Objective To assess an effect of 5-fluorouracil (5-FU) applied topically on the tendon adhesion and the healing process after the flexor tendon repair in Leghorn chickens. Methods Thirtytwo white Leghorn chickens, aged 4 months and weighing 1.5-1.7 kg, were randomly divided into 2 groups: Group A andGroup B, with 16 chickens in each group. The flexor digitorum profundus tendons of the 2nd, 3rd and 4th toes were transected and repaired. The repair site in Group A was given 5-FU in a concentration of 25 mg/ml with a soaked sponge that wascut into pieces 7 mm×20 mm×1 mm in size, and the synovial sheath of the repair site was wrapped with the 5-FU-soaked sponge for 1 min for 4 times. The repair site in Group B was served as a control, with no 5-FU but with the sterile normal saline. At 3 and 6 weeks postoperatively, the repaired tendons and the tendon adhesion formation were examined macroscopically and histologically，and the repaired tendons were tested biomechanically. The tissue blocks from the tendon repair site were examined under the transmission electron microscope. Results At 3 and 6 weeks postoperatively, the macroscopic and histological observation showed that the peritendinous adhesions in Group A were looser when compared with those in Group B. The length of the tendon gliding and the extent of yieldance to exercise were found to be 4.85±1.31 mm, 0.67±0.42 mm and 5.74±1.61 mm, 1.55±0.35 mm respectively at 3 and 6 weeks after operation in Group A，but 2.99±0.51mm，0.24±0.14 mm and 3.65±0.54 mm, 1.22±0.16 mm in Group B.Group A was significantly greater in the abovementioned parameters than Group B (P＜0.05).At 3 weeks after operation, the ultimate breaking strength was 20.28±4.92 N in Group A and 21.29±4.88 N in Group B, with no statistically significant difference found between the two groups (P＞0.05). At 6 weeks, the ultimate breaking strength was 47.12±6.76 N in Group A but 39.31±7.20 N in Group B, with a significant difference between the two groups (P＜0.05). Conclusion 5-fuorouracil, when appliedtopically, can reduce the tendon adhesion, with no inhibition of the intrinsic healing mechanism. It is an ideal treatment strategy to prevent peritendinous adhesion.
ObjectiveTo investigate the effects of dipyridamole (DP), one of the human equilibrative nucleoside transporters (hENTs) blockers, on 5-fluorouracil (5-FU) induced cell apoptosis and cell cycle changes of the pancreatic cancer Panc-1 cell line. MethodsPancreatic cancer cell line Panc-1 was divided into hENTs blocked group and hENTs unblocked group. The hENTs blocked group was further divided into two subgroups according to the DP concentration, 5 μmol/L DP group and 10 μmol/L DP group. Each group was incubated in culture medium with or without 1.5×106 ng/L 5-FU for 24 h. Cell apoptosis and cell cycle were detected by flow cytometry. Results①The apoptosis results of each group： Incubated in culture medium with 1.5×106 ng/L 5-FU for 24 h, the apoptosis rates of 5 μmol/L DP group and 10 μmol/L DP group were higer than those of hENTs unblocked group （Plt;0.05）, and which of 10 μmol/L DP group was higer than that of 5 μmol/L DP group (Plt;0.05). Incubated in culture medium without 5-FU for 24 h, there were no significant differences of the apoptosis rates among three groups (Pgt;0.05). ②The cell cycle results of each group: Incubated in culture medium with 1.5×106 ng/L 5-FU for 24 h, the percentages of S phase cells in the 5 μmol/L DP group and 10 μmol/L DP group were less than those of hENTs unblocked group (Plt;0.05). The percentage of S phase cell of 5 μmol/L DP group reduced to 87.09% and that of 10 μmol/L DP group reduced to 74.06% as compared with hENTs unblocked group. 5-FU had little influence on G2 phase (Pgt;0.05) except for the percentage of G2 phase cells in the 5 μmol/L DP group increased significantly (Plt;0.05) as compared with the hENTs unblocked group. Incubated in culture medium without 5-FU for 24 h, there were no significant differences of the cell cycles among three groups (Pgt;0.05). ConclusionsIn pancreatic cancer Panc-1 cell, DP could enhance the cytotoxicity of 5-FU by blocking hENTs. The enhanced cytotoxicity is related to elevation of 5-FU concentration in cells, and unrelated to DP itself.
