Mucosal Injury Of Small Intestine Research Articles

Small intestinal mucosal injury and its risk factors in patients with gastrointestinal cancer who developed complicated fluoropyrimidine-induced diarrhea

BackgroundDiarrhea is a common adverse event of fluoropyrimidine-based chemotherapy. However, limited data are available on the frequency and risk factors of complicated chemotherapy-induced diarrhea (CID) and small intestinal mucosal damage. In this current study, we aimed to determine the incidence of complicated CID and mucosal injury among patients with complicated CID receiving fluoropyrimidine via small bowel capsule endoscopy (CE) and determined baseline risk factors associated with complicated CID.MethodsIn total, 536 patients with advanced or recurrent gastrointestinal cancer who received fluoropyrimidine-based chemotherapy were retrospectively analyzed. Diarrhea was evaluated using the Common Terminology Criteria for Adverse Events version 4. Complicated CID was defined according to the American Society of Clinical Oncology guidelines. To evaluate small intestinal mucosal injury in patients with complicated CID, CE was performed. Multivariate analysis was performed to identify risk factors for complicated CID.ResultsTotal number of 32 (6%) patients developed complicated CID. Complicating symptoms were noted in 25 (78%) patients, with cramping, vomiting, and sepsis being observed in 15 (60%), 8 (32%), and 3 (12%) patients, respectively. Among the 13 patients who underwent CE, 11 (85%) showed abnormal findings. Multivariate analysis revealed that oral fluoropyrimidine administration was a risk factor for complicated CID (odds ratio 2.95; 95% confidence interval 1.06–8.19).ConclusionsDespite the relatively low incidence of complicated CID, mucosal injury of small intestine was common in patients with complicated fluoropyrimidine-induced diarrhea and oral fluoropyrimidine was an independent risk factor.

Mucosal injury of small intestine in patients with advanced gastric cancer who developed chemotherapy induced diarrhea (CID).

28 Background: Fluoropyrimidine is a key drug for patients with advanced or recurrent gastric cancer. It causes diarrhea, a common non-hematological toxicity. The consensus guideline suggests aggressive treatment including intravenous fluids and antibiotics, is necessary for patients with severe diarrhea accompanied by fever and sepsis. However, the frequency of complicating signs and the actual degree of damage of small intestinal mucosa have not been reported. We evaluated complicating signs and mucosal injury in patients with complicated CID. Methods: Between April 2007 and December 2016, 170 patients with advanced or recurrent gastric cancer who underwent S-1 or capecitabine based chemotherapy were retrospectively analyzed. Diarrhea was evaluated with CTCAE v4.0, and complicated CID was defined as CTC grade 3 or 4 diarrhea or grade 1 or 2 diarrhea with following signs: cramping, vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, and dehydration. To evaluate mucosal injury of small intestine, capsule endoscopy was performed in patients with complicated CID. Results: Among 170 patients, 15 patients (8.8%) showed complicated CID during chemotherapy (S-1 based chemotherapy, n = 13/148; capecitabine based chemotherapy, n = 2/22). Among the profile of complicated signs, cramping, fever, and vomiting were frequent, and observed in 11 (73%), 7 (47%), and 5 (33%) patients, respectively. Ten patients received capsule endoscopy after improvement of CID, and 6 (60%) patients had multiple erosions or ulcerations in small intestine. Conclusions: The incidence of complicated CID caused by fluoropyrimidine based chemotherapy was less frequent in patients with advanced or recurrent gastric cancer. However, most patients showed mucosal injury of small intestine in capsule endoscopy. Therefore, these findings strongly support the guideline that recommends aggressive therapeutic approach for patients with complicated CID.

Abstract 792: Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: A shorter drug-free interval leads to more efficient antitumor effects

Abstract [Background] A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. The aim of this study was to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models. [Methods] Mice were treated with S-1/LV either in a daily group (two weeks of administration followed by two weeks of withdrawal) or an alternate-day group (administration on alternate days for four weeks), then the mice of both groups were sacrificed and the xenograft tumors were resected. To assess the adverse reactions, the body weight changes, the condition of feces, mucosal injury of small intestine and myelosuppression were compared between both groups. Furthermore, tumor volume, tumor growth inhibition (TGI) and the expression of Ki67, TUNEL, cIAP2 and XIAP were analyzed to evaluate the antitumor activity and tumor apoptosis. [Results] Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, no adverse reactions were observed in the alternate-day group, except slight myelosuppression. The TGI in the alternate-day group was better than that in the daily group, possibly resulting from apoptosis of tumor cells due to the suppression of cIAP2. [Conclusion] Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve higher antitumor activity without severe adverse reactions. Therefore, we propose that clinical trials with this regimen should be conducted in CRC patients. Citation Format: Toshihiro Komura, Shinobu Ohnuma, Koh Miura, Tetsuhiko Shirasaka, Taiki Kajiwara, Katsuyoshi Kudoh, Sho Haneda, Masahide Toshima, Atsushi Kohyama, Hiroaki Musha, Takeshi Naitoh, Yu Katayose, Michiaki Unno. Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: A shorter drug-free interval leads to more efficient antitumor effects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2014-792

