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Pay attention to the mucosal damage of the digestive tract caused by chemotherapeutic drugs-the exploration of the comprehensive mucosal protection mechanism of Ruilaisheng

Pay attention to the mucosal damage of the digestive tract caused by chemotherapeutic drugs-the exploration of the comprehensive mucosal protection mechanism of Ruilaisheng

  • Categories:Stomach healthy
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  • Origin:
  • Time of issue:2020-12-01
  • Views:0

(Summary description)

Pay attention to the mucosal damage of the digestive tract caused by chemotherapeutic drugs-the exploration of the comprehensive mucosal protection mechanism of Ruilaisheng

(Summary description)

  • Categories:Stomach healthy
  • Author:
  • Origin:
  • Time of issue:2020-12-01
  • Views:0
Information

 

 Preface

  Relaisen (Polaprezinc, PZ) is a chelate composed of zinc ions and L-carnosine. It is a gastric mucosal protective agent and is used clinically to treat gastric ulcers. The protective effect of polyprezinc on gastric mucosa is achieved through its anti-oxidation, anti-inflammatory, membrane stabilization and promotion of mucus secretion. Studies have shown that Polyprezinc can significantly improve the small intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) and protect crypt cells from apoptosis. 5-Fluorouracil (5-FU) is a chemotherapeutic drug that prevents tumor cell growth by inhibiting the synthesis of nucleic acid in the cell. However, due to lack of specificity, it often causes digestive tract mucosal damage and serious side effects such as diarrhea in clinical applications. This greatly reduces the quality of life of patients, and also limits the clinical use of 5-FU. This study aims to explore the protective effect of Relaisen on 5-FU-induced intestinal mucosal injury in mice and its effect on the efficacy of 5-FU in the treatment of colon cancer in mice, and provide an experimental basis for clinical research.

  1 Materials and methods

  1.1 The drug and animal Ruilaisheng (Polyprezinc raw material) are produced by Jilin Province Boda Weiye Pharmaceutical Co., Ltd., prepared with distilled water before the experiment, and administered by gavage to mice. Fluorouracil injection is a product of Shanghai Xudong Haipu Pharmaceutical Co., Ltd. ICR mouse, male, 18-22g, SPF grade animal, provided by China Institute for Food and Drug Control. The animals are kept in the Laboratory Animal Room of Tumor Hospital, Cancer Institute, Chinese Academy of Medical Sciences. 1.2 Cell line and mouse vaccination

  C26 colon cancer cells were cultured in 10% FBS/RPMI 1640 medium, 37°C, 5% CO2, and 95% humidity. The cells were counted under a microscope, and 5×106 C26 cells were inoculated subcutaneously in the right foreleg of BALB/C mice to prepare F1 tumor-bearing mice. Observe the tumor growth and prepare tumor cells when the tumor grows to about 1cm³. C26 cells from F1 tumor-bearing mice were inoculated subcutaneously in the right front leg of BALB/C mice, and the tumor diameter was measured and recorded every 3 days with a vernier caliper.

  1.3 Animal grouping and experimental design

  The 32 ICR mice were randomly divided into 4 groups, each with 8 mice, namely the control group (C), the 5-FU group (5-FU, 200 mg/kg, iv), and the 5-FU + low-dose PZ group (5 -FU/LPZ, 200mg/kg, iv+100mg/kg, po) and 5-FU+ high-dose group (5-FU/HPZ, 200mg/kg, iv+200 mg/kg, po). Two days before 5-FU administration, 5-FU/LPZ group and 5-FU/HPZ group were pretreated with PZ (100mg/kg and 200mg/kg) every day. 5-FU was injected on the 1st and 4th day, and the mice were sacrificed about 24h after the last administration on the 7th day. During the experiment, the incidence of diarrhea was recorded and graded as 0/no diarrhea, 1/mild diarrhea (anal staining), 2/moderate diarrhea (staining the top of the legs and lower abdomen) and 3/severe diarrhea (legs and upper abdomen) Staining, with continuous exudation). Twenty-four C26 tumor-bearing BALB/C mice were randomly divided into 4 experimental groups, each with 6 mice. The effect of 5-FU on 5-FU treatment of colon xenograft tumors was observed, including the control group, the PZ alone group and the single Use 5-FU group and 5-FU+PZ group. Mice began to receive different doses of drug treatment on the second day after tumor cell inoculation. During the experiment, the tumor diameter was measured and recorded every 3 days. After 10 days, the mice were sacrificed for statistical analysis of body weight.

  1.4 Intestinal histological evaluation

  In order to evaluate the protective effect of 5-FU-induced intestinal mucositis and PZ, the mice were sacrificed and weighed, and the small intestine was surgically removed and fixed in formalin for histological analysis. The tissue sections were embedded in paraffin and stained with hematoxylin and eosin. According to the changes in mucosal structure (mucosal aspect, cell distribution and villus height), histological score was performed under microscope observation.

