多柔比星载药微球经导管动脉化疗栓塞治疗肝癌临床疗效观察

摘 要 目的：观察多柔比星载药微球治疗肝癌患者的临床疗效及安全性。方法: 129例无手术切除指征肝癌患者随机分为观察组（DCB TACE）60例和对照组（cTACE）69例。观察组给予装载50 mg多柔比星的载药微球（直径150~400μm）肝动脉化疗栓塞（TACE）治疗;对照组给予装载40~60 mg多柔比星的5~10 ml传统碘化油混合乳剂TACE治疗。两周进行一次治疗,3个月后观察肿瘤疾病进展情况。结果:观察组完全缓解率为55.0%,显著高于对照组的23.1%（P<0.001）。观察组患者的肿瘤进展时间和存活率均显著优于对照组（P＜0.05）; 两组药品不良反应发生率比较,差异无统计学意义（P>0.05）。结论:多柔比星载药微球可显著延长肝癌进展期、不良反应轻度,临床应用前景广阔。     

多柔比星海藻酸钠微球体内肝动脉栓塞的药代动力学和评价

目的对多柔比星海藻酸钠微球(DOX-AM)进行体内肝动脉栓塞后药代动力学的研究。方法以中华小型猪为实验动物，动脉造影后超选择至肝动脉分支，实验组行DOX-AM肝动脉化疗栓塞，两个对照组分别行碘油多柔比星(DOX-lipiodol)肝动脉化疗栓塞和单纯多柔比星(DOX)肝动脉灌注；定时取实验动物的外周静脉血，采用高效液相色谱法(HLPC)测定其血药浓度并进行药代动力学方面的相关统计处理。栓塞前后进行影像学检查。结果DOX-AM与单纯DOX溶液灌注和DOX-lipiodol栓塞相比，在血浆半衰期﹑药时曲线下面积、最大血药浓度和平均滞留时间等方面均呈现明显的差异性；肝组织学检查证实DOX-AM栓塞后阻塞在血管内并停留一定时间。数字减影血管造影(DSA)和计算机断层扫描(CT)检查显示栓塞效果可靠，组织学检查显示对肝脏的副作用按碘油多柔比星栓塞、多柔比星海藻酸钠微球栓塞及单纯DOX肝动脉灌注的顺序下降。结论DOX-AM在肝脏行动脉栓塞后，具有明显的缓释作用，可以显著延长药物在体内的停留时间，对肝脏的副作用小于碘油多柔比星肝动脉栓塞。     

靶向给药系统—顺铂肝动脉栓塞微球的研究

用改良的油/油(o/o)溶媒蒸发法制备的顺铂-乙基纤维素非生物降解微球作为肝动脉栓塞化疗的新剂型。试用 TLC 和 UV 比值(A_(301nm)/A_(247nm)结合,301nm 处的吸光度进行了药物含量及体外稳定性的检测。兔肝动脉灌注顺铂微球后血清铂浓度的上升与下降速度均较灌注顺铂溶液缓慢,兔灌注顺铂微球后,组织铂含量较低,衰减速度也较慢。对原发性肝癌病人用顺铂微球和临床常规栓塞治疗的比较表明,疗效有显著差异。     

中晚期原发性肝癌46例综合治疗的临床体会

目的 :探讨肝动脉化疗栓塞术加局部放射治疗治疗原发性肝癌的疗效。方法 :治疗 46例原发性肝癌 ,应用 5 -氟脲嘧啶针 1.2 5g、顺铂针 6 0mg、阿霉素针 40mg加 10～ 2 0ml40 %碘化油、明胶海绵颗粒实施肝动脉化疗栓塞术 ;两周后B超定位采用 6MeV -X线直线加速器局部放射治疗。结果 :完全缓解率 4.3 % ,部分缓解率 5 2 .1% ,总有效率 5 6 .5 %。一年生存率为 5 1.3 %。结论 :肝动脉化疗栓塞术加局部放射治疗可提高原发性肝癌的疗效 ,延长生存期 ,提高生活质量。     

顺铂白及胶微球的制备及栓塞特性

目的:顺铂白及胶微球的制备及栓塞特性的考察.方法:采用乳化-冷凝-化学交联技术制备顺铂白及胶微球,利用正交试验设计法优选顺铂白及胶微球的制备条件和工艺;对微球的载药量、大小及分布、形态及表面状态、体外释放以及栓塞特性等进行了研究.结果:微球平均粒径为(108.3±35.2)μm,顺铂含量为(20.7±6.2)%;电镜扫描显示,微球球形圆整,表面粗糙;微球经60Co辐射灭菌要求;其体外释药实验表明顺铂白及胶微球有明显的缓释性能;动物栓塞试验以及对肿瘤患者的栓塞治疗均显示良好的栓塞效果.结论:该微球制备工艺可行,制得的顺铂白及胶微球可达到介入栓塞和化疗的双重目的,适用于肝癌患者的介入栓塞治疗.     

