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Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan (CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-colitis activity. In this study, andrographolide treatment was found to significantly relieve CPT-11-induced colitis in tumor-bearing mice without decreasing the tumor suppression effect of CPT-11. CPT-11 causes DNA damage and the release of double-stranded DNA (dsDNA) from the intestine, leading to cyclic-GMP-AMP synthase (cGAS)‒stimulator of interferon genes (STING)-mediated colitis, which was significantly decreased by andrographolide both in vivo and in vitro. Mechanistic studies revealed that andrographolide could promote homologous recombination (HR) repair and downregulate dsDNA‒cGAS‒STING signaling and contribute to the improvement of CPT-11-induced gastrointestinal mucositis. These results suggest that andrographolide may be a novel agent to relieve gastrointestinal mucositis caused by CPT-11.
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Objective:Considering the efficacy of Gegen Qinliantang （GQT） in releasing exterior and clearing interior to alleviate dampness-heat dysentery， we analyzed the mechanism of the chloroform extract of GQT in alleviating enterotoxicity caused by irinotecan to provide an experimental basis for the development of GQT. Method:Kunming mice （<italic>n</italic>=60） were randomly divided into a blank group， a model group， a loperamide group （positive drug of loperamide hydrochloride capsule， 0.4 mg·kg<sup>-1</sup>）， and high- （2.3 g·kg<sup>-1</sup>） and low-dose （1.16 g·kg<sup>-1</sup>） GQT chloroform extract groups. The mouse model of delayed diarrhea was established by intraperitoneal injection of irinotecan hydrochloride （CPT-11， 55 mg·kg<sup>-1</sup>） for four consecutive days， meanwhile， the mice in the blank group only received the same volume of normal saline. Corresponding drugs were administered by gavage on the fifth day， respectively， while the ones in the blank group and model group were given distilled water for five consecutive days. The general condition of mice in each group was observed， and diarrhea indexes of mice were recorded. Pathological changes in colon tissues of mice were observed by hematoxylin-eosin （HE） staining. The tumor necrosis factor （TNF）-<italic>α</italic>， interleukin （IL）-1<italic>β</italic>， cyclooxygenase （COX）-2， intercellular adhesion molecule （ICAM）-1， glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， malondialdehyde （MDA） and nitric oxide （NO） levels in colon tissues were detected with the assay kits. Furthermore， the expression levels of Kelch sample epoxy chloropropane associated protein 1 （Keap1）， nuclear factor E<sub>2</sub> related factor 2 （Nrf2）， tight junction protein-1 （ZO-1）， heme oxygenase-1 （HO-1） and tight junction protein （Occludin） were detected by Western blot. Result:Compared with the blank group， the model group showed declined body weight and reduced contents of GSH-Px and SOD （<italic>P</italic><0.01）， whereas increased diarrhea indexes and TNF-<italic>α</italic>， IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO levels （<italic>P</italic><0.01）. Abundant inflammatory cells and colonic mucosa with defects， swelling， bleeding， and inflammatory exudation were revealed by HE staining in the mice of the model group. The expression levels of Keap1， Nrf2， ZO-1， HO-1 and Occludin in colon tissues significantly declined （<italic>P</italic><0.01）. Compared with the model group， the loperamide group and the high- and low-dose GQT chloroform extract groups exhibited improved weight loss， reduced diarrhea indexes， diminished TNF-<italic>α</italic>，<italic> </italic>IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO， and elevated GSH-Px and SOD. HE staining indicated that the cells were compactly arranged with clear nuclei in the high- and low-dose GQT chloroform extract groups， and the expression levels of Keap1， Nrf2， HO-1， Occludin， and ZO-1 were up-regulated. Conclusion:GQT chloroform extract may alleviate CPT-11-induced delayed diarrhea by regulating inflammation and oxidative stress for enhancing the intestinal barrier function. These findings are expected to provide a reference for exploring the toxicity-attenuating effect of Chinese medicinals on chemotherapy drugs and for developing famous classical formulas.
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AIM To observe the therapeutic effects of Shengjiang Xiexin Decoction (Zingiberis recens Rhizoma,Zingiberis Rhizoma,Coptidis Rhizoma,etc.) on irinotecan (CPT-11)-induced delayed diarrhea in colorectal carcinoma mice and to discuss its possible action mechanism.METHODS The AOM/DSS-induced female colorectal carcinoma mice were randomly divided into normal group,model group and Shengjiang Xiexin Decoction group.The Shengjiang Xiexin Decoction group was intragastrically administered with Shengjiang Xiexin Decoction,the normal group and the model group were intragastrically administered with normal saline.The diarrhea index and rectum pathologic morphology were measured,and the β-glucuronide activity,IL-15 content and UGT1A1 expression were detected.RESULTS The diarrhea index of Shengjiang Xiexin Decoction group was significantly lower than that of the model group,which might be related to the significant inhibition of β-glucuronide activity,and sig-nificant improvement of IL-15 content and UGT1A1 expression.CONCLUSION Shengjiang Xiexin Decoction shows therapeutic effects on irinotecan-induced delayed diarrhea in AOM/DSS-induced colorectal carcinoma mice.
