Synthesis and biological activity of phthalimide‐based polymers containing 5‐fluorouracil

The attachment of anticancer agents to polymers is a promising approach towards reducing the toxic side‐effects and retaining the potent antitumour activity of these agents. A new tetrahydrophthalimido monomer containing 5‐fluorouracil (ETPFU) and its homopolymer and copolymers with acrylic acid (AA) and with vinyl acetate (VAc) have been synthesized and spectroscopically characterized. The ETPFU contents in poly(ETPFU‐co‐AA) and poly(ETPFU‐co‐VAc) obtained by elemental analysis were 21 mol% and 20 mol%, respectively. The average molecular weights of the polymers determined by gel permeation chromatography were as follows: M_n = 8900 g mol^?1, M_w = 13 300 g mol^?1, M_w/M_n = 1.5 for poly(ETPFU); M_n = 13 500 g mol^?1, M_w = 16 600 g mol^?1, M_w/M_n = 1.2 for poly(ETPFU‐co‐AA); M_n = 8300 g mol^?1, M_w = 11 600 g mol^?1, M_w/M_n = 1.4 poly(ETPFU‐co‐VAc). The in vitro cytotoxicity of the compounds against FM3A and U937 cancer cell lines increased in the following order: ETPFU > 5‐FU > poly(ETPFU) > poly(ETPFU‐co‐AA) > poly(ETPFU‐co‐VAc). The in vivo antitumour activities of all the polymers in Balb/C mice bearing the sarcoma 180 tumour cell line were greater than those of 5‐FU and monomer at the highest dose (800 mg kg^?1). © 2002 Society of Chemical Industry     

5-氟尿嘧啶-1-基乙酸合成新方法

5-氟尿嘧啶与氢氧化钾作用得到5-氟尿嘧啶单钾盐,5-氟尿嘧啶单钾盐与氯乙酰乙酯得到N1-乙酸乙酯取代5-氟尿嘧啶,再经酸性条件下水解合成了5-氟尿嘧啶-1-基乙酸,产率85%,产品纯度99.52%,并采用红外、核磁、紫外的方法表征了产物的结构,确定了产品的最佳反应条件。采用此法制备5-氟尿嘧啶-1-基乙酸原料便宜易得,操作方法简单,产物具有较高的产率和纯度。     

左旋聚乳酸/氟尿嘧啶复合纳米纤维膜的制备

为研制一种具有缓释作用的药物纤维膜,拟通过静电纺丝的方法制备出左旋聚乳酸/氟尿嘧啶复合纳米纤维膜,考察了左旋聚乳酸质量分数、添加的氟尿嘧啶质量分数对复合纳米纤维成型性的影响,并对其力学性能以及润湿性能进行了测试与分析.结果表明:随着左旋聚乳酸质量分数的增加,纳米纤维直径变粗,随着添加氟尿嘧啶质量分数的增加,纤维直径变细...     

Synthesis and biological activity of medium molecular weight polymers containing 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidobutanoyl‐5‐fluorouracil

A new monomer, 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidobutanoyl‐5‐fluorouracil (ETBFU), was synthesized by reaction of 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidobutanoyl chloride and 5‐fluorouracil. The homopolymer of ETBFU and its copolymers with acrylic acid (AA) or vinyl acetate (VAc) were prepared by photopolymerization using 2,2‐dimethoxy‐2‐phenylacetophenone as an initiator at 25 °C. The synthesized ETBFU and its polymers were identified by FTIR, ¹H NMR and ¹³C NMR spectroscopies. The ETBFU content in poly(ETBFU‐co‐AA) and poly(ETBFU‐co‐VAc) was 43 and 14 mol%, respectively. The apparent number‐average molecular weight (M_n) of the polymers determined by GPC ranged from 8400 to 11 300. The in vitro cytotoxicity of the samples against mouse mammary carcinoma (FM3A), mouse leukaemia (P388), and human histiocytic lymphoma (U937) cancer cell lines decreased in the order 5‐FU ≥ ETBFU > poly(ETBFU) > poly(ETBFU‐co‐AA) > poly(ETBFU‐co‐VAc). The in vivo antitumour activity of the polymers against Balb/C mice bearing sarcoma 180 tumour cells was greater than that of 5‐fluorouracil at all doses tested. © 2000 Society of Chemical Industry     

