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Review the application of polyprezinc in radiotherapy

Review the application of polyprezinc in radiotherapy

  • Categories:Stomach healthy
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  • Time of issue:2020-12-01
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(Summary description)

Review the application of polyprezinc in radiotherapy

(Summary description)

  • Categories:Stomach healthy
  • Author:
  • Origin:
  • Time of issue:2020-12-01
  • Views:0
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 Radiotherapy plays an important role in the treatment of many malignant tumors. Modern radiotherapy has been successfully applied to the treatment of malignant tumors, but related toxicity and adverse reactions will seriously affect the quality of life (QOL) of patients. Adverse reactions of radiotherapy are divided into early or late. Early adverse reactions occur during or after treatment, and are usually reversible, recovering within weeks to months. Late-stage adverse reactions are observed months to years after the completion of treatment, which is refractory or permanent. In order to protect patients from adverse reactions and toxicity caused by radiation, and to improve the therapeutic indicators of radiotherapy, the use of radioprotective agents has received extensive attention.

  Amifostine is currently the only radioprotectant recommended by clinical guidelines approved by the US FDA. It is an exogenous free radical scavenger, especially a radioprotective agent used to prevent radiation xerostomia. However, due to gastrointestinal symptoms and toxicity such as hypotension, amifostine is often avoided. In another clinical trial, it was shown that benzydamine can reduce the incidence of severe mucositis in patients with head and neck cancer receiving low-dose radiotherapy. Although many potential radioprotective agents have been studied, no mature radioprotective agents have yet been applied.

  Polaprezinc (Polaprezinc, PZ) is a chelate composed of zinc ions and L-carnosine, which is clinically used to treat gastric ulcers. It has the effect of anti-oxidation and scavenging free radicals. Studies have shown that polyprezinc has a certain effect on oral mucositis, esophagitis, proctitis and improving taste function during and after radiotherapy, which can reduce radiation toxicity and improve the quality of life of patients. This article reviews the current research on the role of polyprezinc as a radioprotective agent to provide a theoretical basis for clinical research.

  method

  In order to ensure the transparency of research reports, this article follows the preferred reporting items of the Guidelines for Systematic Review and Meta-Analysis (PRISMA). Use PubMed database to conduct a literature search to identify all relevant studies. Use the keywords "polaprezinc" and "radiotherapy" and "radiation" to retrieve articles, including peer-reviewed studies that have evaluated the role of polyprezinc as a radioprotectant. A preliminary search was conducted in August 2017, and a total of 12 articles were retrieved. It also includes prospective randomized clinical trials of the effect of zinc on radiation protection in English and Japanese.

  oral mucositis

  Radiation mucositis often occurs in patients undergoing radiotherapy for head and neck tumors, which can delay the completion of treatment and significantly reduce the quality of life of patients. The clinical trial guidelines of the European Society of Oncology indicate that oral zinc supplements can prevent oral mucositis. However, there is not enough consensus and evidence for the clinical application of zinc in cancer treatment. Here, the research on the use of zinc and polyprezinc in radiotherapy to prevent oral mucositis is summarized.

  Polyprezinc is effective for mucositis caused by chemotherapy and radiotherapy of head and neck tumors [15]. This trial tested the efficacy of polyprezinc on 31 patients with head and neck cancer. The results showed that the effective rate of polyprezinc oral rinsing was 88%, which significantly improved ≥grade 2 mucositis, pain, dry mouth, and dysgeusia. A recent study [16] examined the same patient group, in which the incidence of grade 3 oral mucositis in the polyprezinc group was significantly lower than that of the control group (16.5 and 52.0%, respectively; p=0.0003), and, The use of polyprezinc can significantly shorten the median duration of radiotherapy (51.5 and 56.0 days, respectively; p=0.0149).

  A new approach was adopted to prepare polyprezinc mouthwash, which enhanced the adhesion of the drug to the oral and oropharyngeal mucosa, thereby enhancing its direct effect on the mucosa [17]. Polyprezinc mouthwash based on carboxyvinyl polymer. Use 4 times a day without swallowing, the total amount is 150mg/day. As a result, in a retrospective analysis, Polyprezinc mouthwash reduced the incidence of severe mucositis and promoted recovery.

