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British Journal of Radiology (2006) 79, 409-414
© 2006 British Institute of Radiology
doi: 10.1259/bjr/16265085
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Effect of ticlopidine in the prevention of radiation enteropathy

S Akyurek, MD 1 L Atahan, MD 2 M Cengiz, MD 2 C Sokmensuer, MD 3 I Haberal, MD 4 F Yildiz, MD 2 and C Onal, MD 1

1 Department of Radiation Oncology, Ankara University School of Medicine, Ankara, Departments of, 2 Radiation Oncology and, 3 Pathology, Hacettepe University School of Medicine, Ankara and, 4 ENT and Head and Neck Surgery Department, Health Ministry Ankara Education and Training Hospital, Ankara, Turkey


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 Conclusion
 References
 
Impairment of vascular function is considered to play an important role in chronic radiation enteropathy. In this experimental study, the role of ticlopidine, an inhibitor of ADP-induced platelet aggregation, was investigated in radiation enteropathy. 80 male Wistar albino rats, each weighing 170–200 g, were divided into four groups: (a) radiation alone (n = 20); (b) radiotherapy plus ticlopidine (n = 20); (c) ticlopidine control (n = 20) and (d) control (n = 20). Both radiation groups received 19 Gy radiation to the exteriorized intestinal segments in a single fraction. Ticlopidine or vehicle was administered 12 h after radiotherapy and continued for 1 month. Rats from every group were euthanized randomly at intervals of 6 weeks from 2 weeks to 26 weeks. Histopathological radiation injury was assessed using radiation injury scoring (RIS). Radiation with ticlopidine or radiation alone groups showed significant RIS deterioration compared with controls in all time points studied. Comparison of median RIS of radiotherapy and radiotherapy+ticlopidine groups at the 2nd, 14th and 26th weeks yielded statistically significant RIS in favour of radiotherapy+ticlopidine group (p = 0.05). However, these differences were less pronounced at the 8th and 20th week (p = 0.07). Both radiation groups had poor weight gain when compared with control and ticlopidine groups. The weight gain in radiotherapy+ticlopidine group was significantly superior to only radiation group between 10th and 20th weeks (p = 0.05). This study showed that inhibition of platelet aggregation with ticlopidine might be useful in radiation enteropathy. However, the precise role of antiaggregant therapies on radiation enteropathy should be comprehensively studied before clinical consideration.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 Conclusion
 References
 
Normal tissue damage is the main dose-limiting factor in clinical radiotherapy. The small intestine is one of the most radiosensitive organs and unavoidably included in most abdominal or pelvic radiotherapy fields [1]. Despite efforts to keep doses below tolerance doses, severe chronic radiation enteropathy (CRE) occurs in about 10–15% of patients and has an adverse effect on the quality of life of long term survivors [2, 3]. To date there has been neither an effective method of preventing radiation-induced intestinal injury nor the treatment once it has occurred.

Intestinal radiation injury (radiation enteropathy) is classified as either acute or chronic. Acute radiation enteropathy is usually a self-limiting condition, which is the result of the cell kill of the rapidly renewing epithelial cells of the mucosa leading to a temporary breakdown of the mucosal barrier and inflammation. CRE, on the other hand, is associated with high rates of morbidity and mortality [3, 4], and the underlying molecular mechanisms have not been clearly identified yet. The characteristic histopathological findings after radiotherapy in acute phase are reported to take the form of endothelial cell swelling, increased permeability and interstitial fibrin deposition, and development of platelet-fibrin thrombi in submucosal capillaries and microvasculature has been accused of being the main target for radiation damage. As the injury progress to chronic radiation enteropathy, the prominent histopathological changes appear to be intestinal wall fibrosis and vascular sclerosis [5–8].

It has previously been reported that CRE is associated with significant upregulation of the transforming growth factor beta (TGF-beta) and fibrogenic cytokine, and downregulation of endothelial cell surface protein, thrombomodulin (TM) [9–12]. Thrombomodulin plays a key role in protein C anticoagulant pathway. Reduced endothelial TM levels and increased prothrombotic properties of endothelium seem to contribute to hypercoagulation with increased fibrin formation, tissue factor activity and platelet aggregation [8, 13–15]. Platelets are the most important sources of fibrogenic factors and cytokines, such as TGF-beta which is critically involved in radiation enteropathy [16, 17]. Adenosine 5'-dipohosphate (ADP), on the other hand, is a potent and specific mediator of platelet aggregation and activation that is released by damaged endothelial cells, red blood cells and activated platelets [18].