氟脲嘧啶白蛋白缓释微球的制备及体外性质的研究

目的:探讨以牛血清白蛋白为载体的氟脲嘧啶白蛋白微球的最佳制备方法及有关体外性质。方法:使用均匀设计法筛选制备氟脲嘧啶白蛋白微球(FU-BM)。以七个因素十二个水平,优化出最佳工艺。并对FU-BM体外性质进行研究。结果:制得FU-BM外观呈米黄色,粉末状,球形圆整,粒径分布在1~10μm。载药量为(11.37±0.42)%,包封率(62.58±3.24)%。结论:氟脲嘧啶白蛋白微球具有缓释作用。     

高效液相色谱法测定卡莫氟及其片剂含量

报道了用高效液相色谱法测定卡莫氟及其片剂含量测定的方法。     

凹凸棒石及其磁性药物载体的吸附及解吸性能

研究了提纯凹凸棒石(坡缕石)及其磁性靶向药物载体对抗癌药物氟尿嘧啶的吸附性能,以及载体中所吸附的氟尿嘧啶在模拟胃液、肠液中的解吸行为.在药物浓度为10mg/mL,pH值为6的60℃药液中,提纯凹凸棒石及其磁性靶向药物载体对氟尿嘧啶的吸附量分别为26.3mg/g和27.2mg/g.结果表明:提纯凹凸棒石及其磁性药物载体具有极好的酸、碱中和能力和药物缓释性能,预示着它们可作为理想的长效缓释药物载体,用于消化道疾病的治疗,具有较好的应用前景.     

藠头提取物对氟尿嘧啶的增效减毒作用的研究

研究了藠头提取物对人宫颈癌Hela细胞和人胃癌BGC-823细胞体外生长的影响、该提取物与5-FU对抑制这两种癌细胞中的协同作用,探讨了该提取物对5-FU所致小鼠免疫功能抑制的保护作用,并测定了药物对两种癌细胞增殖抑制率的影响和检测药物对小鼠腹腔巨噬细胞吞噬功能及淋巴细胞活性的影响。发现药物作用48h后,联合用药对胃癌细胞的抑制率高于单药组,并表现明显的协同作用;联合用药且能明显拮抗5-FU所致体重降低、腹腔巨噬细胞功能降低及淋巴细胞活性降低等毒副作用。表明藠头提取物与5-FU联合使用能有明显提高5-FU抗肿瘤及降低其毒副作用。     

羧甲基茯苓多糖对氟尿嘧啶肝损伤小鼠减毒及肝脏保护作用

建立5-Fu肝损伤小鼠模型,给药后检测外周血白细胞(WBC)数、骨髓有核细胞(BMNC)数及脏器指数,血清ALT和AST活性;肝组织病理切片观察CMP对小鼠肝组织的影响;Western Blot检测肝组织中Keap1、Nrf2、GCL、NF-κB、p38、pp38、Bax和Bcl-2蛋白的表达,免疫组化检测NF-κB和pp38表达。结果表明,与正常组相比,5-Fu导致小鼠肝、脾指数、ALT和AST活性分别升高13.75%、53.76%、39.48%和62.81%;WBC和BMNC数分别降低7.15%和50.81%;肝组织中NF-κB、pp38、Bax表达明显增加,Bcl-2则下降,表明肝损伤模型成功建立。CMP使肝损伤小鼠的肝、脾指数、ALT和AST活性分别下降了12.40%、31.45%、20.83%和20.14%;WBC和BMNC数分别增加了7.47%和18.95%;还明显增加Bcl-2水平,降低NF-κB、pp38和Bax表达。CMP对正常小鼠肝脏无明显作用,但能明显减轻5-Fu毒性,并对肝损伤有明显保护作用,其机制与调控NF-κB、p38MAPK及Bcl-2信号通路有关。     

Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.