Objective To assess the effect of topical appl ication of 5-fluorouracil (5-FU) on intimal hyperplasia in rabbit vein graft. Methods Sixty-four male New Zealand white rabbits, aged 5 months and weighing 2.8-3.0 kg, were randomly divided into group A, B, C, and D (n=16 rabbits per group). Artery defect model was establ ished by cutting about 1 cm artery from the middle part of the dissociated left common carotid artery. A section about 3 cm was cut from the right external jugular vein, and the harvested vein was inverted and end-to-end anastomosed to the artery defect with 9-0 non-traumatic suture. After anastomosis, the extima of the grafted veins in group A, B, and C was completely wrapped with cotton sheet (12 mm × 30 mm × 1 mm in size) immersed by 5-FU at a concentration of 50.0, 25.0, and 12.5 mg/mL, respectively, and eachvein was treated 5 times (1 minute at a time). In group D, the extima of the graft veins was treated with normal sal ine instead of 5-FU. The grafted veins were obtained 1, 2, 4, and 6 weeks after operation, HE staining and Masson staining were preformed for histological changes of grafted vein wall, prol iferating cell nuclear antigen (PCNA) immunohistochemistry staining and TUNEL label ing staining were conducted for prol iferation and apoptosis of smooth muscle cell of the grafted vein, and transmission electron microscope observation was performed for cellular ultrastructure. Results The HE staining, Masson staining, and PCNA immunohistochemistry staining showed that the thickness of intima in group A and B was obviously less than that in group C and D at 1, 2, 4, and 6 weeks after operation, and the prol iferation cells in group A and B were less than that in group C and D at 1, 2, and 4 weeks after operation. The thickness of the intima, the degree of intima hyperplasia, the degree of vessel lumen stenosis of four groups at different time points were as follows: at 1 week after operation, group A [(12.69 ± 1.68) μm, 0.73 ± 0.05, 0.025 ± 0.003], group B [(17.52 ± 2.01) μm, 0.86 ± 0.06, 0.027 ± 0.004], group C [(21.92 ± 1.85) μm, 1.06 ± 0.09, 0.036 ± 0.006] and group D [(26.45 ± 3.86) μm, 1.18 ± 0.08, 0.041 ± 0.005]; at 2 weeks after operation, group A [(24.61 ± 2.91) μm, 0.86 ± 0.06, 0.047 ± 0.003], group B [(37.28 ± 2.78) μm, 1.17 ± 0.09, 0.060 ± 0.004], group C [(46.52 ± 2.25) μm, 1.44 ± 0.08, 0.073 ± 0.003], and group D [(52.07 ± 3.29) μm, 1.45 ± 0.05, 0.081 ± 0.006]; at 4 weeks after operation, group A [(61.09 ± 6.84) μm, 1.38 ± 0.08, 0.106 ± 0.007], group B [(63.61 ± 8.25) μm, 1.40 ± 0.07, 0.107 ± 0.010], group C [(80.04 ± 7.65) μm, 1.64 ± 0.07, 0.129 ± 0.011], and group D [(84.45 ± 9.39) μm, 1.68 ± 0.10, 0.139 ± 0.014]; at 6 weeks after operation, group A [(65.27 ± 5.25) μm, 1.46 ± 0.07, 0.113 ± 0.005], group B [(65.82 ± 7.12) μm, 1.45 ± 0.05, 0.112 ± 0.011], group C [(84.45 ± 9.39) μm, 1.69 ± 0.09, 0.135 ± 0.007], and group D [(87.27 ± 8.96) μm, 1.76 ± 0.05, 0.140 ± 0.012]. Group A and B were inferior to group C and D in terms of the above three parameters and cell prol iferation index 1, 2 and 4 weeks after operation (P lt; 0.05). Group A and B were superior to group C and D in terms of cell apoptosis index of intima and media 1 and 2 weeks after operation (P lt; 0.05). Transmission electron microscope observation showed that the synthetic cell organelles such as rough endoplasmic reticulum, golgi apparatus, and ribosome in group A and B were obviously less than those in group C and D (P lt; 0.05). Conclusion Topicalappl ication of 5-FU can effectively inhibit intima hyperplasia of the vein grafts.
