Reversible corneal keratinization following trabeculectomy and treatment with 5-fluorouracil.

A 66-year-old pseudophakic man with primary open-angle glaucoma and ocular cicatricial pemphigoid underwent trabeculectomy and was given postoperative subconjunctival 5-fluorouracil. He developed an inferior corneal epithelial defect and, later, a well-demarcated area of inferior corneal keratinization. Since the corneal keratinization clinically improved with conservative management, surgical intervention was not required.     

Complications of penetrating keratoplasty: graft infections

Microbial infection of a corneal transplant is a complication that is a bane to all corneal surgeons, the sequelae of which can be devastating. Identified risk factors include exposed, loose, or broken sutures; persistent epithelial defects or severe punctate keratopathy; soft contact lens wear including therapeutic lenses; graft hypoesthesia; kerato-conjunctivitis sicca; previous herpetic eye disease; graft failure; ocular adnexa and lid abnormalities; and ongoing external and corneal infections. Management includes preventive measures, microbiologic diagnostic procedures, and antibiotic therapy. Infectious crystalline keratopathy is a unique corneal infection that predominantly occurs in corneal transplants. It is characterized by the slowly progressive development of needle-like opacities in the corneal stroma and is most commonly caused by streptococcal species. Another group of infections that occur in grafts is recurrence of an infectious process for which the patient was originally grafted. Two notable pathogens in this group include Acanthamoeba and herpes simplex.     

Low-dose 5-fluorouracil and glaucoma filtration surgery

We show that a 40-mg total dose of subconjunctival 5-fluorouracil after glaucoma filtering surgery can provide a success rate comparable to that demonstrated in prior studies employing a higher dose. Sixty-four eyes with poor prognoses underwent filtering surgery with postoperative subconjunctival injections of 5 mg of 5-fluorouracil daily for seven days followed by one injection 1 week later. In 75% percent of the eyes intraocular pressure stabilized at 21 mm Hg or less regardless of medications used. The majority of failures occurred within 6 months of treatment. Postoperative corneal epithelial defects occurred in 30% of the cases, conjunctival wound leaks in 6.3%. A 40-mg dose of subconjunctival 5-fluorouracil appears to be effective and may be associated with a lower incidence of postoperative complications than higher doses.     

Lipid deposits posterior to impermeable intracorneal lenses in rhesus monkeys: clinical, histochemical, and ultrastructural studies

Synthetic materials are being evaluated for their potential long-term use in corneal refractive surgery. Clinical and histopathologic studies were performed with polymethylmethacrylate (PMMA) and polysulfone intracorneal lenses in rhesus monkey eyes that were followed for up to 3 years. The 5 mm diameter lenses were placed in the deep posterior corneal stroma of four eyes. Fine, polychromatic crystalline deposits formed a layer posterior to the implants. Enucleated eyes had the corneas either frozen for histochemistry or fixed for electron microscopy. Special stains included oil red 0 and filipin on fresh frozen tissue. The cornea, with a PMMA intracorneal lens showed myriad crystalline aggregates in the deep corneal stroma behind the implant. These crystalline deposits stained positively with oil red 0 and with filipin indicating the presence of neutral fat as well as unesterified cholesterol. The polysulfone implant showed no evidence of crystalline deposits histologically but was surrounded by homogeneous aggregates that could represent nonspecific reaction to the lens material or protein deposits. Electron microscopy of all four corneas revealed dissolved lipid aggregates and laminated electron dense material that were most abundant posterior to the implant where the keratocytes appeared disintegrated. The PMMA lens appeared to induce lipid keratopathy.     

Subconjunctival 5-fluorouracil mechanisms of ocular penetration

Aqueous, corneal, and tear film 14C 5-fluorouracil (5-FU) levels were measured in rabbit eyes to better understand the mechanisms of intraocular penetration after subconjunctival injection. Significantly higher aqueous and tear 5-FU levels were achieved one hour after administration when the subconjunctival injection was given transconjunctivally rather than percutaneously through the upper lid [aqueous = 65.7 +/- 9.1 micrograms/ml vs 21.3 +/- 5.1 micrograms/ml (mean +/- SE; p = 0.02, 2-tailed t-test); and tears = 5408.8 +/- 357.3 micrograms/ml vs 228.0 +/- 46.4 micrograms/ml (mean +/- SE; p = 0.004, 2-tailed t-test)]. The aqueous 5-FU levels four hours after transconjunctival injection were significantly greater in anesthetized rabbits without blink reflexes than in those with intact reflexes [32.0 +/- 3.2 micrograms/ml vs 13.4 +/- 0.5 micrograms/ml (mean +/- SE; p = 0.026, 2-tailed t-test)]. The corneal 5-FU levels four hours after transconjunctival injection were greatest nearest the injection site. Direct corneal penetration appears to account for the majority of the aqueous 5-FU concentration after subconjunctival injection; however, there may also be diffusion through the limbus.     

