbed in a greater concentration in normal tissues compared to tumor tissues. [23] This differential uptake of free thiol is a result of differences in the microenvironment at the tissue level, such as lower capillary alkaline phosphatase activity, lower pH, and poorer vascularity in tumoral tissues than normal tissues, resulting in the slow entry of free thiol into tumor masses. Its mucosa protective effect against to irradiation on the gastrointestinal tract has been well known. There are several preclinical and clinical studies focused on the cytoprotective effect of amifostine against radiation-induced toxicity in pelvic irradiated areas. [6],[24] Pretreatment amifostine administered either by intracolonic or intraperitoneal instillation demonstrated a radioprotective effect on the murine colon and the rectum. France et al. demonstrated that when compared with controls, a radioprotective effect with a dose modifying factor of 1.8 was yielded with intracolonic WR 2721 by histologic evaluation of colons from irradiated rats. [25] In another study, Ito et al. concluded that WR-2721 is indeed effective at protection against late damage from large single doses of radiation to the rectum as measured histologically and also improves the long-term survival of the mice, although the target cells for this damage are not known. [26] Prassana et al. applied amifostine intraperitoneally prior to whole body irradiation in mice and observed that amifostine protected both crypts and villi. [27] Additionally, they stated that amifostine increased the survival rate of mice. On the other hand, Delaney et al. showed that when amifostine applied topically to the small bowel mucosa of the rat before irradiation, it provides substantial protection against radiation damaged. [28] They observed that amifostine improved crypt survival both at neutral pH and at pH 9. Recently, Katsanos et al. stated that amfostine given subcutaneously can lower the risk of acute severe radiation colitis in a randomised phase II exploratory clinical trial. They revealed that acute radiation colitis and grade IV radiation colitis did not occur in the amifostine arm, but in 17.4% of patients who did not receive amifostine prophylaxis (P = 0.05). [29] Similar results showing the radioprotector activity of amifostine was obtained in the present study. It was significantly protective against both vascular and degenerative radiation induced damage on small intestine tissue. Moreover, the degree of its protection was superior to protection yielded from LC. This superiority can be related to possible higher intestinal concentrations of amifostine than LC, although there has yet any study compared their intestinal uptake. Further studies will be focused on their pharmacokinetics in the intestinal tissues which can be helpful for understanding the differences of their effectiveness.

LC is a substance that can act as an antioxidant and free radical scavenger. [30] In addition, LC has the capacity to control carbohydrate metabolism, to maintain cell membrane structure and cell viability, and it is an essential cofactor in the oxidation of long-chain fatty acids. [31] To the best of our knowledge, there has not yet been any study on the effects of LC on radiation-induced acute small intestine damage. However, a limited number of studies have been shown that LC has protective effects on intestinal tissues against several injurious factors including ischemia-reperfusion injury, [32] cisplatin, [33] and methotrexate. [34] Hosgorler et al. showed that morphologic damage was statistically lower, number of perfused microvessels and epithelial regeneration were statistically higher when LC applied prior to reperfusion of small intestine in rats. [32] In another study, Derin et al. showed that LC provided marked protection against ischemia-reperfusion related gastric injury reducing reactive oxygen metabolites through lessening neutrophil accumulation in ischemic tissue. [35] Similarly, Sener et al. stated that LC protected several tissues including ileum against methotrexate caused oxidative damage in rats. [34] Furthermore, the endogenous antioxidant defense mechanisms of LC may protect the animals from radiation-induced organ toxicity. [14] We used LC as a possible modulator of radiation-induced toxicity, based on the previous reports. Caloglu et al. showed that LC ameliorated radiation-induced renal damage in rats. [9] Altas et al. showed that LC could improve radiation-induced cochlear damage in guinea pigs. [15] LC also was shown to serve as a protective agent against irradiation-induced lens damage in a rat study by Kocer et al. [16] The radioprotective properties of LC in delaying the onset and reducing the severity of radiation-induced oral mucositis have also been reported in another animal study. [17] In the present study, we observed that LC has limited radioprotective effects which are mainly against vascular damage. Due to the lack of studies on protective effects of LC against radiation-induced intestinal damage, it remains as a challenge to define its protective vascular activity, whereas it was not protective against degenerative damage. Possible mechanism underlying this partial effect might be related to limited cellular intake of LC.

Consequently, this is the first study that investigated the efficacy of LC in the prevention of radiation-induced acute small intestine damage and showed a partial effectiveness. Moreover, no study has compared its effect to standard radioprotective amifostine to date. However, our study has some limitations. First, the radiation-induced intestine model was set on a single-dose irradiation, which is different from routine clinical application. The impact of fractionated irradiation with amifostine and LC implementation should also be taken into account in future studies. Second, we used only a histopathological model. Further studies are necessary to determine the mechanisms of the protection afforded by these compounds, by evaluating markers of oxidative stress in intestinal tissue.

 > Acknowledgments Top

M.C. was involved in the study design, data collection, and writing and editing all aspects of this manuscript. V.Y-C., T.Y., O.Y., and C.U. were involved in the study design, data collection and editing this manuscript. All of the authors have read and approved the final version of this manuscript.

 > References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4]

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