  In a prospective randomized trial, zinc supplementation can significantly inhibit the occurrence of radiation mucositis in 30 patients with head and neck cancer [18]. During radiotherapy and 6 weeks after treatment, zinc sulfate (containing 50 mg of zinc) was administered 3 times a day. In another study, 50 head and neck cancer patients in each group, compared with placebo, zinc supplements (25mg) given 3 times a day during radiotherapy significantly reduced mucosal inflammation, and patients had better compliance [19]. At the same time, polyprezinc can significantly reduce the incidence of oral mucositis in patients receiving high-dose chemotherapy and hematopoietic stem cell transplantation for treatment of hematological diseases [20.22]. In addition, polyprezinc significantly reduces the incidence of oral mucositis in patients receiving chemotherapy and whole body irradiation of 12Gy as hematopoietic stem cell transplantation for hematological malignancies [21]

  PZ can relieve severe oral mucositis. The y-axis represents the incidence of severe mucositis (≥ grade 3) in each group. Patients who received polyprezinc oral irrigant (n=11) had significantly less severe mucositis compared with those who did not (n=8; p=0.046). The bar graph is generated based on the data in [21]. PZ: Polyprezinc.

  Esophagitis and gastrointestinal mucositis

  Radiation esophagitis is a common acute toxicity in chest malignancies, such as lung cancer and esophageal cancer. Radiation damage to the gastrointestinal tract ranges from self-limiting mucosal inflammation that causes dyspepsia to acute toxic ulcers and bleeding during and several weeks after treatment. Radiation-induced fibrosis can cause obstruction and obstruction several weeks or months after radiotherapy. ulcer. Rectal complications of radiotherapy for pelvic malignancies (including genitourinary system malignancies and rectal cancer) occur in 5-20% of patients, especially acute and chronic radiation proctitis. Rectal bleeding is the most common symptom. The guidelines point out that radioprotective agents, such as sucralfate enema to treat chronic radiation proctitis, oral systemic sulfasalazine and probiotics containing lactic acid bacteria, to prevent radiation-induced enteropathy. However, the efficacy of these drugs is not satisfactory and they are not commonly used. Therefore, further research is needed to overcome radiation mucositis of the digestive tract from the esophagus to the rectum. See Table 2 for related studies on esophagitis and gastrointestinal mucositis. Table 2 Summary of studies on prevention of esophagitis and gastrointestinal mucositis by zinc in radiotherapy

  In 38 patients with non-small cell lung cancer who received radiotherapy and chemotherapy at the same time, compared with the mixture of sodium alginate solution and aluminum hydroxide gel and PZ, the use of sodium alginate solution and PZ alone can significantly inhibit the occurrence of severe radiation esophagitis [31].

  According to reports, the administration of polyprezinc (100 mg/kg) 1 hour before irradiation significantly reduces the apoptosis of epithelial cells in the jejunum, and also reduces the expression of p53, p21 and Bax [32]. In addition, polyprezinc can reduce normal intestinal cell apoptosis and protect intestinal stem cells from radiation damage [33]. In addition, polyprezinc also protects the intestinal mucosa from 5-fluorouracil-induced damage and promotes intestinal mucosal proliferation [34].

  Polyprezinc prevents radiation proctitis through anti-inflammatory effects in animal models. After irradiation, the rats were given polyprezinc ointment rectal, and the results showed that polyprezinc significantly inhibited mucosal changes caused by radiation exposure and rectal mucosal inflammation [35]. Witepsol-based polyprezinc suppositories, each containing 75 mg polyprezinc, were administered rectally to 5 patients with advanced radiation proctitis[36]. The results showed that about 60% of the patients had improved symptoms, one of them In typical cases, the effect is very obvious (Figure 2). Suppositories are safe, and no obvious adverse events occurred. Therefore, polyprezinc is a potential non-invasive treatment option for radiation proctitis, but further data support is needed before large-scale prospective clinical studies. Figure 2 Patients receiving radiotherapy for proctitis and then treated with polyprezinc suppositories. A 71-year-old man with advanced radiation proctitis. (A) Endoscopy results before taking Polyprezinc. Biochemical failure after prostatectomy for localized prostate cancer, the patient developed rectal bleeding after 3 years of external beam radiation therapy (70Gy, 35 parts). (B) Endoscopy results 23 days after starting polyprezinc treatment. The erosion turned into a white scar, and active rectal bleeding disappeared.

  taste improvement

  In a study, the incidence of loss of taste was observed in 50-90% 2 months after radiotherapy, and taste changes would reduce the patient’s quality of life. The decrease in zinc enzymes is believed to be responsible for the decreased taste sensitivity, because the turnover rate of taste buds is reduced. See Table 3 for studies on taste improvement.