There are some encouraging data in the literature which show that anticoagulation therapy, such as heparin, warfarin, or acetyl salicylic acid (ASA) may be beneficial in the treatment of radiation injury [19–21]. Ticlopidine is a powerful platelet aggregation inhibitor recently used with encouraging success in human clinical trials. It has been reported to decrease recurrence and severity of cerebrovascular and cardiovascular accidents, peripheral arterial disease, and to decrease the occlusion rates of coronary saphenos vein bypass grafts [22]. Ticlopidine achieves antiplatelet efficacy by blocking activation of platelets by ADP. It selectively and irreversibly inhibits the binding of ADP to its receptor on platelets, thereby effecting ADP-dependent activation of the glycoprotein IIb/IIIa complex, the major receptor for fibrinogen present on the platelet surface [23]. The study reported here was designed to determine whether ticlopidine has ability to prevent or retard the development of radiation induced enteropathy if it is used prophylactically.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 Conclusion
 References
 
Animals
80 male Wistar rats, weighing 170–200 g (aged 8–12 weeks) at the time of irradiation, were used in this experimental study. They were housed with five to a cage and had free access to water and commercial food pellets. All animals were kept under the same experimental conditions.

Irradiation
Before irradiation, all rats including the controls were anaesthetized with 80 mg kg–1 ketamin hydrochloride (Ketalar; Parke-Davis, Morris Plains, NJ) and 10 mg kg–1 xylazin (Rompun; Milles Lab, Shawnee, KS). A surgical procedure which has been described by Hauer-Jensen et al [24] was performed to all rats, including sham-irradiated animals, before radiotherapy. Briefly, a 1.5–2 cm midline incision was made and 10 cm mid-small intestinal segment, 30–40 cm proximal to the caecum, was exteriorized and marked with silk ligatures in the adjacent mesentery. Rats were placed in a specially designed box, with the exteriorized intestinal segment lying on gauze compress soaked in 0.9% saline, and care was taken to avoid tension of the mesentery during irradiation. Only the exteriorized intestinal segment was irradiated and the rest of animal was protected by a 5 mm lead shield. The intestine was again placed into the abdomen at the end of the procedure.

The intestinal segment was irradiated with 6 MeV electron beams using a Philips SL-25 linear accelerator (Philips, Best, The Netherlands). Before irradiation, animals were randomly assigned to one of the four groups. A single fraction of 19 Gy was delivered through a 6 cmx6 cm anterior portal in group 1 (RT, n = 20). Same dose was given in group 2 (RT+T, n = 20) with 100 mg kg–1 daily oral ticlopidine HCl (Ticlid-Sanofi) for 1 month starting from 12 h after irradiation. Similar procedures except irradiation were performed in 2 age-matched control groups, a ticlopidine control group (T, n = 20) and no-drug control group (C, n = 20).

All animals were followed up weekly for weight loss and for complications. Experiments were performed in accordance with the national regulations for animal experimentation, and experimental protocols were approved by the local animal ethics committee before the start of studies.

Morphological assessment
Four animals from each group were randomly selected and euthanized by bleeding under ether anaesthesia at intervals of 6 weeks from 2 (early inflammatory phase) to 26 weeks (chronic, fibrotic phase). Specimens suturated before irradiation procedure from irradiated and sham-irradiated animals were excised and fixed in 4% formaldehyde solution, dehydrated and embedded in paraffin. After that cross sections and longitudinal sections of the intestine were performed then stained with haematoxylin-eosin for histopathological evaluation.

Each specimen was examined with light microscopy and histopathological changes were scored by a single pathologist (CS) blinded to the study. Scoring (RIS) was done by recording the macroscopical and 7 histopathological changes: mucosal ulcerations (0–2), epithelial atypia (0–3), thickening of subserosa (0–3), vascular sclerosis (0–3), intestinal wall fibrosis (0–3), ileitis cystica profunda (0–3), and lymphatic congestion (0–1) within the irradiated segment. The RIS has been shown to be a reliable indicator of the severity of intestinal radiation injury [3, 24–28]. Total RIS was calculated by adding the scores of the individual parameters.

Statistical methods
The Mann-Whitney U-test was used to compare median RIS values among the treatment groups. Student t-test was used to compare mean weights±standard errors. A significance level of p<0.05 was selected as the minimal level for significance.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 Conclusion
 References
 
All animals were followed-up to 6 months after treatment. All but eight rats survived during this period. Five deaths (14th , 28th, 49th, 126th, 161st days) from RT group and three deaths (14th, 42nd, 147th days ) from RT+T group were found dead during the follow-up time. Autopsies revealed intestinal perforation in three rats, obstruction in two rats and haemoperitoneum for the rest. There is no difference regarding to haemoperitoneum between RT and RT+T groups.

