99m锝标记紫杉醇脂质体在移植荷瘤鼠体内分布的研究

对 2 0只雌性裸鼠建立人卵巢癌裸鼠皮下移植瘤模型 ,经其尾静脉注射锝标紫杉醇脂质体 (99m TC- TL) 0 .2m l,于 15 min、 30 m in、 90 m in各处死动物 5只 ,将心、肝、脾、肺、肾、小肠、子宫附件、骨及肿瘤组织分别称重。其余 5只动物尾静脉注射游离锝 (99m TC— F) 0 .2 m l,于 90 min处死 ,取肝、脾、肺及肿瘤组织称重 ,用 γ-定标仪测其放射强度 (单位 :CPM/ 10 0 mg)。肝、脾、肺脏器内 99m TC动态放射值最高 (5 5 2 .1± 92 .8～ 2 6 0 .1± 2 1.0 cpm/ 10 0m g) ,其放射强度随时间延长呈下降趋势 ,肿瘤组织放射值较低 (3.6± 0 .6 cpm/ 10 0 m g) ,动态测量呈水平位。99m TC- TL组与 99m TC- F组在 99m TC示踪显示 90 min时 ,TC- TL 组肝、脾、肺内放射强度高于 99m TC- F组 (P<0 .0 5 ) ,而肿瘤组织中两组无显著性差异 (P>0 .0 5 )。结论 :静注紫杉醇脂质体在荷瘤鼠体内主要定向分布于网状内皮系统丰富的肝、脾、肺器官内 ,肿瘤组织有一定滞留性 ,但亲和力较差     

Crystal Structure of 2-Debenzoyl, 2-Acetoxy Paclitaxel (Taxol®): Conformation of the Paclitaxel Side-Chain

Crystals of the C2-acetate analog of paclitaxel, grown from a mixture of isopropyl alcohol and methanol, belong to the space group P2_l with a = 9.058(3), b = 18.306(5), c = 15.043(1) , = 97.09(1)°, Z = 2, V = 2475.1(9)³, D _calc = 1.269 gcm^–3 and µ = 0.75 cm^–1. The structure was determined by direct methods and refined to R(F) = 0.054 and wR(F) = 0.057 for 605 variables and 3496 observed reflections. The paclitaxel side chain possesses a conformation similar to that observed in the crystal structure of docetaxel (Taxotere^®). A three dimensional network of hydrogen bonds is formed through solvent molecules and stabilizes the crystal lattice.     

紫杉醇和三尖杉磷碱在多孔硅胶上的吸附及扩散研究

吸附和扩散特性是进行色谱过程的基础,本文测定了紫杉醇及其类似物的三尖杉磷碱在多孔的吸附及扩散特性,结果表明：紫杉醇和三尖杉磷酸在硅胶上的吸附不符合Ｌａｎｇｍｕｉｒ单分子层吸附理论,但在低浓度下可用溶剂调整型Ｌａｎｇｍｕｉｒ模型描述。扩散研究表明,用醇和三尖彬磷碱在硅胶上吸附罗弱,表面扩散可以忽略,相同条件下,紫杉醇的吸附量受强溶剂影响罗大,强溶剂组成的增加会造成紫杉醇吸附量很快下降,这和在正相色谱     

An exploratory study of frequent pain measurement in a cancer clinical trial

The ideal methodology for quality of life (QOL) measurement in cancer clinical trials matches the evaluation to the anticipated outcomes, thereby increasing the likelihood that clinically relevant changes are captured. The present study explored the importance of such methodological tailoring in a phase II trial of paclitaxel and recombinant human granulocyte-colony stimulating factor (rhG-CSF) for metastatic breast cancer. Prior to the trial, clinical observation suggested that frequent short-lived episodes of pain might occur during this treatment regimen. Twenty-one patients provided longitudinal data for at least three cycles of chemotherapy. To assess transient pain, aroutine QOL assessment at baseline and every third cycle was supplemented with pain measurements twice weekly. The interval assessment included a multidimensional QOL instrument (Functional Living Index-Cancer) and measures of psychological state (Rand Mental Health Inventory), symptom distress (Memorial Symptom Assessment Scale), and performance status (Karnofsky Performance Status Score). The frequent pain measurements were acquired using visual analogue and categorical scales for pain intensity (Memorial Pain Assessment Card). From baseline to the end of cycle three, global pain scores declined and the results on other QOL measures were variable. The data obtained using these measures did not reveal the existence of episodic pains. In contrast, the twice weekly pain measurements clearly demonstrated transient severe pains in approximately half the patients. These data highlight the importance of specific measurement of troubling symptoms or other relevant QOL concerns at clinically appropriate intervals during the routine QOL assessment of clinical trials. The additional burden involved in these assessments is warranted if the information derived is highly relevant, would not be adequately captured otherwise and could improve therapy.     

Pharmacokinetics of paclitaxel-containing liposomes in rats

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K_p) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K_p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.     

紫杉醇与顺铂联合治疗晚期鼻咽癌50例分析

[目的]探讨紫杉醇与顺铂(TP)联合应用治疗复发和远处转移的晚期鼻咽癌疗效.[方法]用TP方案治疗晚期鼻咽癌病人50例.3周为1个疗程,2个疗程后评定疗效,有效者继续原方案治疗4个疗程.[结果]有效率62%,其中CR 12%,PR 50%;随访时间24个月(10个月～4年),中位生存期16.5个月(4～30个月).所有病例均出现脱发,Ⅰ～Ⅱ度骨髓抑制,消化道反应较重,其他不良反应轻微.[结论]TP方案对晚期鼻咽癌有较好的近期疗效,缓解期为6个月左右,多疗程治疗有利于改善预后.     

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.     

反应停、紫杉醇对Lewis肺癌小鼠的抑瘤作用

目的　研究反应停、小剂量紫杉醇对 L ewis肺癌小鼠皮下移植瘤和肺转移瘤的抑制作用 ,并探讨其与肿瘤细胞凋亡和细胞周期的关系。方法　 50只荷 L ewis肺癌小鼠随机分为四组 ,分别给予生理盐水、反应停、小剂量紫杉醇、反应停联合小剂量紫杉醇治疗 ,第 2 1天处死动物 ,称取鼠重、瘤重、肺重 ,计数肺转移结节数 ,免疫组化染色记数肿瘤组织微血管密度 ,流式细胞仪检测肿瘤细胞凋亡率及细胞周期。结果　反应停、小剂量紫杉醇单独及联合治疗组肿瘤重量与对照组间差异无显著性 (P>0 .0 5)。反应停、小剂量紫杉醇单独及联合治疗组肺重、肺转移结节数及肿瘤组织微血管密度均小于对照组 ,差异有显著性 (P<0 .0 5)。各治疗组肿瘤细胞凋亡率及 G1、S、G2 期肿瘤细胞百分数与对照组间差异无显著性 (P>0 .0 5)。结论　反应停、小剂量紫杉醇不能抑制 L ewis肺癌皮下移植瘤生长 ,但可抑制肿瘤肺转移 ,两药间无协同或拮抗作用。反应停、小剂量紫杉醇不诱导 L ewis肺癌细胞凋亡 ,不影响肿瘤细胞生长周期     

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.