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Objective:To identify the ABCG2 expression levels in colorectal cancer patients and its relationship with clinicopath-ological features and the efficacy of irinotecan-based chemotherapy and to provide further theoretical basis for individualized treatment. Methods:Clinical data and tumor samples from patients with metastatic CRC who have received irinotecan-based chemotherapy at the Department of Gastroenterological Oncology, Peking University Cancer Hospital from January 1996 to December 2011 were collected. The immunohistochemical method was used to detect ABCG2 expression levels both in colorectal carcinoma and tumor-adjacent nor-mal tissues. The correlations of the expression of ABCG2 with clinicopathological features and the efficacy of irinotecan-based chemo-therapy were statistically analyzed. Results:1) Immunohistochemical staining shows that the positive rate of ABCG2 expression in the colorectal cancer samples is 93.2%, which is significantly higher than that in normal colon mucosa at 43.6%(P0.05). Conclusion:ABCG2 expression has no significant correlation with the efficacy of irinotecan chemotherapy in patients with colorectal cancer.
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<b>Introduction</b>: CPT-11 induced diarrhea reduces patient compliance, lowers quality of life, and can be potentially life threatening. Loperamide is effective in the majority of cases of CPT-11-induced diarrhea. However, the case of advanced gastrointestinal cancer where oral administration is difficult. We adapted octreotide for use in a case of CPT-11-induced diarrhea where oral administration was difficult due to digestive tract stenosis. <b>Case Report</b>: A 61-year old man was diagnosed with advanced gastric cancer. He was treated with CPT-11 100mg/m² weekly for three weeks followed by a 1-week rest. CPT-11-induced diarrhea developed after 10 days of treatment. At the same time, his digestive tract stenosis worsened, making Loperamide unusable. We administered octreotide 200μg continuous intravenous drip infusion. One day after octreotide administration, the number of diarrhea has decreased from 20 times to four times. <b>Conclusions</b>: Octreotide is one of the effective treatments for CPT-11-induced diarrhea. Palliat Care Res 2010; 5(2): 338-341
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PURPOSE: The aim of this study was to evaluate the responsiveness to CPT-11 with respect to hMLH1 and hMSH2 protein expressions in primary colorectal tumors. MATERIAL AND METHODS: 91 patients with colorectal cancer treated having undergone surgery and postoperative CPT-11-based adjuvant chemotherapy, between 1997 and 2002, were prospectively recruited. Tumor samples were immunohistochemically analyzed for the expressions of hMLH1, hMSH2, p53 and CEA proteins. RESULTS: Of the 91 tumors, 6 (6.6%) and 4 (4.4%) showed loss of hMLH1 and hMSH2 protein expressions, respectively. The response rate of patients with tumors not expressing either hMLH1 or hMSH2 was higher than that of those expressing either of these proteins (p=0.026). Patients with tumors not expressing hMLH1 showed a significantly better response to CPT-11 (p=0.04). The responsiveness was not associated with the expressions of hMSH2, p53 or CEA. There were no correlations between drug toxicity and the expressions of hMLH1, hMSH2 or p53. The overall survival was better in patients responsive to CPT-11-based chemotherapy compared to non-responders. CONCLUSION: The immunohistochemical determination of loss of hMLH1 and hMSH2 expressions may be used in determining the responsiveness to CPT-11-based chemotherapy. Our results suggest that hMLH1 protein expression may be a predictor for CPT-11 responsiveness in patients with colorectal cancer.
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Humans , Chemotherapy, Adjuvant , Colorectal Neoplasms , Drug Therapy , Drug-Related Side Effects and Adverse Reactions , Prospective StudiesABSTRACT
PURPOSE: To evaluate the radiation enhancement by a combination of CPT-11 and etoposide, with in vitro ionizing radiation. MATERIALS AND METHODS: H460 human lung carcinoma cells were plated, and treated with 4.5 microM CPT-11 for 4 hr, then irradiated with various doses of radiation, and treated with 1microM etoposide for 1.5 hr. The survival and sublethal damage recovery (SLDR) were determined by a clonogenic assay. The analysis of apoptosis, due to the combined treatment with drugs and radiation, was performed using 7-AAD staining and flow cytometry. RESULTS: The survival experiments resulted in radiation dose enhancement ratios (DER) of 1.30, 1.39, and 1.65 for CPT-11, etoposide, and CPT-11 plus etoposide, respectively. The analysis of apoptosis, using 7-AAD staining and flow cytometry, indicated an synergistic effect. Inhibition of the SLDR was not observed with the CPT-11 plus etoposide. CONCLUSION: These data show that the combination of CPT-11 and etoposide is a more effective radiation enhancer in human lung cancer cells than either agent used individually in human lung cancer cells. This radiation enhancement is not caused by the inhibition of the SLDR, but other mechanisms may be involved in the combined treatment of CPT-11 and etoposide combined treatment.