Weight changes
Time-related weight changes for each group are shown in Figure 1Go. Both radiation groups had significantly poor weight gain when compared with C and T groups. There was no statistically significant difference between irradiated groups during the first 20 weeks, but a significant difference (p<0.05) in favour of RT+T group was observed between 10th and 20th weeks.


Figure 1
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  		Figure 1. Weight changes as a function of time after irradiation.

 
Morphological changes
There were no significant changes in control groups except minor histopathological alterations, which were considered to be due to ageing. The median RIS value, as a function of time, is given in Figure 2Go and Table 1Go.


Figure 2
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  		Figure 2. Median radiation injury scores as a function of time after irradiation.

 

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  		Table 1. Median RIS values stratified by groups

 
At 2 weeks after irradiation, the RT group showed deterioration in the crypt morphology, increase in epithelial proliferation, superficial and deep ulceration, and serosal thickening. Total RIS score was assessed as 11 in this group. The RT+T group on the other hand only showed minimal crypt epithelial changes and subserosal thickening due to increased amount of fibrin deposits and oedema. Median RIS score was 6 and the difference was statistically significant between these 2 groups (p<0.05).

At 8 weeks after irradiation, macroscopic thickening of the bowel wall was apparent in the RT group and prominent vascular hyalinization in addition to histopathological changes in the crypt morphology was recorded. Median RIS score was 11. For the RT+T group, macroscopic thickening of the bowel wall was similar to the RT only group, whereas light microscopic evaluation revealed only superficial mucosal ulcerations and serosal thickening. Median RIS was 7, which was not statistically significant, although there was a trend in favour of RT+T (p = 0.07).

At the 14th week after irradiation, prominent bowel wall thickening, stenosis and adhesions were recorded macroscopically for RT only group. Severe mucosal ulcerations, vascular sclerosis, hyalinization and apparent serosal thickening were observed by light microscopy and the median RIS was 14. RT+T group, on the other hand, showed only wall thickening with superficial ulceration, minimal serosal thickening and increase in vascular hyalinization at this week. Median RIS was 6, which was significantly better than the RT only group (p<0.05).

At the 20th week, histopathological appearance in the RT group was not remarkably different from the 14th week of evaluation. The RT+T group on the other hand showed some improvement on the mucosal crypt morphology, although vascular hyalinization and sclerosis continued. There was a significant difference both macroscopically and microscopically between the two groups at the 26th week of evaluation. Apparent wall thickening, adhesions and stenosis with similar light microscopic findings to the previous weeks were recorded for the RT group. However, although minimal, some improvement was shown compared with the 20th week for the RT+T group (GoGoGoFigures 3–6Go).


Figure 3
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  		Figure 3. Radiotherapy(RT) alone group. Specimen exhibits extensive mucosal ulceration and vascular sclerosis, 26 weeks after irradiation (vs, vascular sclerosis; ul, ulcer; s, serosa).

 

Figure 4
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  		Figure 4. Radiotherapy+ticlopidine (RT+T) group. Specimen exhibits mild thickening of muscularis mucosa, 26 weeks after irradiation (vs, vascular sclerosis; m, muscularis mucosa).

 

Figure 5
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  		Figure 5. Macroscopic appearance of the radiotherapy(RT) alone group 26 weeks after irradiation demonstrates apparent bowel wall thickening, adhesion and stenosis. Arrows show suturated specimen (vs, vascular sclerosis; ul, ulcer; s, serosa).

 

Figure 6
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  		Figure 6. Macroscopic appearance of the radiotherapy+ticlopidine (RT+T) group 26 weeks after irradiation demonstrates mild bowel wall thickening. Arrows show suturated specimen (vs, vascular sclerosis; m, muscularis mucosa).

 

   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
Conclusion
 References
 
The present study demonstrates that ticlopidine, an inhibitor of ADP-induced platelet aggregation, has an ability to reduce radiation induced damage in intestine both in early and late phases in the animal model.

It is important to remember that the animal model does not exactly reflect its human counterpart. Radiation damage in different animal models can be quite different in terms of severity and the presentation of the damage. However, basic physiopathological chain of events and the final appearance looks similar [29, 30]. The histopathological appearance of chronic enteropathy in patients is described as atropic mucosa, thick and fibrotic submucosa and subserosa [31], which were similar to animal model findings. We therefore assume that animal model might be taken as representative of human gastrointestinal toxicity.

