紫杉醇和维甲酸对前列腺癌PC-3细胞的作用

目的　观察紫杉醇 (PA)和维甲酸 (RA)协同对前列腺癌细胞系PC 3的体外作用 ,并探讨其可能的作用机制。方法　应用光镜形态学、噻唑蓝 (MTT)法、流式细胞仪和免疫细胞化学法观察了 10 -6、10 -7、10 -8mol/L浓度紫杉醇和 10 -5、10 -6、10 -7mol/L浓度维甲酸在体外单药或协同对前列腺癌细胞系PC 3的作用和对细胞DNA含量及CyclinD1表达的影响。 结果　 10 -6mol/L以上浓度维甲酸作用 48h可增强 10 -7mol/L以上浓度紫杉醇对前列腺癌PC 3细胞系的生长抑制 [抑制率≥ (5 6.3± 5 .2 ) % ,P <0 .0 5 ] ,增强诱导凋亡作用 [凋亡率≥ (2 0 .5± 2 .3 ) % ,P <0 .0 5 ] ,下调CyclinD1的表达 [表达率≤ (9.2± 1.1) % ]。维甲酸使紫杉醇所致的G2 /M期细胞比例由 (70 .3± 9.3 ) %变为 (5 4.6± 6.7) % ,部分地逆转了其G2 /M期细胞周期阻滞 (P <0 .0 5 )。结论　紫杉醇和维甲酸可以协同增强对前列腺癌细胞系PC 3的生长抑制和诱导凋亡作用 ,显示了紫杉醇和维甲酸协同用于治疗激素非依赖性前列腺癌的可能性。     

Phase I Study of Paclitaxel by Three-hour Infusion: Hypotension Just after Infusion Is One of the Major Dose-limiting Toxicities

The primary objectives of this study were to determine the maximum tolerated dose (MTD) of paclitaxel administered by 3-h infusion to patients with solid tumors, and to characterize the pharmacokinetics of a 3-h infusion in comparison with those of a 24-h infusion. Twenty-seven patients each received one of six levels of paclitaxel, 105, 135, 180, 210, 240 and 270 mg/m², with premedication. Two patients given 240 mg/m² and one patient given 270 mg/m² unexpectedly had grade 3/4 hypotension just after finishing the paclitaxel infusion. Peripheral neuropathy was also dose-limiting at 270 mg/m². Although granulocytopenia was significantly less severe than with a 24-h infusion, more than half of the patients experienced grade 4 toxicity at doses of 240 or 270 mg/m². Severe hypersensitivity reactions (HSRs) were not observed. Pharmacokinetic studies using high performance liquid chromatography demonstrated proportionally greater increases in the peak plasma concentration and area under the curve, and decreases in clearance and volume of distribution with increasing dose, suggesting non-linear pharmacokinetics of paclitaxel when given by 3-h infusion. The MTD of paclitaxel given as a 3-h infusion was determined to be 240 mg/m² with dose-limiting toxicities of granulocytopenia, peripheral neuropathy and hypotension. Hypotension just after infusion, induced by 3-h infusion of paclitaxel, is a new observation which has not been reported previously. The recommended dose for phase II study is 210 mg/m². Although hypotension was observed as an unexpected toxic effect, paclitaxel could be administered safely over 3 h with premedication and proper monitoring, resulting in reduced myelotoxicity and with no increase in the incidence of HSRs as compared with a 24-h infusion.     

A case of scirrhous gastric cancer with peritonitis carcinomatosa controlled by TS-1(R) + paclitaxel for 36 mo after diagnosis

A 34-year-old female complaining of abdominal fullness was diagnosed as scirrhous gastric cancer (type 4')with peritonitis carcinomatosa in July 2002. A combined chemotherapy regimen was selected to control massive ascites; TS-1(R) 80 mg/m2 was given orally on d 1-14,22-35, and paclitaxel 50 mg/m2 was administered intravenously on d 1, 8, 22 and 29. After 2 courses of this regimen, the primary tumor was markedly reduced,and ascites completely vanished. Alopecia (grade 1,since d 30), leukocytopenia (grade 2, on d 34) and anemia (grade 2, on d 34) were the only adverse events throughout the following courses. The chemotherapy was effective for 28 mo, and then it was discontinued upon the patient's own request, and she survived for 36mo after diagnosis.     