顺铂在肿瘤治疗中的应用

晚期肺癌顺铂单一用药 ,采用每日静脉滴注 2 0ｍｇ ,总量 2 0 0ｍｇ。合并癌性胸水者 ,抽水后灌注 40ｍｇ·次 1 ,每周 2次。临床疗效总缓解率 66 .9%。顺铂加依托泊苷 (ＶＰ 1 6)治疗晚期肺鳞癌 2 3例 ,有效率 56 .5 % ,肺腺癌 6例 ,有效率 33 .0 %。顺铂配合钴60体外放疗方案 ,每日静脉滴注顺铂 2 0ｍｇ,每周 5次 ,治疗 1 0周。经过治疗的 2 0例 ,缓解率 74.4 % ,优于单纯化疗。可见 ,顺铂加钴60 是目前治疗晚期肺癌的较佳方案。2　原发性肝癌经肝动脉导管灌注化疗 :顺铂 1 0ｍｇ加 0 .9%氯化钠注射液1 0ｍＬ,1 0ｄ为 1个疗程。每天静脉…     

顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

双介入治疗原发性肝癌并发脾功能亢进51例

［摘要］目的探讨原发性肝癌并发脾功能亢进（脾亢）双介入的临床疗效。方法原发性肝癌并发脾亢患者51例，超选部分脾动脉栓塞术给予明胶海绵栓塞，同时进行肝动脉选择性灌注化疗栓塞术，化疗应用多柔比星50～60 mg，氟尿嘧啶500～1 000 mg，顺铂20～40 mg三联或四联，用超液化碘油超选做肝动脉栓塞。结果近期有效率78.43%，生活质量改善率74.51%（P＜0.05），不良反应有发热、腹痛、恶心、呕吐、麻痹性肠淤胀等。结论双介入治疗原发性肝癌并发脾亢的临床疗效较好，不良反应可以耐受，值得进一步研究。     

西艾克顺铂毗柔比星联合动脉灌注治疗51例中晚期肺癌

目的:探讨支气管动脉灌注(BAI)治疗中晚期肺癌的联合化疗方案,观察不同病理类型的肺癌对西艾克、顺铂、毗柔比星联合动脉灌注治疗的疗效。方法:本组51例经影像和病理证实后,先行支气管动脉造影(BAG)确定肿瘤供血动脉后,再行BAI。结果:灌注113次,其中完全缓解4例(7.8％)、部分缓解36例(70.6％)、稳定9例(17.6％)、进展2例(3.9％)、总有效率78.4％;非小细胞肺癌(鳞癌+腺癌)总缓解率为76.6％(36/47)。疗效小细胞未分化癌>鳞癌>腺癌,三者疗效差异无显著性。结论:西艾克、顺铂、毗柔比星联合BAI近期疗效显著。     

100～300μm微球栓塞治疗70例肝癌患者的安全性及疗效评价

观察100～300μm微球栓塞治疗肝癌是否可靠安全,评价其疗效。对70例经股动脉插管,选择肝动脉和肠系膜动脉造影,再超选择肿瘤供血动脉,采用表柔比星和碘油混悬液联合微球栓塞肿瘤,观察其手术效果、患者术中及术后并发症发生情况及恢复情况和初步短期疗效评价。在肝癌化疗栓塞治疗手术中,应用100～300μm微球栓塞治疗肝癌是安全的、可靠的,近期疗效满意,长期疗效尚待观察。     

Biodegradation rate of embolized protein microspheres in lung, liver and kidney of rats

The targeting and sustained release characteristics of cytotoxic drug-loaded protein microspheres may prove useful in the therapeutic chemoembolization of solid tumours. Because biodegradation rate of embolized particles will influence rate of incorporated drug release and duration of exposure, this parameter was studied for microspheres (10-30 microns mean diam.) prepared from the proteins albumin and casein, that we have previously used as carriers for doxorubicin. As a measure of microsphere loss in-vivo the radionuclide 125I was chosen because it can be covalently bound to proteins and also homogeneously distributed throughout the matrix. Radiolabelled microspheres were administered to rats both intravenously (lung as target organ, 1.4-2.2 mg/100 g) and via the hepatic artery (liver as target organ, 0.4-0.8 mg/100 g). In both cases it was observed that the casein system biodegraded more slowly than the albumin in-vivo. Thus, time taken for loss of 50% of embolized microspheres from lung was: albumin 2.0 days; casein 3.5 days and from liver:albumin 3.6 days; casein 6.8 days. Microsphere "debris" did not markedly accumulate in other organs. In-vitro experiments showed that microspheres were stable in serum and that albumin microspheres were not innately more sensitive to enzymic digestion than casein. The results may be useful in estimating duration of exposure of target organs to drug-loaded microsphere systems prepared from these proteins.     

Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma

The aim of this study was to select the best candidate drug for transarterial chemoembolization by in-vitro cytotoxic evaluations of 11 anticancer drugs on three human hepatocellular carcinoma (HCC) cell lines. The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed for 30 min to 11 concentrations of doxorubicin, epirubicin, idarubicin, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel. Cytotoxicity was measured using a quantitative colorimetric assay. For each drug and cell line, we calculated the drug concentration that caused 90% cell death (IC90). To enable comparisons of drugs with different concentration ranges, we computed the cytotoxic index (CyI) as the ratio of maximal drug concentration of more than IC90. Parameters were estimated using nonlinear regression models. Idarubicin was the most active drug on all three cell lines. With SNU-398 cells, the idarubicin CyI was 2.4-fold, 2.5-fold, 57-fold, 148-fold, and more than 58 748-fold higher than the CyIs of mitoxantrone, epirubicin, doxorubicin, gemcitabine, and other drugs, respectively. With HepG2 cells, the idarubicin CyI was 27-fold, 28-fold, 51-fold, and more than 1343-fold higher than the CyIs of doxorubicin, epirubicin, mitoxantrone, and other drugs, respectively. On the resistant SNU-449 cell line, the idarubicin CyI was 2.9-fold and 14-fold higher than the CyIs of paclitaxel and gemcitabine, respectively, the only other drugs effective on this cell line. Among 11 chemotherapeutic agents including doxorubicin, cisplatin, and epirubicin, the most effective on three HCC cell lines was idarubicin. Further clinical investigations are needed to evaluate the safety and efficacy of idarubicin for transarterial chemoembolization in HCC.     

异长春花碱联合顺铂治疗晚期非小细胞肺癌32例

目的：观察异长春花碱和顺铂治疗晚期非小细胞肺癌的疗效。方法：32例晚期非小细胞肺癌患者，给予异长春花碱联合顺铂治疗，观察疗效及毒副作用。结果：32例完全缓解1例，部分解14例，有效率46．9％。主要副作用为骨髓抑制。结论：异长春花碱与顺铂联合化疗对晚期非小细胞肺癌有较好疗效。     

Covalent coupling of doxorubicin in protein microspheres is a major determinant of tumour drug disposition

Doxorubicin is shown to be present in albumin microspheres (10-40 microns) in two forms: the native drug and a fraction of drug covalently coupled to the protein matrix probably via glutaraldehyde. Upon trypsin digestion the fraction covalently coupled is released and can be resolved from native doxorubicin by high performance liquid chromatography and quantitated either by using 14C-labelled doxorubicin or by measuring the absorption of the doxorubicin chromophore at 480 nm. Albumin microspheres contained 6.9 micrograms/mg protein covalently bound drug versus 11.1 micrograms/mg native drug when 1% glutaraldehyde was used in microsphere preparation. The covalently bound fraction increased significantly with 2% glutaraldehyde. Albumin/polyaspartic acid microspheres lacked a covalently bound fraction when prepared under the same conditions as pure albumin microspheres (35 micrograms/mg native drug, 1% glutaraldehyde) but transferrin microspheres contained similar amounts of bound and native albumin. In vivo, albumin microspheres altered the disposition of doxorubicin in a rat mammary carcinoma (Sp107) compared to albumin/polyaspartic acid microspheres by reducing the rate of parent drug elimination from the tumour and by reducing its biotransformation to 7-deoxyaglycone metabolites. These data indicate that covalent coupling is a key component in the way doxorubicin is handled in tumours after administration of protein microspheres.     

