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.     

25例晚期及复发子宫内膜癌紫杉醇联合化疗分析

[目的]评价紫杉醇联合化疗治疗晚期、复发子宫内膜癌的近期疗效及毒副作用.[方法]25例Ⅲ、Ⅳ期或复发的子宫内膜癌行紫杉醇 卡铂(或顺铂)化疗,紫杉醇135mg/m2～150mg/m2,卡铂AUC 4～5,或顺铂70mg/m2.[结果]有可测肿瘤或CA125/CA199升高16例,共进行63个疗程化疗,完全缓解37.5%,部分缓解25.0%,总有效率62.5%.完全缓解者无进展期平均5.3个月.无肿瘤监测指标9例,进行29个疗程化疗,中数随诊11.5个月无复发.3、4级白细胞下降40.0%,3级血小板下降11.4%.[结论]紫杉醇 卡铂或顺铂联合化疗对晚期、复发的子宫内膜癌有较好疗效.     

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.     

表柔比星加紫杉醇新辅助化疗方案治疗乳腺癌

目的:研究表柔比星加紫杉醇新辅助化疗方案治疗乳腺癌的近期疗效及毒副反应。方法:用TE方案(紫杉醇加表柔比星)对Ⅱ、Ⅲ期的20例乳腺癌进行新辅助化疗,3-4周为1个周期,患者完成2-4个周期后评价疗效;并以VE方案(长春瑞滨加表柔比星)作对照组进行比较,TE方案:表柔比星(EPI)60 mg/m2,第1天,静脉注射;紫杉醇(TAX)150mg/m2,第2天,静脉点滴;3周为1个周期。VE方案:EPI 60mg/m2,第1天,静脉注射;长春瑞滨(VNR)30mg/m2,第1、8天,静脉注射;4周为1个周期。结果:TE组有效率为80％,其中临床完全缓解(cCR)3例,部分缓解(PR)13例,无变化(NC)4例,病理完全缓解(pCR)2例;VE组有效率为80％,其中cCR 3例,PR 13例,NC 4例,pCR2例。两组均无进展(PD)者。进行4周期新辅助化疗患者有效率高于2周期患者。两组白细胞下降、胃肠道反应、面色潮红和静脉炎等毒副反应相似,VE组乏力、脱发、神经毒性程度比TE组显著(P<0.05),而在关节头痛方面TE组显著(P<0.05)。结论:两组新辅助化疗方案治疗乳腺癌近期有效率较高,疗效相当;VE组毒副反应较TE组高,但均可耐受。     

氟尿嘧啶/亚叶酸联合奥沙利铂或紫杉醇治疗晚期胃癌--临床随机对比研究

目的：比较氟尿嘧啶／亚叶酸(5-FU／FA)联合奥沙利铂与5-FU／FA联合紫杉醇治疗晚期胃癌的近期疗效和毒副反应。方法：40例进展期胃癌患者随机分成两组，5-FU／FA联合奥沙利铂组(A组)20例，70．0％为复治患者，5-FU／FA联合紫杉醇组(B组)20例，55．0％为复治患者，转移部位包括肝、淋巴结、腹腔、腹壁等。结果：两组患者各有20例可评价疗效，A组CR2例，PR7例，有效率(CR PR)45．0％，B组PR9例，有效率45．0％。A组有20例评价毒性反应，主要为骨髓抑制、外周神经毒性、消化道反应、肝功能损害；B组有20例可评价毒性反应，主要为骨髓抑制、肝功能损害。结论：5-FU／FA联合奥沙利铂与联合紫杉醇治疗晚期胃癌疗效相当．毒性反应可耐受。两者相比，联合奥沙利铂具有用药方便，严重的毒副反应少等优点。     

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 study of carboplatin, doxorubicin and weekly paclitaxel in patients with advanced ovarian carcinoma.

BACKGROUND: Doxorubicin is an active compound in epithelial ovarian cancer (EOC), but adding it to carboplatin-paclitaxel causes toxicity. Toxicity can be reduced by weekly administration. We examined the tolerability of weekly paclitaxel in combination with carboplatin and doxorubicin. PATIENTS AND METHODS: Chemotherapy na?ve patients with EOC were treated with doxorubicin (50 mg/m(2) day 1), carboplatin (AUC 6 day 1) and paclitaxel (days 1, 8, 15, 21), 28-day cycle. Three patients were treated at each paclitaxel dose level, starting at 60, 75 and 90 mg/m(2)/week. If more than two patients in a cohort experienced dose-limiting toxicity (DLT) three more patients were treated at the dose level below. RESULTS: Twelve patients with advanced EOC received a median of six cycles (range 2-6) of the three-drug combination. DLT occurred at dose level 3: prolonged grade 4 febrile neutropenia, 1 patient; grade 3 peripheral neuropathy, 1 patient. All six patients treated at dose level 2 experienced short-lived grade 4 neutropenia, which led to dose modifications resulting in an actual delivered dose of paclitaxel of 64 mg/m(2)/week. Eight out of 12 patients had measurable disease on CT scan: four obtained a partial remission; three had stable disease. CONCLUSIONS: The combination of carboplatin, doxorubicin and paclitaxel in patients with EOC is active and its main toxicity is myelosuppression. Dose intensity of paclitaxel can be maintained in a three-drug combination through weekly administration (65 mg/m(2)).     

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.     

小白菊内酯抑制紫杉醇诱导的肿瘤细胞凋亡

目的　探讨NF κB在紫杉醇诱导肿瘤细胞凋亡中的作用及小白菊内酯对紫杉醇诱导凋亡的影响。方法　以人乳癌BCap37细胞和人表皮KB细胞为研究对象 ,用 5,1 0和 2 0 μmol·L-1 小白菊内酯预处理细胞 ,以DNA凋亡梯状条带、DNA含量、MTT、细胞甩片及电泳迁移率变动分析 (EMSA)法检测它对紫杉醇诱导细胞凋亡的影响并探索其作用靶点。结果　通过检测DNA凋亡梯状条带、DNA含量和细胞生存率 ,2 0μmol·L-1 小白菊内酯能显著抑制紫杉醇所诱导的BCap37和KB细胞凋亡 ,但不影响紫杉醇诱导肿瘤细胞G2 /M期阻滞。EMSA实验表明小白菊内酯能抑制紫杉醇诱导激活NF κB。结论　小白菊内酯通过抑制NF κB的激活来抑制紫杉醇所诱导的肿瘤细胞凋亡 ,而紫杉醇诱导肿瘤细胞凋亡的过程可能与G2 /M期阻滞无关