A phase I and pharmacokinetic study of oral uracil,ftorafur, and leucovorin in patients with advanced cancer

 A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m² of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m² UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m² was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m²) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (C_max 1.4±1.9 μM) were comparable to those achieved with protracted venous infusions, and folate levels (C_max 6.1±3.6 μM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs. Received: 20 January 1995/Accepted: 29 June 1995     

HPLC法测定花鹿茸饮片中尿嘧啶及次黄嘌呤的含量

目的:研究花鹿茸饮片中尿嘧啶及次黄嘌呤的定量方法。方法:采用高效液相色谱法。色谱柱:Diamonsil NH2(250×4.6mm5μm);流动相:0.2mol/L磷酸二氢钠溶液-0.1mol/L氯化钠缓冲液;检测波长:262nm。结果:尿嘧啶的线性范围为0.0097~0.13095μg(r=0.9996,n=5),次黄嘌呤的线性范围为0.00738~0.09963μg(r=0.9999,n=5),尿嘧啶平均加样回收率为100.0%,RSD=1.10%,次黄嘌呤平均加样回收率为99.0%,RSD=1.84%。结论:本法简便、灵敏、准确,可用于鹿茸饮片的质量控制。     

Role of action potentials and calcium influx in ATP- and UDP-induced noradrenaline release from rat cultured sympathetic neurones

Adenine and uracil nucleotides release noradrenaline from rat postganglionic sympathetic neurones by activation of P2X-receptors and distinct receptors for uracil nucleotides, respectively. The present study on cultured neurones of rat thoracolumbal paravertebral ganglia has analysed the involvement of action potentials and calcium influx in the nucleotide-induced transmitter release. ATP and UDP (100 μM each) caused a marked release of previously incorporated [³H]noradrenaline. The P2-receptor antagonists suramin (300 μM) and cibacron blue 3GA (3 μM) decreased the ATP-induced but not the UDP-induced release. The response to ATP was decreased by the sodium channel blocker tetrodotoxin (0.5 μM; by 47%), by the N-type calcium channel blocker ω-conotoxin GVIA (100 nM; by 35%), and by the α₂-adrenoceptor agonist UK-14,304 (1 μM; by 45%); it was not changed by the potassium channel blocker tetraethylammonium (10 mM). The response to UDP was abolished by tetrodotoxin, greatly decreased by ω-conotoxin (by 78%), also abolished by UK-14,304, and increased by tetraethylammonium (by 410%). ATP (100 μM) caused a marked increase in intraaxonal free calcium as measured by fura-2 microfluorimetry. Withdrawal of extracellular calcium diminished the calcium response to ATP by 85%, and tetrodotoxin and ω-conotoxin diminished it by about 40%. As studied with the amphotericin B-perforated patch method, ATP (100 μM) induced a large depolarisation and action potential firing. UDP (100 μM) induced only a small depolarisation but it also elicited action potentials. UDP increased the excitability of the neurones. The results indicate that the ATP-induced release of noradrenaline depends on influx of calcium from the extracellular space. Calcium passes through two structures: voltage-gated channels and – probably – the P2X-receptor itself. Only that component of ATP-induced transmitter release which is triggered by opening of voltage-gated calcium channels is sensitive to modulation by α₂-adrenocep-tors. In contrast to ATP, the UDP-induced release of noradrenaline is entirely due to generation of action potentials followed by calcium influx through voltage-gated channels. All of the UDP-induced release is therefore sensitive to α₂-adrenoceptor modulation. Received: 22 September 1998 / Accepted: 25 January 1999     

食管腔内渗疗及其临床意义

目的探讨食管腔内渗疗的机制及其临床意义。方法用5-131I尿嘧啶作为示踪剂,对26例食管癌患者进行了临床渗透治疗的研究。结果经渗疗器渗透的抗癌药物除部分被肿瘤组织吸收外,还进入体循环;肿瘤及癌旁淋巴结中的T／N、L／N比值高,循环中抗癌药物浓度低。结论食管腔内渗疗是部分中晚期食管癌患者有效的治疗方法。     

mdr1启动子调控胞嘧啶脱氨酶-尿嘧啶磷酸核糖转移酶融合基因对卵巢癌裸鼠耐药移植瘤的抑制作用

目的:观察人多药耐药基因mdrl启动子调控的胞嘧啶脱氨酶-尿嘧啶磷酸核糖转移酶融合自杀基因(CD::upp)对紫杉醇耐药卵巢癌裸鼠皮下移植瘤的抑制作用及对荷瘤裸鼠生存时间的影响。方法:建立卵巢癌耐药及非耐药细胞的裸鼠模型,将含mdrl-CD::upp的重组腺病毒0．1ml(1×10~9 pfu/ml)注入裸鼠皮下移植瘤体内,腹腔内注射5-氟胞嘧啶(5-FC),观察各组裸鼠肿瘤生长速度及存活时间。结果:实验组裸鼠移植瘤明显受到抑制,与对照组的差异有统计学意义(P＜0．05)。实验组荷瘤裸鼠的生存时间明显延长,对照组在69天内全部死亡,差异有统计学意义(P＜0．001)。结论:mdrl启动子调控的CD::upp基因能特异性地抑制卵巢癌裸鼠耐药移植瘤的生长并延长生存时间。     

An in situ STM investigation of uracil on Ag(111)

The structure of the chemisorbed uracil overlayer that is formed on Ag(111) at potentials positive to ?0.70 V (SCE) following a two-dimensional disorder–order phase transition, has been investigated by in situ STM. The uracil molecules are arranged in parallel rows, the distance between the rows, 10.5±0.5 Å, being appreciably greater than that between uracil molecules within a row, 6.5±0.2 Å. A packing model in which the rows consist of chains of flat, H-bonded uracil molecules is hypothesized. The domains of regularly arranged molecules cover the electrode surface completely only at uracil bulk concentrations c>4×10^?4 M. At lower c values a steady state is attained in which the surface coverage by the domains is <1 and decreases with a decrease in c.     

