ZD1839对胰腺癌细胞的生长抑制作用及机理

目的 探讨ZD1839对胰腺癌细胞的生长抑制作用机理.方法 应用MTT方法检测ZD1839对胰腺癌细胞的生长抑制作用、应用不同的生长因子刺激胰腺癌细胞的生长刺激,并检测ZD1839对不同生长因子作用的影响.应用western blot检测不同生长因子对EGF酪氨酸激酶受体的磷酸化作用,以及ZD1839对EGFR受体磷酸化的影响,并检测ZD1839对EGFR信号的下游MAPK磷酸化的影响.结果 ZD1839呈剂量依赖性抑制胰腺癌细胞的生长,ZD1839阻断EGF对胰腺癌细胞的生长刺激作用,但不阻断对IGF-1的作用.ZD1839抑制了基础的与EGF诱导的EGF受体磷酸化水平与MAPK的磷酸化水平.结论 结果表明,EGF对胰腺癌细胞有生长刺激作用,ZD1839对胰腺癌细胞的生长抑制作用是通过对抑制EGF受体磷酸化而特异性起作用的.     

ZD1839（Iressa）在晚期非小细胞肺癌治疗中的应用

目的　探讨表皮生长因子受体酪氨酸激酶抑制剂———ZD183 9(Iressa)治疗晚期非小细胞肺癌的疗效和毒副反应。方法　分析 2 0 0 2年 12月至 2 0 0 3年 8月期间我院 3 9例晚期非小细胞肺癌患者经ZD183 92 5 0mg/d口服治疗的情况。应用 χ2 检验、t检验、Kaplan Meier进行统计分析。并采用欧洲癌症研究和治疗组织 (EuropeanOrganizationforResearchandTreatmentofCancer ,EORTC)简体中文版的生活质量调查核心问卷QLQ C3 0和肺癌专用问卷QLQ LC13对患者的生活质量进行评价。结果　全组患者有效率 (完全缓解 +部分缓解 )为 2 8.2 %,疾病控制率 (有效 +稳定 )为 5 9.0 %。疗效与患者性别和病理类型有密切关系。综合生活质量改善率为 3 4.8%,功能状态改善率为 65 .2 %,临床症状缓解率为 73 .9%。全组无疾病进展时间为 6.6月± 1.6月 ( 95 %CI为 3 .4～ 9.7) ,到截尾时间 5 6.4%( 2 2 /3 9)的患者仍存活 ,1年生存率为 5 4.3 %( 19/3 5 )。毒副反应主要为Ⅰ、Ⅱ度皮疹和腹泻 ,经对症处理可缓解。结论　ZD183 9治疗晚期非小细胞肺癌疗效确切 ,同时可改善生活质量     

Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.     

新一代胸苷酸合成酶抑制剂ZD1694的体内外抗肿瘤作用

目的:观察ZD1694对小鼠体内S180肉瘤生长的抑制作用及其在体外对人胃腺癌SGC-7901细胞增殖的影响.方法:采用荷瘤小鼠模型,腹腔注射不同剂量的ZD1694,分单次给药与连续 5 d 分次给药两种方案.处死动物后称取肿瘤组织重量,计算抑瘤率.另外采用MTT比色法及流式细胞仪观察ZD1694对人SGC-7901胃腺癌细胞株生长的影响.结果:ZD1694可抑制小鼠体内S180肉瘤的生长,其抑瘤率无论是单次给药组(200、100、50 mg·kg-1)还是连续 5 d 给药组(40、20、10 mg·kg-1·d-1),均可见剂量依赖性增加.ZD1694(0.001～1 000 mmol·L-1)对SGC-7901人胃腺癌细胞的生长抑制率呈浓度依赖性和时间依赖性增加,可使G0-G1期细胞增多, S期和G2-M期细胞减少.结论:ZD1694对荷瘤小鼠产生明显的抗瘤作用,一次性给药的抑瘤率大于相同剂量分5次给药的抑瘤率.该药在体外可抑制人胃腺癌SGC-7901细胞生长,使细胞发生G1期阻滞.     

Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

BACKGROUND: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors. PATIENTS AND METHODS: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. RESULTS: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing. CONCLUSIONS: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.     

ZD 7288,an HCN channel blocker,attenuates chronic visceral pain in irritable bowel syndrome-like rats

AIM:To investigate the effects of ZD 7288,a hyperpolarization-activated cyclic nucleotide-gated(HCN)channel blocker,on rats with chronic visceral pain.METHODS:Rats with visceral hypersensitivity were generated using neonatal colon irritation during postnatal days 8-15 as described previously.Visceral hypersensitivity was evaluated using electromyographic(EMG)responses of abdominal external oblique muscles to 20-80 mmHg colorectal distentions(CRD).Abdominal withdrawal reflex(AWR)scores and pain thresholds were also detected in adult rats.Different doses of ZD7288(25,50,and 100 nmol/L)were intrathecally administered in rats to study the role of spinal HCN channel in chronic visceral hypersensitivity.RESULTS:EMG responses to 20-80 mmHg CRD and AWR scores under 20-60 mmHg CRD significantly increased in rats with visceral hypersensitivity compared to control rats(P<0.05).The pain threshold in rats with visceral hypersensitivity significantly decreased compared to control rats(P<0.05).Treatment with50-100 nmol/L ZD 7288 significantly inhibited EMG responses(16%-62%,80-20 mmHg CRD,P<0.05)and AWR scores(24%-37%,40-20 mmHg CRD,P<0.05;12%-61%,80-20 mmHg CRD,P<0.05,respectively),and significantly increased pain thresholds(32%-77%,P<0.05).CONCLUSION:Spinal HCN channels may play an important role in chronic visceral hypersensitivity.     

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze

Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. ( 2012 ) Neuropharmacology 62:155–160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the I_h blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem‐evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model. © 2012 Wiley Periodicals, Inc.     

丹参治疗妊娠期高粘血症的疗效探讨

[目的]探索丹参对改善妊娠期高粘血症的作用。[方法]150例高粘血症孕妇随机分为三组,每组50例。观察组（A组）予丹参及扩容治疗,B组以不加丹参行扩容治疗及对照组（C组）不予治疗,比较三组治疗前后血液流变学及血管内皮素-1（ET-1）的变化。[结果]A组红细胞压积、血浆粘度、高及低切变率下的全血粘度均有降低（P〈0.05或P〈0.01）;B组低切变率下的全血粘度、ET-1变化差异无显著性（P〉0.05）;C组上述各指标差异无显著性（P〉0.05）。A组新生儿体重增加,羊水过少及胎儿生长受限（FGR）的发生率降低（P〈0.05）。[结论]妊娠期高粘血症的治疗,关键在于降低ET-1的释放,改善低切变率下的全血粘度,丹参能有效地降低孕妇的血粘度,改善围产儿的预后。     

ZD7288抑制急性内脏痛大鼠痛觉敏化

观察超极化激活环核苷酸门控阳离子通道（HCN通道）的特异性阻断剂ZD7288对急性内脏痛大鼠痛觉敏化的影响。方法：选用成年雄性SD大鼠,通过结肠内注射1％醋酸1mL,建立急性内脏痛模型;免疫组织化学法检测HCN2在模型大鼠腰骶段背根神经节及胸腰段与腰骶段脊髓背角的表达;通过腹壁撤退反射评分和腹外斜肌放电测量,观察模型大鼠鞘内分别给予50与100nmol／LZD7288后内脏痛觉敏化是否发生改变。结果：HCN2在模型大鼠腰骶段背根神经节及胸腰段与腰骶段脊髓背角的表达均较对照大鼠增强（P〈0．05）。鞘内注射50～100nmol／LZD7288可以剂量依赖性降低急性内脏痛模型大鼠的腹壁撤退反射评分和腹外斜肌放电幅值（P〈0．05）。结论：ZD7288可抑制急性内脏痛大鼠的痛觉敏化,而背根神经节和脊髓的HCN2通道可能在其发病中起作用。