紫杉醇诱导胰腺癌细胞凋亡Survivin表达的变化及意义

目的研究紫杉醇（PA）体外化疗对胰腺癌细胞凋亡抑制蛋白Survivin基因表达的影响。方法培养人胰腺癌细胞株SW1990，加入低浓度的PA，用流式细胞仪分别检测加药前和加药后24、48h的细胞凋亡率，用逆转录-聚合酶链反应（RT-PCR）和免疫印迹技术（Western blot）检测Survivin mRNA和蛋白的表达。结果SW1990细胞给予低浓度的PA后，加药前和加药后24、48h的细胞凋亡率分别为（2．59±0．35）％、（14．75±1．29）％、（22．65±2．80）％；其Survivin mRNA的表达则分别比加药前提高了1．1倍和2．9倍；Survivin蛋白的表达分别增加了1．3倍和3．6倍。结论应用PA化疗可促使胰腺癌细胞内Survivin表达的增加，抵抗化疗诱导的细胞凋亡。     

紫杉醇联合草酸铂、卡培他滨三药方案治疗晚期转移性鼻咽癌的临床研究

目的探讨紫杉醇联合草酸铂、卡培他滨三药方案治疗晚期转移性鼻咽癌的疗效及不良反应。方法2002年1月至2005年1月，110例晚期转移性鼻咽癌病人入组：试验组55例患者．第1天应用紫杉醇135mg／m^2、草酸铂130mg／m。静脉滴注，口服卡培他滨1650mg／m^2／d，连服l-14d，每3周为一个周期，连用2-4个周期；对照组55例患者，第1-5天应用DDP 20mg／m^2、5-Fu 0．5g／m^2静脉注射，3周为一个周期，连用2-4个周期；治疗结束2-4周后评价疗效。结果试验组疗效可评价55例，对照组疗效可评价53例。试验组与对照组有效率分别为（CR＋PR）50．9％（28例）和32．1％（17例），两者差异有统计学意义（P〈0．05）。试验组和对照组中位生存时间为10．6个月和8．6个月，两者差异有统计学意义（t〈0．05）。安全性方面：试验组Ⅳ反应主要为手足综合征8例（14．5％）、骨髓抑制2例（3．6％）和消化道毒性4例（7.3％）；对照组Ⅳ反应主要为消化道毒性8例（15.1％）、骨髓抑制2例（3.8％）。结论紫杉醇联合草酸铂、卡培他滨三药方案对晚期转移性鼻咽癌的疗效较DDP＋5-Fu有优势，且不良反应可以耐受。     

重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌的疗效及安全性分析

目的探讨重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌的疗效及安全性。方法 80例晚期宫颈癌患者随机分为两组各40例,对照组给予顺铂与紫杉醇治疗,研究组在对照组基础上给予重组人p53腺病毒注射液治疗。比较两组的治疗效果、不良反应以及复发率、转移率、死亡率。结果研究组的治疗总有效率高于对照组,1年内病死率、复发率及转移率均低于对照组(P <0.05)。两组的不良反应发生率比较,差异无统计学意义(P>0.05)。结论重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌患者的疗效显著,安全性高,能够有效减少近期死亡、复发及转移。     

单用国产紫杉醇治疗乳腺癌

目的评价国产紫杉醇（特素）对乳腺癌的治疗效果和不良反应。方法自１９９５年３月至１９９５年７月,采用紫杉醇治疗乳腺癌２２例。紫杉醇１７５ｍｇ／ｍ２（１７０．９～２１０．８ｍｇ／ｍ２）,２１天为１个周期,共１～４次（中位数３次）。结果紫杉醇近期客观疗效：完全缓解３例,部分缓解１１例,总有效率６３．６％（１４／２２）,有效患者的病情已全部再度进展,缓解期２～７个月（中位３．５个月）。特素化疗的主要不良反应为白细胞下降（９６．２％）、脱发（１００％）和肌肉疼痛（８４．９％）。结论国产紫杉醇治疗乳腺癌有效,不良反应可以耐受。     