Liposome-encapsulated 5-fluorouracil in the treatment of proliferative vitreoretinopathy

Liposomes, small bilayer vesicles composed of phospholipids, can entrap and thus slow the release of drugs. We investigated the use of liposome-encapsulated 5-fluorouracil (5-FU), an antiproliferative agent, in the treatment of proliferative vitreoretinopathy (PVR) in an animal model. Doses of up to 1.6 mg administered intravitreally in rabbits demonstrated no retinal toxicity by histologic or electroretinographic criteria. In an experimental animal model of PVR, intravitreal injection of homologous rabbit corneal fibroblasts caused tractional retinal detachments in 90% of eyes after 4 weeks. The addition of 1.6 mg of liposome-encapsulated 5-FU decreased the rate of detachment to 32%, compared with 55% for 1 mg of free 5-FU. Thus, liposomal encapsulation of an anti-proliferative agent such as 5-FU may be a valuable adjunct to conventional vitreous surgery in managing PVR.     

Intraoperative application of 5-fluorouracil during trabeculectomy.

We report the preliminary results of the first 20 consecutive cases in which the antimetabolite 5-fluorouracil (5-FU) was applied directly beneath the conjunctival flap during trabeculectomy in high-risk patients. Seventeen were considered early successes, with 3-month postoperative intraocular pressures less than 21 mmHg, representing at least a 20% decrease from preoperative values. Successful blebs were pale, with conjunctival microcysts and without significant vascularization over the trabeculectomy site, similar to the appearance of blebs in eyes administered postoperative subconjunctival injections of 5-FU. There were no cases of corneal epithelial defects, and no eyes had lost more than one line of preoperative vision at the time of last follow up. Although the longer term efficacy of this method is unknown, these results suggest that it may represent a safe and effective alternative for administering 5-FU.     

下调X连锁凋亡抑制蛋白基因表达增强结肠癌细胞对5-氟尿嘧啶敏感性的研究

目的 观察下调X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein,XIAP)基因表达后结肠癌细胞对5-氟尿嘧啶(5-Fu)敏感性的变化.方法 采用脂质体包裹方法将携带靶向干扰XIAP序列的表达载体转染人结肠癌细胞HCT-8和HCT116,观察结肠癌细胞生长活性的变化;应用5-Fu后,观察结肠癌细胞对5-Fu敏感性的变化,并应用蛋白印迹方法检测结肠癌细胞内凋亡相关因子caspase-3的活性变化. 结果抑制XIAP基因表达后,结肠癌细胞HCT-8和HCT116的生长活性受到有效抑制;结肠癌细胞HCT-8对5-Fu的耐药性得到逆转(P＜0.01),HCT116对5-Fu的敏感性得到明显提高(P＜0.05);结肠癌细胞内caspase-3的表达活性提高,5-Fu诱导细胞凋亡的活性得到增强. 结论XIAP的表达是结肠癌细胞HCT-8和HCT116对5-Fu耐药的一个重要机制;抑制XIAP基因表达后能够增强结肠癌细胞HCT-8和HCT116对5-Fu化疗的敏感性.

Abstract：

Objective To investigate sensitivity of colon cancer cells to 5-fluorouracil after downregulation of XIAP gene expression. Method Colon cancer cells HCT-8 and HCT116 were transfected with a short hairpin RNA targeted to XIAP by liposome, cells viability were examined.5-fluorouracil was applied into two kinds of colon cancer cells. Tumor cells sensitiviy to chemotherapeutic drug was evaluated. Caspase-3 activity in tumor cells was examined by Western blot. Result After downregulation of XIAP expression, cell growing viability of these two kinds of colon cancer cells was restricted, HCT-8 resistance to 5-fluorouracil was reversed ( P ＜ 0. 01 ), HCT116 sensitivity to 5-fluorouracil was enhanced (P ＜ 0.05), caspase-3 expression in colon cancer cells was highly activated, apoptosis inducing activity of 5-fluorouracil was increased significantly. Conclusions XIAP expression was a important mechanism in colon cancer cells HCT-8 and HCT 116 resistant to 5-fluorouracil, sensitivity to 5-fluorouracil of HCT-8 and HCT-116 was increased by downregulation of XIAP expression.     