Subject(s)
Humans , Apoptosis , Etoposide , Flow Cytometry , Lung Neoplasms , Lung , Radiation, IonizingABSTRACT
Objective:To observe modulation of gut functions and intestinal mucosal immune barrier by ShengJiangXieXinTang in rats receiving Irinotecan(CPT-11).Methods:Sprague Dawley male rats(n=18)were randomly assigned to three groups:(1)herb group (using ShengJiangXieXinTang by oral administration once a day from day 1 to day 9 and being injected with 150 mg/kg?d CPT-11 on day 4 and 5 into the tail vein); (2)diarrhea control group: using distilled water instead of ShengJiangXieXinTang,with the same treatment of CPT-11 as the herb group; (3)normal control group: using normal saline instead of CPT-11, distilled water instead of ShengJiangXieXinTang,and with the same treatment of as the CPT-11 herb group.The animals were scored in terms of delayed-onset of diarrhea. Rats were killed on day 10,collecting ileum,cecum and colon for pathological examination.The damages in intestinal mucosa were assessed under light microscope according to the criterion of chiu's score.CD4+,CD8+T-lymphocytes and SIgA were enumerated by immunohistochemical staining and calculated by imaging analyzer.Results:Compared with diarrhea control group,the incidence of diarrhea and the damage in intestinal mucosa of the herb group was milder(P
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Background and purpose:Gastric cancer is one of the common malignancies seen in our country, most patients were diagnosed at a late stage. Surgery remains as one of the main treatments for the patients but the local local and regional failures were still high. The importance of the role of chemotherapy and radiotherapy has been investigated in the treatment of gastric cancer.We evaluated the efficacy and side-effects of CPT-11 combined with capecitabine for the treatment of advanced gastric cancer. Methods:Since May 2004 to May 2006, twenty patients with pathologically proved gastric cancer have been treated by CPT-11 plus capecitabine in our hospital. The regimen consisted of CPT-11 120 mg/m2 infusion at 1st day and 8th day, capecitabine 1000 mg/(m2?d) twice a day from 1st-14th day . The cycles were repeated every three weeks. All the patients were planned to receive at least 2 cycles of chemotherapy.Results:In 20 evaluable patients, 1 case had complete response; 8 case had partial response; 6 case had stable disease and 5 case with progressive disease. The response rate of the whole group was 45.0%(9/20); Clinical tumor control rate was 75.0%(15/20). The major toxicities were bone marrow suppression (52.1%) and reactions relative to digestive system (35.2%). All of complications were RTOGⅠ/Ⅱ degree.Conclusions:Combination of CPT-11 and capecitabine is effective for advanced gastric cancer and well tolerated by the patients. For the patients with either old age, poor general status or relapse after other chemotherapeutic regimen, the regimen could be the one of choice.
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Background and purpose:Irinotecan(CPT-11) is a derivative of camptothecin,an inhibitor of DNA topoisomerase I.CPT-11 is oxidized to inactivated metabolites(including APC)by CyP3A enzymes and activated to SN-38 by Carboxylesterase-2(CES-2).CPT-11 has been shown to exhibit excellent antitumor activity against colorectal cancer.Our research is to evaluate the efficacy and toxicity of CPT-11 combined with 5-FU/CF in the treatment of advanced or metastatic colorectal cancer.Methods:thirty-two cases of advanced or metastatic colorectal cancer patients were treated,and thirty cases were evaluable for efficacy.of which 19 cases were grouped with one cycle every two weeks and 13 cases were grouped with one cycle every three weeks.Results:In 30 evaluable patients,2 cases had complete response,11 cases had partial response,14 cases had stable disease and 3 cases with progressive disease.The response rate of the whole group was 43.3% and the stability rate was 46.7%.The clinical beneficial response rate was 83.3%.Median time to progression was 7.2 months and median overall survival time was 13.8 months. Dose limiting toxicity was delayed diarrhea and neutropenia.There was no death during the treatment.Conclusions:CPT-11 combined with 5-Fu/CF is an effective and well tolerated regimen in the treatment of advanced or metastatic colorectal cancer.which can relieve symptoms and improve quality of life of the patients.It can be used as the first-line or second-line therapy for advanced or metastatic colorectal cancer.