Isolation,purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces

Three metabolites of the cytotoxic drug paclitaxel (Taxol) were isolated and purified from the feces of cancer patients receiving the agent as an intravenous infusion. The procedures involved sample homogenization in water followed by liquid-liquid extraction with diethyl ether and high-performance liquid chromatography (HPLC). Approximately 1–3.5 mg of each metabolite was obtained from 100 g of feces. As judged from the chromatographic traces of analytical HPLC with ultraviolet (UV) detection at 227 nm, the purity of each compound was >97%. On-line photodiode-array detection demonstrated that the UV spectrum of the isolated compounds closely resembles that of the parent drug. Mass spectrometry provided evidence that these metabolites are mono- and dihydroxy-substituted derivatives, namely, 6-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and 6,3-p-dihydroxypaclitaxel. The two 6-hydroxy-substituted metabolites were shown to have lost their cytotoxicity in in vitro clonogenic assays using the A2780 human ovarian carcinoma and the CC531 rat colon-carcinoma tumor cell lines. In addition, the metabolites showed reduced myelotoxic effects as compared with paclitaxel in an in vitro hemopoietic progenitor toxicity assay. Our procedure for the isolation and purification of paclitaxel metabolites in milligram quantities should be useful for testing the biological activities of these compounds and for the preparation of calibration standards essential for pharmockinetics studies.     

The distribution of systemically administered [3H]-paclitaxel in rats: a quantitative autoradiographic study

Paclitaxel is an important agent in the treatment of many common malignancies. Although the symptomatic peripheral neuropathy caused by this drug is its principal nonhematologic toxicity, little is known about the distribution of paclitaxel within the peripheral or central nervous system following systemic administration. In order to study paclitaxel's distribution in neural and extraneural tissues, adult Sprague-Dawley rats were sacrificed 2 h after a tail vein injection of [³H]-paclitaxel (0.03 mg/kg, 250 Ci/rat). Samples of lung, heart, liver, spleen, kidney, skeletal muscle, brain, spinal cord, dorsal root ganglion, and peripheral nerve were then removed and snap-frozen. These tissues were sectioned at 10 m in a cryostat and exposed to autoradiography film for 2 weeks. The distribution and concentrations of [³H]-paclitaxel in plasma, urine and cerebrospinal fluid were also determined using liquid scintillation spectrometry. [³H]-Paclitaxel concentrations (and organ/plasma concentration ratios) in plasma, urine and cerebrospinal fluid were 2.6 nM (1), 38 nM (15) and 0.7 nM (0.3), respectively. A relatively homogeneous distribution of [³H]-paclitaxel was observed in liver [412 nM (151)], spleen [351 nM (133)], heart [319 nM (117)], lung [268 nM (93)] and muscle [69 nM (26)]. Higher concentrations of [³H]-paclitaxel were noted in the portal triads [869 nM (361)], glomeruli [797 nM (304)], and renal medulla [961 nM (363)], which may reflect biliary excretion and glomerular filtration. A high concentration of [³H]-paclitaxel was also noted in the choroid plexus [432 nM (167)], but [³H]-paclitaxel was not detected in the brain parenchyma, spinal cord, dorsal root ganglion, peripheral nerve, or the testicles. The pathogenesis of paclitaxelinduced neurotoxicity remains obscure given its limited distribution in the nervous system. In addition, these results suggest that systemically administered paclitaxel is not likely to be effective for the treatment of malignancies in the testes or the nervous system.     

反相高效液相色谱法测定紫杉醇浓度及其稳定性考察

目的　建立了反相高效液相谱法测定紫杉醇浓度的方法。 方法 　以 C1 8为固定相 ,甲醇 -(5∶ 3∶ 2 )为流动相 ,检测波长 2 3 0 nm。 结果 　紫杉醇在 10～ 10 0μg· ml- 1 范围内呈良好的线性关系。 2 4h内对紫杉醇 -5 %葡萄糖溶液的浓度进行检测 ,结论 　紫杉醇在紫杉醇 -5 %葡萄糖溶液中具有良好的稳定性