Radiation induced morphological changes in the intestine were reported to begin just after irradiation. Progressive crypt shrinkage during the first 24–36 h after irradiation was shown by Potten et al [32]. Recently, radiation-induced apoptosis of endothelial cells were reported to play an essential role in the pathogenesis of acute gastrointestinal syndrome [33, 34] and it was prevented when endothelial cell apoptosis was inhibited [34]. Although vascular damage was not prominent at 2 weeks after irradiation in our study, vascular hyalinization and sclerosis was apparent at 8 weeks in the RT only group. Although endothelial cell injury was not assessed separately, we think that vascular damage at 8 weeks supports the endothelial cell damage in the early phase after irradiation. Our findings are consistent with those of Jensen et al, who reported that vascular changes were almost absent 2 weeks after irradiation, increased during the following 8 weeks and stabilized 8 weeks after irradiation [35].

Radiation induced damage to the vasculature has long been considered an important pathophysiological mechanism of CRE [36]. The predominant damage after irradiation has been reported to be in the microvasculature causing endothelial cell swelling, detachment of the endothelium from underlying matrix, increased capillary permeability, progressive loss of endothelial cells, and platelet adhesion and aggregation [37, 38]. It has also been shown that radiation enhances von Willebrand factor release, down-regulation of endothelial TM and prostacyclin, which promote prothrombotic properties. Some encouraging results were reported, that administration of anticoagulation therapy such as heparin, warfarin, or ASA may be effective against radiation injury in some organs [19–21]. Glantz et al studied heparin and warfarin in radiation induced nervous system injury [20] and reported that anticoagulation therapy may reverse small vessel endothelial injury, which is the fundamental lesion of radiation necrosis, and produce clinical improvement in some patients. Furthermore, Ludgate et al demonstrated antiplatelet properties of ASA in radiation enteropathy, whereas 5-amino salicylic acid, a potent anti-inflammatory agent with minimal effect on platelet aggregation, was found to be ineffective and possibly even harmful in radiation enteropathy [39, 40]. These observations support the hypothesis that decreasing the platelet adhesiveness by antiaggregant therapy may produce the decrease of microvascular thrombosis and improve the microcirculation, finally decreasing late damage. Antiplatelet agents in the prevention of CRE, on the other hand, have been studied in the literature with promising results [22, 23]. The role of these agents in prevention are assumed to be directed on their activities against thrombocytes, since a large number of studies have shown that these drugs selectively inhibit ADP-induced platelet activation by antagonizing the binding of ADP to platelet receptors [23]. ADP elicits various effects on platelets after binding to the specific receptor for ADP, such as inhibition of adenyl cyclase, mobilization of calcium from internal stores and expression of fibrinogen receptor [23, 41, 42].

In a study by Wang et al, short-term clopidogrel (a recently developed analogue of ticlopidine), administration starting 2 days before until 10 days after irradiation, produced protection against early and, to a lesser extent, delayed radiation enteropathy [43]. In this particular report, the authors suggested that temporary inhibition of platelet aggregation is not sufficient to permanently interrupt the fibrogenic cycle responsible for intestinal fibrosis, and that prolonged treatment or combination therapies may be necessary. Contemporary to this study we administered ticlopidine for 1 month. Median RIS values in our study showed statistically significant differences between RT and RT+T groups in the 2nd, 14th and 26th weeks of evaluation, which leads us to think that the drug not only attenuates the early, but also the late effects of irradiation. Platelets are the first cellular elements that involved and initiate the haemostatic and inflammatory responses and release a number of proinflammatory and fibrinogenic mediators, and the main effect of antiaggregants in prevention are assumed to be directed by their antiplatelet activity. In recent years, however, it was shown that ticlopidine and clopidogrel increase endothelial nitric oxide and prostacyclin production [42, 44–46] and modulate the contractile response of vascular smooth muscles [46]. So it may be rational to think that the main effect is not only due to antiaggregant property but also positive modulation of endothelial cell function.

We used ticlopidine as a daily dose of 100 mg kg–1 based on the preliminary experiments, in which Yamamoto et al studied antithrombotic effect of ticlopidine on He-Ne laser induced thrombus formation in rat mesenteric microvessels [47]. In that experimental study, Yamamoto et al reported that at a dose of 100 mg kg–1, ticlopidine inhibited thrombus formation both in arterioles and venules and appeared to be more potent than ASA. Our results confirm the efficacy of this dose in terms of preventing radiation induced enteropathy.


   Conclusion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusion
References
 
This study supports that ticlopidine can ameliorate early and chronic radiation enteropathy. The effect of antiaggregant therapies on radiation enteropathy should be comprehensively studied in phase II and III studies before clinical considerations.

Received for publication March 17, 2005. Revision received June 22, 2005. Accepted for publication August 30, 2005.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusion
 References
 

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