  During chemotherapy, intravenous infusion of zinc is used to prevent dysgeusia in lung cancer patients undergoing chemotherapy, and has achieved remarkable results. Moreover, the results of a randomized controlled trial showed that polyprezinc was effective in 109 patients with dysgeusia, and the improvement rate of 300 mg polyprezinc was significantly higher than that of placebo, and no serious adverse events occurred.

  In a randomized controlled trial, 18 patients receiving head and neck radiotherapy with an average dose of 62.3Gy, compared with placebo, zinc sulfate promoted the recovery of oral acuity [44]. Zinc sulfate was administered starting from the change in taste and continued during the course of radiotherapy and one month after radiotherapy. The taste sensitivity of patients receiving zinc treatment at the end of radiotherapy was significantly higher than that of the control group. Among 22 patients with head and neck malignant tumors after radiotherapy, 20 patients (90.9%) improved their symptoms within 3 months after the administration of polyprezinc, while 12 patients (54.5%) experienced partial or complete remission [45] . In addition, polyprezinc not only has a significant effect on mucositis, but also improves taste dysfunction. After taking polyprezinc, patients with ≥2 grade dysgeusia are significantly reduced [36]. Several studies have failed to prove the preventive effect of zinc on taste changes. 61 patients receiving radiation therapy for head and neck cancer were given zinc sulfate 45 mg three times a day. Compared with 71 placebo patients, although zinc sulfate administration reduced the median time interval for taste changes (p=0.09), there was no evidence that zinc administration improved taste recovery (p=0.16) [46]. Compared with placebo, oral administration of 220 mg of zinc sulfate twice a day did not improve chemotherapy-related taste changes, and there was no significant difference in the loss or distortion of taste or smell. According to reports, the life span of taste cells in taste buds is about 10 days [47]. In clinical trials, the taste change started 1-2 weeks after radiotherapy, and the condition worsened, which can last for more than 1 year after radiotherapy, but there is still some improvement [48]. These studies have proved that the different administration routes and doses of zinc and PZ are a subjective form of assessment, but are usually used in clinical care. These restrictions have led to conflicting results. Therefore, further research should be conducted to support the use of PZ, and a large number of samples should be studied in the taste test.

  dermatitis

  Radiation dermatitis is one of the most common adverse reactions of radiotherapy, affecting up to 95% of cancer patients. A study showed that zinc supplements (25mg) given 3 times a day during radiotherapy can delay the development of dermatitis, and the number of patients with head and neck cancer (50 in each group) who developed grade 3 dermatitis was less than in the placebo group.

  Research shows that oral zinc sulfate can prevent severe radiation dermatitis and is dose-dependent. In the rat model, zinc sulfate has a significant effect on radiation dermatitis. Two days before and three days after 30 Gy irradiation, zinc sulfate was taken orally. The results showed that compared with irradiated rats that received only zinc or growth hormone, rats that received zinc plus growth hormone had significantly more clinical and pathological dermatitis symptoms. light. The combined application of zinc and growth hormone has the strongest protective effect on radiation dermatitis. However, the effect of growth hormone on tumor growth is unclear, and further studies are needed on the ability of zinc sulfate and growth hormone supplements to reduce radiation-induced toxicity.

  The biological response of normal tissues to radiation not only produces free radicals, which directly leads to DNA damage, but also changes proteins, lipids, carbohydrates and other complex molecules, leading to acute to chronic inflammation of normal tissues. Studies have shown that the level of zinc in the skin increases or decreases simultaneously with the increase or decrease of superoxide dismutase (an antioxidant enzyme).

  These data are sufficient to support the use of zinc in the treatment of radiation dermatitis, because it has anti-inflammatory and antioxidant effects. In addition, zinc can promote tissue repair after radiation damage.

  Polyprezinc may affect tumor treatment

  Polyprezinc's effect in reducing radiation-induced damage can be attributed to its antioxidant effect. However, in addition to inhibiting the damage of oxidative stress to normal tissues, the antioxidant effect can also inhibit the effect of anti-tumor therapy. Radiation therapy involves the production of reactive oxygen species (ROS). In the presence of oxygen, these free radicals cause the formation of other ROS. Therefore, the adverse effects of radiation are largely affected by the increase in the number of free radicals, which affect the antioxidant status of cells. In a clinical trial, high-dose antioxidants in the form of vitamin C and vitamin E showed potential radioprotective effects on normal tissues, but reduced the effect of radiotherapy in patients with head and neck cancer.

