Protective Effect of Amifostine on High-Dose Methotrexate-Induced Small Intestinal Mucositis in Mice

Chen, Changying; Tian, Li; Zhang, Mingzhi; Sun, Qiaozhi; Zhang, Xudong; Li, Xiaodan; Cao, Xiaoqin; Liu, Qianqian; Li, Xiang; Li, Hao

doi:10.1007/s10620-013-2826-3

Cited by 22 publications

(15 citation statements)

References 23 publications

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“…Kaynar et al demonstrated that oxidant parameters were increased and antioxidant parameters decreased in small intestines of the rats administered MTX, in addition reported marked villus and crypt epithelial damage, mixed inflammatory cell infiltration containing PMNL and eosinophil leukocytes [12]. MTX was reported to cause hyperemia, inflammatory cell infiltration and loss of villus epithelial cells in the small intestines of rats [6]. In another study, MTX has been reported to lead to the cellular loss, severe villus atrophy and PMNL leukocyte infiltration [7].…”

Section: Discussionmentioning

confidence: 99%

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

et al. 2016

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Intestinal mucositis is one of the major problems in the patients receiving cancer treatment. Nimesulide is a drug with antioxidant, antiinflammatory and antiulcer features. We aimed to investigate the effect of nimesulide on the small intestine mucositis induced by methotrexate (MTX) in rats. Experimental animals were divided into the control group, MTX group (MTXG) and nimesulide+MTX administered group (NMTXG) with eight rats per group. The control and MTXG groups were given distilled water by gavage and the NMTXG was given nimesulide 100 mg/kg orally. After one hour, the NMTXG and MTXG rat groups were administered oral MTX 5 mg/kg. This procedure was repeated once a day for 15 days and the rats were sacrificed. The duodenum and jejunum of each rat was removed for the assessment of biochemical markers and histopathological evaluation. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels were significantly higher in the duodenal and jejunal tissues of the animals which received MTX, compared to the control and NMTXG (P<0.001). Also, the levels of total glutathione (tGSH), glutathione reductase (GSHRd), glutathione peroxidase (GSHPx), catalase (CAT) and superoxide dismutase (SOD) were significantly lower in the MTXG (P<0.001) compared to other groups. MTX led to villus and crypt epithelial damage and inflammation containing marked PMNL and eosinophils in the intestinal tissues histopathologically. Whereas, there was only mild irregularities in the villus structures of the NMTXG. Nimesulide protected the small intestines against damage by MTX. Intestinal mucositis caused by MTX may be preventable by co-administered nimesulide.

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Section: Discussionmentioning

confidence: 99%

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

et al. 2016

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“…Animal models, particularly rats, have been used to study toxicities of other therapeutics [24] and diseases, such as nonalcoholic steatohepatitis [25]. Rodent models have been used for pharmacokinetic modeling of methotrexate [26], exploring leucovorin rescue [27], and preclinical studies of investigational interventions to reduce toxicity (including pentoxifylline [28], amifostine [29], melatonin [30], and activators of peroxisome proliferator activator receptor a and g [31]). Critically, the mechanism of MTX crystal formation in the renal tubule was elucidated in monkeys [32], and the concept of enzymatic cleavage of MTX using glucarpidase was first described in a mouse model by Chabner et al in 1972 [33].…”

Section: Other Toxicitiesmentioning

confidence: 99%

Preventing and Managing Toxicities of High-Dose Methotrexate

et al. 2016

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High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury. This article provides comprehensive recommendations for prevention of toxicity from HDMTX, along with detailed treatment guidance to mitigate acute kidney injury and subsequent toxicity.

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“…[ 1 ] Several attempts have been made to ameliorate MTX-induced intestinal damage. [ 4 5 6 7 ] However, the outcomes were not completely satisfactory.…”

Section: Introductionmentioning

confidence: 99%

Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

2016

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Background:Intestinal toxicity is a serious side effect in methotrexate (MTX) chemotherapy.Objective:To investigate the mechanisms by which the anticancer drug MTX-induced intestinal damage could be prevented by thymoquinone (TQ), an active ingredient of Nigella sativa.Materials and Methods:TQ was given orally for 10 days, and MTX toxicity was induced at the end of day 3 of the experiment, with or without TQ pretreatment.Results:MTX caused intestinal damage, represented by distortion in normal intestinal histological structure, with significant oxidative stress, exhibited as decrease in reduced glutathione concentration and catalase activity, along with significant increase in malondialdehyde level compared to control group. MTX also caused nitrosative stress evident by increased intestinal nitric oxide (NO) level, with up-regulation of inducible NO synthase expression shown in immunohistochemical staining. Furthermore, MTX caused inflammatory effects as evident by up-regulation of intestinal necrosis factor-kappa beta and cyclooxygenase-2 expressions, which were confirmed by increased intestinal tumor necrosis factor-alpha level via enzyme-linked immunosorbent assay. Moreover, MTX caused apoptotic effect, as it up-regulated intestinal caspase 3 expression. Concomitant TQ significantly reversed the MTX-induced intestinal toxic effects by reversing intestinal microscopic damage, as well as significantly improving oxidative/nitrosative stress, inflammatory and apoptotic markers tested compared to MTX alone.Conclusion:TQ may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. TQ protection is conferred via antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.SUMMARY Methotrexate induces oxidative and nitrosative stress in intestinal tissuesMethotrexate also initiates inflammatory and apoptotic intestinal injuryThymoquinone co-administration ameliorates methotrexate-induced intestinal toxicityThymoquinone has antioxidative, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms. Abbreviations used: COX-2: Cyclooxygenase-2, ELISA: Enzyme-linked immunosorbent assay, H and E: Hematoxylin and eosin, iNOS: Inducible nitric oxide synthase, MDA: Malondialdehyde, MTX: Methotrexate, NO: Nitric oxide, NF-κB: Nuclear factor-κB, GSH: Reduced glutathione, TQ: Thymoquinone, TNF-α: Tumor necrosis factor-alpha

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Protective Effect of Amifostine on High-Dose Methotrexate-Induced Small Intestinal Mucositis in Mice

Abstract: The effect of amifostine plus CF was greater than amifostine or CF alone in preventing high-dose methotrexate-induced intestinal mucositis and improving intestinal recovery in mice.

Cited by 22 publications

References 23 publications

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

Preventing and Managing Toxicities of High-Dose Methotrexate

Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

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