Superior clinical response and survival rates with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally advanced head and neck cancer

One hundred ninety-one patients were treated by one of three cisplatin-containing multidrug protocols. The initial 77 patients received two courses of cisplatin and vincristine plus bleomycin. The next 26 patients received two courses of 5-fluorouracil and cisplatin, and the final 88 patients were placed on a three course 5-fluorouracil and cisplatin protocol. Overall response rates were similar for each of the three protocols. The complete response rate, however, was much better (54 percent) for three course 5-fluorouracil and cisplatin versus cisplatin vincristine, and bleomycin (29 percent) and two course 5-fluorouracil and cisplatin (19 percent). Survival curves were also better for the three course 5-fluorouracil and cisplatin segment of this nonrandomized pilot study.     

1,25二羟维生素D3与5-氟尿嘧啶对乳腺癌细胞生长及凋亡的影响

目的研究1，25二羟维生素D3[1，25(OH)2D3]与5-氟尿嘧啶(5-Fu)对人乳腺癌细胞株MCF-7生长及凋亡的影响。方法采用噻唑蓝(MTT)比色法分析细胞生长抑制作用，流式细胞术测定细胞周期和凋亡率，免疫组织化学法检测bcl-2蛋白表达。结果1，25(OH)2D3与5-Fu均可抑制MCF-7细胞生长、1，25(OH)2D3阻滞细胞周期于G0／G1期，5-Fu阻滞细胞周期于S期，并可诱导细胞凋亡；当两药联合应用时，上述作用得到显著加强，凋亡率明显上升。两药均可下调bcl-2蛋白表达，当两药联合应用时，bcl-2蛋白几乎不表达。结论1，25(OH)2D3与5-Fu联合应用对乳腺癌细胞具有协同抑制生长和诱导凋亡作用。     

A prospective randomised clinical trial of the intra-operative use of 5-fluorouracil on the outcome of dupuytren's disease

5-Fluorouracil reduces proliferation rates of fibroblasts, myofibroblast differentiation and contractility of ocular fibroblasts in vitro. This double-blind randomized clinical trial assesses whether intra-operative topical treatment with 5-fluorouracil reduces the recurrence rate after limited excision of Dupuytren's tissue. Patients with two-digit disease were randomized to having 5-fluorouracil (25mg/ml) treatment for 5 minutes on one digit and placebo on the other. Fifteen patients were enrolled with 18 months follow-up. There were no peri-operative complications. Wound healing was not delayed and there was no deterioration in the flexion deformity of the 5-fluorouracil treated digits. Patients were subsequently assessed by joint angle measurement at 3, 6, 12 and 18 months. There was no significant difference between control and 5-fluorouracil treated digits.     

Preoperative irradiation and 5-fluorouracil suppository for carcinoma of the rectum

For prevention of local recurrence of rectal carcinoma postoperatively, we attempted to use preoperative irradiation, 5-fluorouracil suppository, or both. When 5-fluorouracil was employed, it produced a remarkably high drug concentration in the rectum and regional lymph nodes. 5-fluorouracil suppository alone did not increase the 5 year postoperative survival rate. Preoperative irradiation combined with 5-fluorouracil suppository (combined treatment group) produced shrinkage of tumor size in 18 of 23 patients, including tumor disappearance in 2 patients, whereas irradiation alone produced shrinkage of tumor size in 13 of 24 patients. Cancer invasions to the external wall of the rectum and lymph node metastases, which were the most influential factors on local rectal recurrence postoperatively, were significantly reduced by preoperative combined treatment.     

食管癌细胞MUC1过表达对5-氟尿嘧啶及顺铂化疗效果的影响

目的探讨食管癌细胞MUC1过表达对5-氟尿嘧啶及顺铂化疗效果的影响。方法构建MUC1过表达及稳定沉默食管癌细胞株,建立食管癌细胞裸鼠移植瘤模型;顺铂（8mg／kg,d1,d7）及5-氟尿嘧啶（20mg／kg,d1～d6）腹腔注射,测量肿瘤体积及裸鼠体重,绘制生长曲线及体重曲线;计算肿瘤抑瘤率。结果顺铂与5-氟尿嘧啶均能抑制MUC1过表达食管癌移植瘤的生长,裸鼠体重及肿瘤体积与对照组比较,差异有统计学意义（P〈0．05）,且顺铂的抑制效应更明显（P〈0．05）;在MUC1稳定沉默裸鼠无明显的抑制效应。结论顺铂与5-氟尿嘧啶都能抑制MUC1过表达食管癌移植瘤的生长,顺铂的抑制效应更明显,同时对体重的影响也更明显。     