  1.5 PCNA immunohistochemistry

  Small intestine sections were washed 3 times with PBS solution, and the primary antibody was added to incubate overnight, and then the secondary antibody was added to incubate for 1 hour. After DAPI staining, observation and image acquisition were performed with a fluorescence microscope, and image analysis was performed with image Pro Plus 6.0 software. The proliferation of small intestinal crypt cells was evaluated based on the intensity of PCNA staining. Choose 5 independent measurements from 4 complete crypts and count each animal. The integrated optical density (IOD) value is equal to the neutral area of ​​the immunofluorescence image multiplied by the optical density. IOD(SUM) represents the sum of cumulative IOD results. Area and area (sum) average optical area and cumulative area used for IOD analysis. Finally, get the average PCNA density, that is, IOD (SUM)/area (SUM).

  1.6 Statistical analysis

  The results are expressed as mean ± standard deviation. Analysis of variance and t test were used to evaluate the statistical significance of the comparison between multiple groups and two groups. P<0.05 was considered to be significant, and p<0.01 was considered to be very significant and statistically significant.

  2 Results and analysis

  2.1 Relaisheng reduces the degree of diarrhea caused by 5-FU

  Mice in the 5-FU group developed diarrhea, while the diarrhea scores of the mice in the PZ (LPZ and HPZ) group were significantly lower than those in the 5-FU group (5-FU/LPZ vs. 5-FU, p<0.05; 5-FU/ HPZ versus 5-FU, p<0.01) (Table 1), and was dose-dependent. Table 1 Effect of PZ on 5-FU-induced diarrhea in mice Daily administration of 5-FU caused a significant decrease in the weight of mice. In addition, the body weight on the 3rd and 6th day after 5-FU administration was significantly lower than that of the control group. On the other hand, in the presence of PZ, the weight of the mice increased slightly after 5-FU administration, in a dose-dependent relationship, and the weight was significantly higher than that of the 5-FU group, and the body weight was still not reached on the 6th day after 5-FU administration. Control level (Figure 1). The weight of the mice in the HPZ group did not significantly decrease, and there was no change in diarrhea and food intake. Figure 1 Weight loss in mice caused by increased 5-FU in PZ

  2.2 Relaisheng reduces the intestinal injury caused by 5-FU 5-FU destroys the structure and integrity of the intestinal mucosa, manifested by shortening of intestinal villi, epithelial atrophy and mucosal damage (Figure 2). The difference in crypt depth between the two groups was significant, while the PZ pretreatment group remained normal structure. The mice in the HPZ group did not have serious intestinal damage. Compared with the 5-FU group, the height of the villi in the PZ group was significantly increased, indicating that Relaisen reduced the intestinal injury caused by 5-FU and had a positive protective effect on the intestinal mucosa. Figure 2 PZ reduces intestinal mucosal damage caused by 5-FU

  2.3 Relaisheng restores the proliferation of small intestinal crypt cells. PCNA immunohistochemistry was used to observe the effect of PZ on the proliferation of injured cells in 5-FU-related intestinal mucositis mice. 5-FU inhibits the proliferation of small intestinal crypt cells in mice, and the proliferating crypt cells in the injured small intestine of mice with 5-FU-associated mucositis are scattered and disordered. 5-FU reduces the proliferation index of small intestinal crypt cells. Relaisen can restore the integrity of mouse small intestine villi and the proliferation index of crypt cells, which has an obvious dose-effect relationship. Table 2 The effect of PZ on 5-FU-induced small intestinal mucositis in mice

  2.4 Relaisen does not affect the anti-tumor effect of 5-FU. Compared with the control group, intravenous injection of 30mg/kg 5-fluorouracil once a day can reduce tumor weight by more than 70%. Co-administration at a dose of 200 mg/kg/day did not significantly enhance the anti-tumor effect of 5-FU on colonic C26 tumors. In addition, compared with mice that did not receive 5-FU, the remission rate of the PZ group (200 mg/kg/day) was 9.4% only on the 9th day. Relaisen had no significant effect on tumor growth in mice. The growth curve further indicates that Relaisen may not enhance the anti-tumor activity of 5-FU. Relaisant neither inhibited nor promoted tumor growth in C26 xenograft mice.

  Discuss

  Chemotherapy is one of the main methods for the treatment of malignant tumors, but when chemotherapy with 5-fluorouracil and other drugs is used, the incidence of small intestinal mucositis is as high as 90%. The occurrence of chemotherapeutic mucositis not only leads to increased treatment costs and longer hospital stays, but also increases the physical and mental pain of the patients and reduces the quality of life of the patients. Relaisen (Polyprezinc Granules) is a mucosal protective drug. Studies have shown that Relaisen can reduce the degree of diarrhea caused by 5-FU and restore weight loss, which greatly improves the quality of life of patients and prevents chemotherapy Adverse reactions. At the same time, Relaisen can effectively reduce the intestinal injury caused by 5-FU, has a positive protective effect on the intestinal mucosa, and is of great significance for improving the clinical effect. In addition, while not affecting the anti-tumor effect of 5-FU, Relaisen can restore the integrity of small intestinal villi and proliferation of crypt cells, and protect the intestinal mucosal barrier structure intact and normal function. The application of Relaisen before chemotherapy can effectively prevent 5-FU damage to the mucosa, improve the tolerance of patients to chemotherapy drugs, reduce the severity of mucositis and shorten the course of mucositis. To prevent and treat intestinal mucositis, choose Relaisheng Polyprezinc Granules.

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