  Polyprezinc has no significant effect on the tumor remission rate of patients with neoadjuvant radiotherapy and chemotherapy for head and neck cancer. The effective rates of polyprezinc treatment group and control group were 88% and 92%, respectively (n=8 vs 12, p=1.000) . Polyprezinc oral douche had no negative effect on the overall survival rate of head and neck cancer patients between the polyprezinc treatment group and the control group (n=31 and 30; p=0.15). Similarly, polyprene zinc suspension had no effect on the overall survival rate (OS), and there was no significant difference in overall survival rate between the polyprene zinc group and the control group (n=79 and 25; p=0.579). For patients with stage II-IV non-small cell lung cancer, there was no significant difference in the tumor response rate between the polyprezinc treatment group and the control group (n=19 and 19), but the polyprezinc treatment group had a higher response rate (94.7 and 68.4 %;p=0.094).

  The median time of polyprezine use in patients with hematological malignancies who received hematopoietic stem cell transplantation after high-dose chemotherapy and radiotherapy, compared with the control group (p=0.38, 0.529 vs 0.859, respectively), the 2-year overall survival rate and no The recurrence survival rate was not affected. Polyprezinc does not affect the anti-tumor effect of 5-fluorouracil chemotherapy on xenograft colorectal cancer.

  The mechanism of polyprezinc to reduce radiation toxicity

  Several anti-ulcer mechanisms of polyprezinc are postulated: direct protection of gastrointestinal mucosa, promotion of wound healing and free radical scavenging. Polyprezinc reduces the expression of p53, p21 and Bax in the intestine after irradiation. Inhibition of these pro-apoptotic genes may be one of the mechanisms of polyprezinc. Studies have also shown that polyprezinc can reduce cell apoptosis, protect intestinal stem cells and acute inflammation after normal intestinal tract irradiation.

  Cancer patients generally suffer from zinc deficiency. Zinc is an important component of wound healing. Chronic zinc deficiency can lead to delayed wound healing, anemia and sexual dysfunction. Zinc deficiency is related to chronic inflammation of the esophagus. Polyprezinc can inhibit the immediate and acute reactions induced by radiation. In addition, zinc is necessary for RNA and DNA synthesis, and plays an important role in a variety of enzyme pathways to heal damaged mucosa.

  Inhibiting the production of ROS in tissues during and after radiotherapy is an effective way to prevent radiation damage. This can be achieved by supplementing zinc. Zinc can reduce chronic inflammation, thereby reducing late-stage radiation-induced toxicity. There is currently no clinical data to directly compare the use of zinc alone with polyo.

  2.7 The effect of polyprezinc on the activation of NF-κB induced by PMA and H₂O₂ in MKN28 cells

  We also studied the effect of polyprezinc on the activation of NF-κB induced by PMA (0.1μM) and H₂O₂ (1μM). Figure 8 shows that both PMA and H₂O₂ can induce significant activation of NF-κB in MKN28 cells, while polyprezinc (300 μM) completely blocks this process.

  Lane 1, medium alone; Lane 2, 0.1 μM PMA; Lane 3, 0.1 μM PMA + 300 μM Polyprezinc; Lane 4, 0.1 μM PMA + a 100-fold amount of cold competitor oligo; Lane 5, 1 μM H₂O₂ ; Lane 6, 1μM H₂O₂ + 300 μM polyprezinc; Lane 7, 1 μM H₂O₂ + a 100-fold amount of cold competitor oligo.

  2.8 The effect of zinc and L-carnosine on the activation of NF-κB in MKN28 cells induced by TNF-α

  As shown in Figure 9, two concentrations of ZnSO4 (100/300μM) completely blocked the activation of NF-κB induced by TNF-α, while L-carnosine had no significant effect, indicating that the efficacy of Polyprezinc is Mediated by zinc. We also studied the effect of ZnSO4 on IL-8 secretion. The results showed that 10 μM and 100 μM ZnSO4 inhibited the IL-8 secretion induced by 10 μM TNF-α (2.79 ± 0.96 ng/ml, n=4) by about 64% and 98%, respectively.