Pharmacokinetics of doxorubicin and cisplatin used in intraoperative hyperthermic intrathoracic chemotherapy after cytoreductive surgery for malignant pleural mesothelioma and pleural thymoma

Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy (HITHOC) is studied in a phase I study in the treatment of malignant pleural mesothelioma and pleural thymoma. We studied the pharmacokinetics of doxorubicin and cisplatin used during the HITHOC procedure. Furthermore, the penetration characteristics of doxorubicin were examined. Between 1998 and 2001, 24 perfusions were performed with a solution containing doxorubicin and cisplatin for 90 min at 40-41 degrees C. The dose was first based on square meters body surface, whereas in later studies a fixed concentration of the perfusion fluid was used. Samples of blood and perfusion fluid were collected for doxorubicin and cisplatin measurements. The penetration characteristics of doxorubicin in tissue were determined by fluorescence microscopy. The mean AUC(perfusate):AUC(plasma) ratios for doxorubicin and cisplatin (ultrafiltration for plasma) were 99 and 59, respectively. During perfusion the concentration in the perfusate declined essentially according to first-order elimination kinetics for both doxorubicin and cisplatin with half-lives of 74 and 138 min, respectively. At the end of the perfusion, about 35 and 52% of the dose of doxorubicin and cisplatin, respectively, was recovered in the perfusion fluid. One patient developed a nephrotoxicity grade II. No leukopenia or hair loss was seen. Doxorubicin penetrated into the intercostal muscle specimen, albeit that there was considerable variation in distribution throughout the specimen. We conclude that HITHOC with doxorubicin and cisplatin is relatively a safe procedure with the advantage of high intrathoracic cytostatic drug concentrations, while having limited systemic side effects.     

Delivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfopropyl dextran microspheres

Intratumoral injection of controlled-release microsphere formulations of anticancer compounds has the potential to selectively increase tumour exposure to drugs. This work aimed to evaluate the therapeutic effect and toxicity of microsphere formulations containing the anticancer drug, doxorubicin, in a murine tumour model. The effect of co-administration of verapamil, a P-glycoprotein modulator or chemosensitizer, was investigated. Initial in-vitro studies confirmed the ability of verapamil to enhance the accumulation of both doxorubicin and [(99mTc)]sestamibi, also a P-glycoprotein substrate, in EMT6 murine breast sarcoma cells and a doxorubicin-selected multidrug-resistant variant, EMT6/AR1.0. Ex-vivo studies using confocal microscopy demonstrated release of doxorubicin from microspheres and diffusion of the drug through tissue. For in-vivo studies, EMT6 and EMT6/AR1.0 cells were grown in BALB/c mice. Following intratumoral injection of doxorubicin-loaded microspheres, alone or in combination with verapamil-loaded microspheres, the tumour diameter was measured serially as an indication of therapeutic effect, while the weight, appearance, and behaviour of the mice were monitored as an indication of general toxicity. Intratumoral injections of doxorubicin-loaded microspheres were tolerated much better than systemic administration of equivalent drug concentrations. There was a modest (up to 34%) delay of tumour growth compared with groups receiving no treatment or blank microspheres. Co-injection of verapamil microspheres with doxorubicin microspheres produced a moderate increase in toxicity but no further delay in tumour growth. Controlled-release microsphere formulations of anticancer agents administered intratumorally were an efficient way to deliver high drug doses to the tumour with little systemic toxicity.     

Formation and characterization of cisplatin loaded poly(d,l-lactide) microspheres for chemoembolization

Cisplatin, a slightly water soluble anticancer drug, has been incorporated into biodegradable poly(d,l-lactide) microspheres using the solvent evaporation process. The optimal experimental conditions to produce spherical and separate drug-loaded particles (45% cisplatin) were as follows: the dispersing phase was a mixture of 0.05% methylcellulose and 4% polyvinyl alcohol (8 mPa-s grade); and the optimal poly(d,l-lactide) concentration in the organic phase was found to be greater than or equal to 7.16%. Microscopic studies showed that increasing the drug content in the microspheres produced the appearance of rod-like crystals at the microparticle surface. In addition, the cisplatin crystals were found homogeneously distributed in the polymer matrix, even at a high drug content. Increased viscosities of the organic phase enhanced the mean microsphere size, while increasing the emulsifier concentration in the aqueous phase decreased the average particle size. The drug incorporation efficiency was markedly improved after saturation of the dispersing phase with cisplatin. It was also noted that the amount of drug incorporated increased with increasing mean microsphere diameter. The methylene chloride content entrapped within the microspheres was found to depend upon the microsphere size distribution and the cisplatin content. An increase of the microsphere system porosity, by the addition of 10% cyclohexane in the organic phase, caused a reduction in the residual methylene chloride content. Finally, the in vitro release kinetics of cisplatin were influenced by the drug loading.     

Use of an ATP-based chemosensitivity assay to design new combinations of high-concentration doxorubicin with other drugs for recurrent ovarian cancer

Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.