Early breaking strength of repaired flexor tendon treated with 5-fluorouracil

This study investigated the effect of a single intraoperative application of 5-fluorouracil, which may diminish peritendinous adhesion formation, on the tensile strength of repaired digital flexor tendons after 7, 14 and 21 days of healing. Twenty-seven deep flexor tendons from 14 rabbits were exposed to 5-fluorouracil (50 mg/ml) for 5 minutes immediately after repair whereas matched control tendons were exposed to normal saline. Tensile testing at 7, 14 and 21 days revealed no significant differences in the gap or ultimate strengths of the 5-fluorouracil treated and control tendons.     

植入用缓释氟尿嘧啶治疗结直肠癌的实验研究

目的 研究氟尿嘧啶（5-Fu）缓释植入剂对结直肠癌移植瘤的治疗效果.方法 将50只直肠癌荷瘤鼠随机分为5组,每组10只.A、B组于瘤周植入5-FU缓释剂,剂量分别为200mg/kg和100 mg/kg;C、D组于瘤周注射5-FU注射液,剂量分别为200 mg/kg和100 mg/kg;E组不予任何治疗.分别于给药后0、3、6、9和12 d,观察裸鼠生存情况、体质量变化及肿瘤体积,12 d后处死小鼠.结果 A、B组肿瘤生长曲线平缓,12 d后A、B、C及D组抑瘤率分别为72%、51%、8%及5%,A、B组肿瘤体积与C、D组比较,差异有统计学意义（P＜0.05）.A、B、C和D组在给药3 d后体质量下降,其中以C组最为明显;以后各组体质量增加,12 d后,各组小鼠体质量间差异无统计学意义（P＞0.05）.在实验过程中,A、B、C和D组小鼠分别死亡1、0、4和1只.结论 5-FU缓释植入剂于瘤周植入能安全有效地抑制结直肠癌移植瘤的生长.     

Preoperative use of 5-fluorouracil suppository for carcinoma of the rectum

A total of 50 patients with carcinoma of the rectum were treated with 5-fluorouracil suppository before operation. The suppository, which was made of Witepsol suppository base containing 5-fluorouracil, yielded high drug concentrations in carcinoma, draining blood and regional lymph nodes. As a clinical response to the suppository, a significant decrease in the size of tumor mass was noted in 8 of 50 carcinomas, but in other cases the gross change was unmeasurable. Thirty-three percent of the surgically resected carcinomas were histologically judged to have responded to the suppository. In such cases, histologic changes correlated well with the total dose of 5-fluorouracil. The adverse effects of the suppository were confined to anal pain, tenesmus and anal bleeding, probably due to the topical effect of 5-fluorouracil on the rectal mucosa.     

5-氟尿嘧啶对瘢痕疙瘩成纤维细胞增殖与凋亡机制影响的初步探讨

目的拟观察5-氟尿嘧啶对瘢痕疙瘩成纤维细胞Smad7和β转化生长因子（transforming growth factor-β,TGF-β）Ⅰ型受体以及细胞凋亡相关基因Bcl-2和Bax蛋白表达的影响。方法（1）瘢痕疙瘩组织成纤维细胞原代培养,取4～6代传代细胞加入5个不同浓度（10,20,40,80,160μmol／L）5-氟尿嘧啶干预24,48,72h。（2）利用四甲基偶氮唑盐法（MTT）测定瘢痕疙瘩成纤维细胞的增殖能力。（3）应用蛋白免疫印迹法（Western-blot）检测各组瘢痕疙瘩成纤维细胞中Smad7和TGF-βI型受体的表达及对Bcl-2、Bax蛋白表达的影响。结果（1）MTT实验中,当5-氟尿嘧啶浓度为10,20μmol／L作用24h时,未发现成纤维细胞死亡,与空白对照组相比差异无统计学意义（P〉0．05）;其他浓度下作用各组成纤维细胞死亡现象差异均有统计学意义（P〈0．01）。（2）免疫印迹法实验结果如下：①与空白对照组相比,TGF-βI组Smad7表达明显减弱,TGF-βI型受体表达则显著增强,差异有统计学意义（P〈0．01）。②加入5-氟尿嘧啶干预后可显著增强Smad7的表达,差异有统计学意义（P〈0．01）。③经不同浓度5-氟尿嘧啶干预后,实验组Bcl-2蛋白表达均低于对照组,差异有统计学意义（P〈0．05）。但实验组Bax蛋白表达均高于对照组（P〈0．05）,TGF-βI型受体表达无明显影响,差异均无统计学意义（P〉O．05）。结论5-氟尿嘧啶对瘢痕疙瘩成纤维细胞具有抑制增殖和诱导凋亡的作用。     