  Lane 1, medium alone; Lane 2, TNF-α (10ng/ml); Lane 3, TNF-α (10ng/ml) + 100μM ZnSO4; Lane 4, TNF-α (10ng/ml) + 300μM ZnSO4; Lane 5 , TNF-a(10ng/ml)+ 100μM L-carnosine; Lane 6, TNF-a(10ng/ml)+ 300μM L-carnosine; Lane 7, TNF-α(10ng/ml)+ a 100-fold amount of cold competitor oligo.

  2.9 The effect of polyprezinc on phosphorylation of IκB-α induced by TNF-α

  The effect of polyprezinc on IκB-α phosphorylation (Ser32) induced by TNF-α (10ng/ml) in MKN28 cells. As shown in Figure 10A, in the absence of polyprezinc, TNF-α transiently increased the amount of phosphorylated IκB-α. Anti-IκB-α antibody experiments showed that after TNF-α treatment, the total amount of IκB-α protein gradually decreased, indicating that IκB-α was phosphorylated and degraded. However, in the presence of 300μM polyprezinc (Figure 10B), TNF-α induction did not significantly affect the phosphorylated IκB-α level. When containing polyprezinc, the total amount of IκB-α is constant after 30 min incubation with TNF-α. These results indicate that in MKN28 cells, polyprezinc inhibits the phosphorylation of IκB-α after TNF-α treatment.

  The MKN28 cell extract (10ng/ml) was treated with anti-phospho IκB-α (Ser32) antibody and anti-IκB-α antibody, and Western was performed without (A) and (B) polyprezinc (300μM) Blot analysis.

  2.10 The effect of polyprezinc on AP-1 activation

  Since AP-1 may also affect the expression of IL-8, we studied the effect of polyprezinc on the AP-1 specific DNA binding activity of MKN28 cells. As shown in Figure 11, AP-1 activation is present in control cells. By incubating with 10 ng/ml TNF-α, 10 ng/ml IL-1β and 1 mM H₂O₂, AP-1 activation is slightly upregulated, while PMA The effect is more effective. Pre-incubation with 300 μM polyprezinc for 3h completely inhibited AP-1 activation, indicating that polyprezinc down-regulated AP-1 activation in addition to NF-κB.

  Lane 1, medium alone; Lane 2, 300μM Polyprezinc; Lane 3, TNF-α (10ng/ml); Lane 4, TNF-a (10ng/ml) + 300μM Polyprezinc; Lane 5, IL- 1β(10ng/ml); Lane 6, IL-1β(10ng/ml)+ 300μM Polyprezinc; Lane 7, 0.1 mM PMA; Lane 8, 0.1 μM PMA 1300μM Polyprezinc; Lane 9, 1mM H₂O₂; Lane 10, 1mM H₂O₂ 1300μM polyprezinc; Lane 11, medium alone+a 100-fold amount of competitor oligo; Lane 12, 0.1 μM PMA +a 100-fold amount of competitor oligo.

  3 Conclusion

  Polyprezinc is a chelate of zinc and L-carnosine, which has antiulcer activity. This study aims to explore the molecular mechanism of its action. In the study, we found that polyprezinc can inhibit the expression and secretion of cytokine-induced IL-8 mRNA in MKN28 gastric epithelial cells; at the same time, it can down-regulate pro-inflammatory cytokines and H₂O₂-induced NF-κB activation. These results suggest that Polyprezinc can inhibit gastric inflammation and is a new type of anti-inflammatory drug. NF-κB is widely involved in the expression of genes related to cell inflammation and immune response. The abnormal regulation of this transcription factor may be related to various pathological conditions. Therefore, NF-κB is one of the potential targets for the treatment of inflammatory diseases. Our early studies showed that NF-κB activation and IL-8 expression in MKN28 cells are more sensitive to redox reactions, so this study can be explained by its antioxidant effect. Because polyprezinc can inhibit the phosphorylation of IκB-α induced by TNF-α, the site of action should be IκB kinase or the upstream kinase of IκB. After oral administration of polyprezinc, it adheres to the surface of the gastric mucosa, and its adhesion to the gastric mucosa is better than ZnSO4 or ZnSO4 and L-carnosine. Therefore, although NF-κB is ubiquitously expressed in most tissues, polyprezinc can be used as a drug that specifically down-regulates the activation of NF-κB in the gastric mucosa, as well as the gastric disorder under long-term inflammation, such as Helicobacter pylori-related gastritis. Drugs that normalize gastric mucosal cells. This study also provides a theoretical basis for polyprezinc as a new anti-inflammatory drug.

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