Objective To investigate the effects and mechanism of 3-methyladenine （3-MA， an autophagy inhib-itor） on the apoptosis of hepatocellular carcinoma cell line SMMC7721 induced by 5-fluorouracil （5-FU）. Methods The autophagy was observed using fluorescent microscope by monodansyicadaverin （MDC） staining. The viability of SMMC-7721 cell induced by 5-FU was measured using CCK8 assay before and after autophagy inhibited by 3-MA， meanwhile the apoptosis of SMMC7721 cell was determined via AnnexinⅤ/PI assay. The light chain 3 protein （LC3， the autophagy specific protein） and caspase-3， PARP protein were detected by Western blot. Results The autophagy of SMMC7721 cell could be induced by 5-FU after treatment for 48 h， the cell survival rate was （60.73±2.65）%， and the apoptosis rate was （40.42±2.34）%. Compared with the group of 5-FU treatment， the survival rate of SMMC7721 cell in the combination of 5-FU and 3-MA after treatment for 48 h decreased to （42.31±1.32）% （P＜0.01）， and the apoptosis rate increased to （60.92±2.99）% （P＜0.01）， meanwhile the expressions of LC3-Ⅱ， activation fragment of caspase-3， and cleavage frag-ment of PARP significantly increased （P＜0.01）. Conclusions Autophagy is a protective phenomenon during the SMMC7721 cell line apoptosis induced by 5-FU， and autophagy inhibition may enhance the sensitivity of SMMC7721 cell line to 5-FU treatment， which is probably associated with the activation of caspase-3 and cleavage of PARP. Therefore， autophagy inhibition could be a promising strategy for adjuvant chemotherapy in hepatocellular carcinoma.
To evaluate the effect of 5-fluorouracil (5-FU) appl ied topically on preventing adhesion andpromoting functional recovery after tendon repair. Methods From August 2003 to June 2007, 48 patients with flexor tendonrupture of the fingers by sharp instrument were treated and randomly divided into two groups. In 5-FU group, 39 fingers of 26 patients included 17 males and 9 females, aged (29.3 ± 9.8) years; the locations were zone I in 19 fingers and zone II in 20 fingers; single finger was involved in 12 cases and more than 2 fingers were involved in 14 cases; and the time from injury to operation was (2.4 ± 1.6) hours. In control group, 36 fingers of 22 patients included 14 males and 8 females; aged (26.1 ± 8.7) years; the locations were zone I in 16 fingers and zone II in 20 fingers; single finger was involved in 10 cases and more than 2 fingers were involved in 12 cases; and the time from injury to operation was (2.1 ± 1.8) hours. No statistically significant difference was found in constituent ratio of age, gender, injured fingers and their zones, between two groups (P gt; 0.05). The repair site in 5-FU group was given 5-FU at a concentration of 25 mg/mL with a soaked sponge, and the synovial sheath of the repaired site was wrapped with the 5-FU-soaked sponge for 1 minute for 4 times after the tendons were repaired; normal sal ine was used in the control group. Results Wound healed by first intention and no infection and tendon rupture occurred in two groups. The patients were followed up for 3-8 months (mean 4.1 months) and 3-8 months (mean 3.9 months) in 5-FU group and in control group respectively. The functional recovery degrees of the fingers were evaluated with total active movement (TAM) evaluation system. In 5-FU group, the results were excellent in 22 fingers, good in 13 fingers, fair in 3 fingers and poor in 1 finger; the excellentand good rate was 89.7%. In control group, the results were excellent in 11 fingers, good in 15 fingers, fair in 9 fingers andpoor in 1 finger; the excellent and good rate was 72.2%. There was statistically significant difference in the functional recovery degrees of fingers between two groups (P lt; 0.05). The 2 fingers which had a poor result in 5-FU group and control group were served with tenolysis was performed in 2 cases having poor results after 6 months of operation and had an excellent result at last. Conclusion 5-FU appl ied topically can reduce tendon adhesions after the ruptured tendon repair.