Glutamine protects the small intestinal mucosa in anticancer drug-induced rat enteritis model

Supportive therapy during chemotherapy has become essential, but effective preventive therapies to gastrointestinal mucosal injury are few. We investigated the efficacy of glutamine in rat anticancer drug-induced enteritis model. In this study, we used twenty male SD rats. They were divided into control, 5-fluorouracil (5-FU) (orally administered at 20 mg/kg day), 5-FU+glutamine (1000 mg/kg/day) and 5-FU+glutamine+fiber and oligosaccharide (GFO(®)) (1000 mg/kg/day) groups. All groups were sacrificed on day 6 and upper jejunums were excised. The jejunal villous height was measured in specimens. IgA level in jejunal washing solution, and serum diamine oxidase activity were also measured. The jejunal villous height was recognized as shorter in the specimen from 5-FU treated rats compared with 5-FU+glutamine treated rats (p<0.001). Serum diamine oxidase activity in 5-FU+glutamine group were significantly superior to that in 5-FU group (p=0.028). IgA level in jejunal washing solution tended to be higher in 5-FU+glutamine group than that in 5-FU group (p=0.076). On the other hand, serum diamine oxidase activity and IgA level in jejunal washing solution showed no significant difference between 5-FU+GFO and 5-FU treatment group. Our results suggest that glutamine showed protective effects on mucosal injury of small intestine in rat anticancer drug-induced enteritis model.

Tu1176 Randomized Controlled Trial of the Effect of Irsogladine Maleate on the Mucosal Injury of Small Intestine in Regular Users of NSAIDs

Tu1176 Randomized Controlled Trial of the Effect of Irsogladine Maleate on the Mucosal Injury of Small Intestine in Regular Users of NSAIDs

The use of nanoparticulate delivery systems in metronomic chemotherapy

Metronomic chemotherapy aiming at inhibiting tumor angiogenesis with conventional chemotherapeutics is a promising strategy for antiangiogenic cancer therapy. However, current metronomic chemotherapy mainly focuses on free small-molecule drugs, without any effort to achieve tumor-specific biodistribution, which may lead to long-term toxicity concerns. Metronomic chemotherapy using nanoparticulate drug delivery system (DDS) offers significant upside to reduce off-target side effects, decrease accumulated dose, and enhance the efficacy of tumor vessel targeting without compromising antitumor efficacy; but there has been a lack of thorough experimental data describing the targeted metronomic chemotherapy. Here, we develop a new nanoparticulate DDS, SP5.2 peptide conjugated, Flt-1 (VEGFR-1) targeted nanoparticles for docetaxel (SP5.2-DTX-NP), as a model for the investigation of targeted metronomic chemotherapy with respect to both antitumor efficacy and toxicity. The results demonstrate that metronomic SP5.2-DTX-NP exerts antitumor activity mainly through the antiangiogenic effect of docetaxel, which is specifically delivered into the tumor vascular endothelial cells through the nanoparticle internalization mediated by the interaction of SP5.2 and over-expressed Flt-1 receptors on tumor vessels. Moreover, the antitumor efficacy of targeted metronomic chemotherapy is better than that of the treatment with the DDS given in the maximum tolerated dose (MTD) regimen, which is shown in significantly prolonged mice survival and minimal drug-associated toxicity (bone marrow suppression, hematological toxicity, and mucosal injury of small intestine). The present research reveals and highlights the significance of targeted metronomic therapy with nanoparticulate DDS in antiangiogenic cancer therapy.

Sulforaphane Protects Small Intestinal Mucosa From Aspirin/NSAID-Induced Injury by Enhancing Host Defense Systems Against Oxidative Stress and by Inhibiting Mucosal Invasion of Anaerobic Enterobacteria