HPLC法测定蕲蛇中核苷类成分的研究

[目的]探讨高效液相色谱法（HPLC）法测定蕲蛇药材中尿嘧啶、黄嘌呤、次黄嘌呤和尿苷的分析方法。[方法]采用HPLC法,色谱条件为Dionex C18（3μm,150 mm×4.6 mm）,以0.05 mol.L-1磷酸氢二钾水溶液为流动相;检测波长为254 nm;流速为0.8 mL.min-1。[结果]尿嘧啶、黄嘌呤、次黄嘌呤和尿苷分别在0.0088～0.220μg、0.0352～0.880μg、0.0344～0.860μg、0.0176～0.440μg范围内具有良好线性关系;平均加样回收率分别为99.0%、98.6%、100.4%、103.0%;RSD分别为2.69%、2.25%、2.90%、2.88%。[结论]HPLC法可以测定蕲蛇药材中尿嘧啶、黄嘌呤、次黄嘌呤和尿苷含量,从而控制蕲蛇药材品质。     

Adenovirus-Mediated Transduction of Escherichia coli Uracil Phosphoribosyltransferase Gene Increases the Sensitivity of Esophageal Cancer Cells to 5-Fluorouracil

Esophageal cancer is associated with the poorest prognosis among the digestive tract cancers, and chemotherapy is the treatment of choice for many patients. In this study, we experimentally introduced an Escherichia coli-derived uracil phosphoribosyltransferase (UPRT) gene to cultured esophageal cancer cell lines to potentiate the antitumor effects of a representative anticancer drug, 5-fluorouacil (5-FU). UPRT is a pyrimidine salvage enzyme that catalyzes the synthesis of uridine monophosphate from uracil and PRPP. The UPRT gene was transduced into five cultured esophageal cancer cell lines, TE1, TE2, TE3, NUEC1, and T.T, using an adenovirus vector. It was confirmed that the sensitivities of all cultured cell lines to 5-FU were increased in vitro. Subsequently, the T.T line was subcutaneously inoculated into nude mice to induce tumors, after which 5-FU was administered intraperitoneally. When a UPRT gene-recombinant adenovirus vector was directly injected into the tumors, tumor proliferation was markedly inhibited compared with that in the group treated with 5-FU alone, suggesting potentiation of 5-FU sensitivity by UPRT gene transduction in vivo. Therefore, we potentiated the effects of commercially available anticancer drugs by gene transduction. Our method may prove useful as a new form of cancer gene therapy in the future. Received: June 23, 2000 / Accepted: March 6, 2001     

网胰藻Hydroclathrus clathratus中次级代谢物的分离与结构鉴定

从中国南海网胰藻Hydroclathrus clathratus中分离得到4个化合物，经MS、^1H NMR、^13C NMR等方法鉴定其结构分别为软酯酸-1-甘油酯(1)、N-(2‘-羟基-1’-羟甲基十五烷基)二十脂肪酸酰胺(2)、尿嘧啶(3)、甘露醇(4)。其中化合物1、2、3均为首次从该藻中分离得到。     

RP-HPLC法测定小鼠各组织中阿糖胞苷及阿糖尿苷浓度

目的:建立在血浆、脑脊液和睾丸组织中同时测定阿糖胞苷及其代谢物阿糖尿苷浓度的反相高效液相色谱法并进行小鼠体检内测定波量长分为析28。0 n方m法,柱:色温谱为柱30为℃X,T进er样ra量C18为,流10动μ相L。为将0.0115 m只o小l.鼠L-随1磷机酸分盐成缓A冲、B液、(Cp H3组=,6分.0)别-乙腹腈腔=注9射5∶阿5,糖流胞速苷为105.09、51 m 0L0.0m、2in 0-010,mg·kg-1,30 min后测定小鼠血浆、脑脊液、睾丸组织中的阿糖胞苷及阿糖尿苷浓度。结果:阿糖胞苷、阿糖尿苷检测浓度线性范围分别为0.25～21.74、0.99～86.96 mg·L-(1r>0.998 8),检测限为0.1～0.4 mg·L-1;平均回收率均≥96%,RSD≤7.19%。阿糖胞苷及阿糖尿苷在小鼠血浆、脑脊液和睾丸组织中的药物浓度有显著性差异,低、中剂量给药组只在血浆中检测出阿糖尿苷。结论:所建立的测定方法简单、快速、准确、重复性好,可为临床上阿糖胞苷和阿糖尿苷血药浓度的监测和药动学研究提供参考。