Objective To explore the postoperative influence of intra-abdominal implantation of sustained-releasing 5fluorouracil on the hepato-renal function, immune function, nutritional state and complications in patients with gastric and colorectal cancer. Methods Sixty-five patients with gastric or colorectal cancer were included into this study from January to June 2009. The patients (35 cases of gastric cancer, 18 cases of colon cancer and 12 cases of rectal cancer) were randomly divided into experimental group (n=25) and control group (n=40). In experimental group, 400 mg sustained-releasing 5-fluorouracil was used. Blood samples were gained before operation, the second day and the seventh day after operation to examine the indexes of hepato-renal function, immune function and nutritional state. Complications， venting time and length of stay after operation were also recorded. Results There was no statistical significance for distribution of tumor stages and patients’ gender between experimental group and control group (Pgt;0.05). Preoperative indexes of hepato-renal function, immune function and nutritional state were also not reached statistical significance between two groups (Pgt;0.05). Compared with control group, the indexes of total protein and transferrin were decreased and urea nitrogen and IgM were increased in the second day after operation in experimental group (Plt;0.05). The number of lymphocyte was increased, while CD4, Alb, total protein and IgA were decreased in the seventh day after operation in experimental group, respectively. The time of passage of gas of experimental group was longer than that of control group (Plt;0.05).Conclusion Intra-abdominal implantation of sustained-releasing 5-fluorouracil is safe and feasible, which does not increase the complications and the time of length stay after operation. However, there is a little influence on immune function and gastrointestinal function after operation for intra-abdominal implantation of sustained-releasing 5-fluorouracil.
ObjectiveTo investigate the value of different minimally invasive surgical techniques, stent placement, laparoscopic surgery, and sustained-releasing 5-fluorouracil, in solving intestinal obstruction due to colorectal cancer. MethodsFrom May 2000 to May 2010, total 68 patients with obstructed colorectal cancers in three centers were treated in two ways in terms of the stage: The first, patients with resectable tumors underwent colorectal stent placement as a ‘bridge to surgery’ guided by enteroscope under X-ray. After clinical decompression and bowel preparation, laparoscopic radical resection was performed. The second, patients with unresectable tumors underwent rectal stent placement just for palliation. Sustained-releasing 5-fluorouracil was implanted into the local cancerous intestinal tract through stent walls. ResultsFifty-one of 52 patients underwent laparoscopic radical resection successfully following stent placement, while one failed and died during follow-up 93 d postoperatively. Forty patients with successful laparoscopic surgery were followed up in 3 to 36 months (with an average of 15 months) without tumor planting in the incision, postoperative local recurrence or anastomotic stricture. Fifteen unresectable patients and one high-risk, intolerable patient underwent rectal stent placement and implantation of sustained-releasing 5fluorouracil. During follow-up 3 to 24 months (with an average of 14 months), 11 died, who survived for (350±222) d (range 101-720 d), and 5 were still alive for 3 to 13 months (with an average of 9 months) without intestinal obstruction. ConclusionsLaparoscopic surgery combined with stent placement is an effective and safe procedure for resectable obstructed colorectal cancer. For unresectal obstructed rectal cancer, rectal stent placement combined with sustained-releasing 5-fluorouracil can prolong survival time avoiding colostomy.
Objective To systematically review the effectiveness and safety of implanting sustained-release 5-fluorouracil during hepatectomy in patients with primary liver cancer (PLC). Methods We electronically searched the following databases including CENTRAL, MEDLINE, EMbase, WanFang Data, CBM, CNKI and VIP to collect randomized controlled trials (RCTs) on the effectiveness and safety of implanting sustained-release 5-fluorouracil during hepatectomy vs. hepatectomy alone for PLC from inception to October, 2012. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and assessed the quality of the included studies. Then, meta-analysis was performed using RevMan 5.0 software. Results A total of 6 RCTs involving 951 patients were included. The results of meta-analysis showed that, implanting sustained-release 5-fluorouracil during hepatectomy significantly decreased the total recurrence rates of 1-year and 3-year (1 year: RR=0.48, 95%CI 0.36 to 0.65, Plt;0.000 01; 3 years: RR=0.69, 95%CI 0.50 to 0.96, P=0.03). However, the two groups were alike in decreasing the surem levels of AFP. Besides, the commonly-seen adverse reaction of implanting sustained-release 5-fluorouracil during hepatectomy included abdominal pain and bile leakage. Conclusion Implanting sustained-release 5-fluorouracil during hepatectomy can decrease the 1-year and 3-year recurrence rates of PLC patients, especially for HCC at the early stage. But this conclusion should be interpreted with caution and needs more strictly-designed RCTs with large sample size and enough long follow-up to verify.