Background and Aims: Recent studies have shown that daily use of NSAIDs, frequently causes small intestinal ulcers and erosions. However, effective drugs to prevent aspirin/NSAIDs-induced small intestinal lesions have not been developed. In the present study, we examined the effects of sulforaphane (SFN), a substance rich in broccoli sprouts, on aspirin/NSAIDs-induced small intestinal injury. Methods: 1. In vitro study: IEC6 cells, derived from rat small intestinal mucosae, were incubated with or without SFN. The cells were subsequently exposed to aspirin. In some experiments, the effect of zinc protoporphyrin-IX (ZnPP), 0.1 μM, an inhibitor of heme oxygenase- 1 (HO-1), was also examined. 2. In vivo study: IND-induced small intestinal mucosal injury was induced in male ddY mice. SFN glucosinolates (SGS), which is glucosinolates precursor of SFN, was orally administered to the mice, at dose of 17 mg/mouse, before and after the injection of IND. Vascular permeability was assessed by measuring the amount of exudated Evans Blue in the mucosa, which had been injected intravenously. Neutrophil activation was evaluated by myeloperoxidase (MPO) activity. Amount of mucosal anaerobic bacteria was also measured. Results: 1. In vitro study: (1) SFN, 5 μM, significantly attenuated aspirin (20 mM)-induced cell injury. (2) SFN enhanced HO-1 expression in IEC-6 cells. The protective effect of SFN against aspirin-induced injury was attenuated by 0.1 μM ZnPP. 2. In vivo study: (1) IND treatment caused mucosal injury in small intestine, increased vascular permeability, enhanced MPO activity, and augmented mucosal invasion of anaerobic enterobacteria. (2) SGS attenuated the IND-induced small intestinal injury. (3) SGS prevented the IND-induced increase in mucosal invasion of anaerobic enterobacteria. Conclusions: These results suggest that SFN protects small intestine from aspirin / NSAIDs-induced injury, presumably by up-regulating nrf2-keap1 dependent antioxidant system and by inhibiting invasion of anaerobic bacteria into the mucosa. Keywords: Sulforaphane, aspirin, indomethacin, small intestine, antioxidant enzyme, anaerobic bacteria, NSAIDs, zinc protoporphyrin-IX (ZnPP), myeloperoxidase (MPO) activity, cell injury

Sulforaphane Protects Small Intestinal Mucosa From Aspirin/NSAID-Induced Injury by Enhancing Host Defense Systems Against Oxidative Stress and by Inhibiting Mucosal Invasion of Anaerobic Enterobacteria

Recent studies have shown that daily use of NSAIDs, frequently causes small intestinal ulcers and erosions. However, effective drugs to prevent aspirin/NSAIDs-induced small intestinal lesions have not been developed. In the present study, we examined the effects of sulforaphane (SFN), a substance rich in broccoli sprouts, on aspirin/NSAIDs-induced small intestinal injury. 1. In vitro study: IEC6 cells, derived from rat small intestinal mucosae, were incubated with or without SFN. The cells were subsequently exposed to aspirin. In some experiments, the effect of zinc protoporphyrin-IX (ZnPP), 0.1 μM, an inhibitor of heme oxygenase- 1 (HO-1), was also examined. 2. In vivo study: IND-induced small intestinal mucosal injury was induced in male ddY mice. SFN glucosinolates (SGS), which is glucosinolates precursor of SFN, was orally administered to the mice, at dose of 17 mg/mouse, before and after the injection of IND. Vascular permeability was assessed by measuring the amount of exudated Evans Blue in the mucosa, which had been injected intravenously. Neutrophil activation was evaluated by myeloperoxidase (MPO) activity. Amount of mucosal anaerobic bacteria was also measured. 1. In vitro study: (1) SFN, 5 μM, significantly attenuated aspirin (20 mM)-induced cell injury. (2) SFN enhanced HO-1 expression in IEC-6 cells. The protective effect of SFN against aspirin-induced injury was attenuated by 0.1 μM ZnPP. 2. In vivo study: (1) IND treatment caused mucosal injury in small intestine, increased vascular permeability, enhanced MPO activity, and augmented mucosal invasion of anaerobic enterobacteria. (2) SGS attenuated the IND-induced small intestinal injury. (3) SGS prevented the IND-induced increase in mucosal invasion of anaerobic enterobacteria. These results suggest that SFN protects small intestine from aspirin / NSAIDs-induced injury, presumably by up-regulating nrf2-keap1 dependent antioxidant system and by inhibiting invasion of anaerobic bacteria into the mucosa.

NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice.

Toll-like receptors (TLRs) and NK receptors are the two most important receptor families in innate immunity. Although it has been observed that TLR signaling can induce or up-regulate the expression of the ligands for stimulatory NK receptors on monocytes or muscle cells, there is not yet a report indicating whether TLR signaling can break down self-tolerance through NK receptors. The present work reports that TLR3 signaling by polyinosinic-polycytidylic acid stimulation induces intestinal epithelial cells (IECs) to express retinoic acid early inducible-1 (a ligand for NKG2D) and to induce NKG2D expression on CD8alphaalpha intestinal intraepithelial lymphocytes by IL-15 derived from TLR3-activated IECs. The blockade of interaction between NKG2D and Rae1 inhibits the cytotoxicity of intraepithelial lymphocytes against IECs in a cell-cell contact-dependent manner and therefore alleviates polyinosinic-polycytidylic acid-induced epithelial destruction and acute mucosal injury of small intestine. These results demonstrate that TLR signaling induces tissue injury through the NKG2D pathway, suggesting that TLR signaling may break down self-tolerance through induction of abnormal expression of ligands for stimulatory NK receptors.