The effects of chemotherapy on murine wound healing and orocutaneous fistula closure

The effects of cisplatin and 5-fluorouracil on wound breaking strength and the rate of closure of an orocutaneous fistula were studied in 80 male rodents. Treatment rats received a total of 4.6 mg/kg cisplatin and 62 mg/kg 5-fluorouracil in six doses/12 days; control rats received 0.9 per cent saline. After treatment, 30 treatment and 30 control rats received a dorsal skin incision which was closed primarily. Wound breaking strength were tested at one, three and five weeks in ten rats from each group. An 8-mm orocutaneous fistula was made in the remaining ten treatment and ten control rats; the rate of closure was noted weekly. Cisplatin and 5-fluorouracil did not significantly impair wound breaking strength at one, three, or five weeks. The rate of closure of the orocutaneous fistula was not effected by cisplatin/5-fluorouracil. The chemotherapy caused severe facial cellulitis and death in four orocutaneous fistula rats. Combined chemotherapy with cisplatin and 5-fluorouracil should not interfere with planned surgical care of head and neck tumors. Concomitant antibiotic coverage, however, is advocated.     

Isolation-perfusion of the liver with 5-fluorouracil.

Isolation-perfusion of the liver was performed in ten pigs using 5-fluorouracil administered in the perfusion circuit at doses of 100, 250, 500, and 1000 mg/kg body weight. Perfusion was performed for 60 minutes at normothermic (37 C) or hyperthermic (41 C) temperatures. One animal died shortly after perfusion. Incomplete isolation of the hepatic vasculature in two animals resulted in significant drug leakage into the systemic circulation with resulting hematologic toxicity. Perfusion with 5-fluorouracil at 1000 mg/kg produced hepatic necrosis. Perfusion with 5-fluorouracil at doses of 100, 250, or 500 mg/kg produced no hepatic toxicity except for transient elevations of hepatic enzymes and resulted in no systemic drug toxicity. Levels of 5-fluorouracil tolerated by the liver in the isolation-perfusion system were more than 1000-fold greater than the maximum drug levels achievable by routine systemic, intra-arterial, or intraperitoneal administration.     

Weekly paclitaxel and high-dose 5-fluorouracil plus leucovorin in hormone-refractory prostate cancer: in vitro combined effects and a phase II trial

PURPOSE: Paclitaxel and 5-fluorouracil have been used to treat hormone-refractory prostate cancer with some success. In vitro data suggest that the combined cytotoxicity may be sequence dependent. Thus, we explored the combined effects of the 2 agents, both in vitro and in vivo. PATIENTS AND METHODS: The combined cytotoxicity of paclitaxel and 5-fluorouracil, and the possible schedule dependence were studied in vitro using PC-3 and DU145 cells and the microculture tetrazolium assay. There were 23 patients with hormone-refractory prostate cancer treated with the regimen T-HDFL: paclitaxel 90 mg/m2 intravenously 1 hour on days 1 and 8; 5-fluorouracil 2000 mg/m2; and leucovorin 300 mg/m2 intravenous 24-hour infusion on days 2 and 9, which repeated every 21 days. The allowed percentage of bone marrow irradiation was 50%. RESULTS: Significant synergistic cytotoxicity was seen only when paclitaxel was given 24 hours before 5-fluorouracil. With the T-HDFL regimen, 11 (52%) of the 21 evaluable patients had > or = 50% reduction of prostate-specific antigen, lasting for 6 weeks. Of the 7 patients with measurable disease, 2 had a partial response. Median overall survival was 14.1 months. Grade III/IV leukopenia occurred in 2 patients. There was no treatment-related death. Toxicities were well tolerated. CONCLUSIONS: The combined cytotoxicity of paclitaxel and 5-fluorouracil is schedule dependent. It is feasible to administer weekly paclitaxel and high-dose 5-fluorouracil infusions in patients with hormone-refractory prostate cancer. Our findings may serve as an important rationale for future trial design.