Objective To evaluate the effectiveness and safety of implanted sustained-release fluorouracil in gastric cancer surgery. Methods Literature search was conducted in the following databases: PubMed, EMbase, The Cochrane Library (Issue 6, 2012), CNKI, VIP and WanFang Data from inception to June, 2012. Randomized controlled trials (RCTs) or quasi-randomized controlled trials on implanted sustained-release fluorouracil for gastric cancer were included. Two reviewers independently identified the literature according to the inclusion and exclusion criteria, and then extracted the data and assessed the quality of the included studies. Then, meta-analysis was conducted using RevMan 5.1 software. Results A total of 7 studies involving 742 patients were included. The results of meta-analysis showed no significant difference in the rate of postoperative complications between the two groups (OR=0.93, 95%CI 0.54 to 1.59, P=0.79), while a significant reduction was found in the recurrence rate in the sustained-release fluorouracil group during 1 to 3 year follow-up (1 year after surgery: OR=0.32, 95%CI 0.22 to 0.46, P=0.02; 2 years after surgery: OR=0.19, 95%CI 0.08 to 0.42, Plt;0.001; 3 years after surgery: OR=0.40, 95%CI 0.24 to 0.67, P=0.004). As for the survival rate, no significant difference was found between the two groups 1 year after surgery (OR=1.98, 95%CI 0.92 to 4.25, P=0.08), while it was significantly higher in the sustained-release fluorouracil group than in the control group 2 to 3 years after surgery (2 years after surgery: OR=2.63, 95%CI 1.17 to 5.91, P=0.02; 3 years after surgery: OR=2.42, 95%CI 1.53 to 3.83, P=0.002). Adverse reaction rates in the sustained-release fluorouracil group were lower than those in the control group, but without significantly differences between the two groups (OR=1.22, 95%CI 0.49 to 3.07, P=0.67). Conclusion Compared with the control group, implanted sustained-release fluorouracil for gastric cancer can significantly reduce the recurrence rate 1 to 2 years after surgery and improve the overall survival rate 2 to 3 years after surgery without increasing the incidences of the postoperative complications and adverse reaction. However, due to the limitation of quantity and quality of the included studies, this conclusion should be further confirmed by more high quality, larger sample and multi-center RCTs.
ObjectiveTo observe effect and safety of interstitial chemotherapy with 5-fluorouracil sustained release agent in radical operation of colorectal cancer. MethodsOne hundred and sixty patients with colorectal cancer from October 2011 to December 2013 were randomly divided into observation group and control group according to an incomplete random method, 78 cases of them were in the observation group and 82 cases of them were in the control group. All the patients were performed radical resection of colorectal cancer. The abdominal cavity and pelvic cavity were washed after surgery. 5-fluorouracil sustained release agent was implanted in the observation group patients for interstitial chemotherapy, the implant site was at the tumor resection area and the mesenteric artery. Routine chemotherapy was performed in these two groups after operation. The postoperative complications were observed. The postoperative local recurrence rate, liver metastasis rate, and 24-month survival rate were recorded. ResultsThe rates of abdominal complications and toxic effects had no significant differences between these two groups (P > 0.05). The rates of 12-month and 24-month local recurrence and the rate of liver metastasis in the observation group were significant lower than those in the control group[1.3% (1/78) versus 8.5% (7/82), x2=8.934, P=0.023; 5.2% (4/78) versus 23.2% (19/82), x2=14.834, P=0.004; 10.3% (8/78) versus 18.3% (15/82), x2=12.034, P=0.016]. The rate of 24-month survival in the observation group was significant higher than that in the control group[94.9% (74/78) versus 84.1% (69/82), x2=11.465, P=0.010]. ConclusionThe good safety of interstitial chemotherapy with 5-fluorouracil sustained release agent could effectively decrease local recurrence rate and liver metastasis rate of colorectal cancer after radical operation and improve survival time of patients.