Ultrastructural Damage in Vascular Endothelium in Rats Treated with Paclitaxel and Doxorubicin

Endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in the cancer therapy. Paclitaxel and doxorubicin are frequently used anticancer drugs and their cardiac side effects are well observed in clinical setting. Their side effects on the endothelium are still not clear enough. There are few investigations assessing the damages elicited by the combination use of chemotherapy agents in animal experimental models. The purpose of this study was to examine and compare the side effects of doxorubicin and paclitaxel on endothelium in vivo. The drugs were administered weekly to rats via intraperitoneal injections singly or in combinations. Lastly, aorta endothelium was examined. The most familiar parts of the aorta endothelium are the nucleus, free ribosomes, Weibel-Palada granules, plasmalemmal vesicles, and clear basement membrane. Examination of the endothelium and the related structures revealed some clear degenerative findings. Notably, administration of a paclitaxel and doxorubicin combinations caused the most dramatic change in ultrastructure, which may disrupt many functions of the endothelium.     

Characterization of PEG–iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery

Hyperthermia, the heating of tissue from 41 to 45?°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n?=?1000) methyl ether methacrylate and PEG (n?=?400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response.     

Self-aggregated nanoparticles of linoleic acid-modified glycol chitosan conjugate as delivery vehicles for paclitaxel: preparation,characterization and evaluation

A series of linoleic acid-modified glycol chitosan (LAGC) conjugates were synthesized and characterized by FTIR and ¹H NMR. The effect of the amount of linoleic acid (LA) on the physicochemical properties of LAGC conjugates was investigated. The mean diameters of three LAGC nanoparticles determined by dynamic light scattering ranged from 204 to 289 nm. The critical aggregation concentration values of LAGC conjugates in aqueous solution were 0.0148, 0.0348, and 0.0807 mg/ml, respectively. Paclitaxel (PTX) was physically loaded into the LAGC nanoparticles by a dialysis method. The drug loading content and encapsulation efficiency of PTX-loaded LAGC (PTX-LAGC) nanoparticles increased with an increasing ratio of the hydrophobic LA to hydrophilic glycol chitosan in the conjugates. PTX-LAGC nanoparticles were almost spherical in shape observed by transmission electron microscopy. In vitro release revealed that PTX release from the nanoparticles was reduced as the LA substitution degree of LAGC conjugates increased. Compared with the commercial formulation Taxol, PTX-LAGC-1 nanoparticles exhibited comparable cellular uptake and cytotoxicity against HepG2 cells in vitro. Importantly, PTX-LAGC-1 nanoparticles demonstrated the stronger antitumor efficacy against hepatic H22 tumor-bearing mice than Taxol (p < 0.05). Therefore, glycolipid-like LAGC nanoparticles had a potential as delivery vehicles for tumor therapy.     

HPLC法测定米铂白蛋白结合型纳米制剂中米铂的含量

目的建立米铂白蛋白结合型纳米制剂中米铂含量测定的高效液相色谱(HPLC)法。方法采用HPLC测定米铂白蛋白结合型纳米制剂中米铂的含量。色谱条件:辛烷基硅烷键合硅胶色谱柱(250 mm×4.6 mm,5μm),甲醇-乙腈-水(91:1:8)洗脱,流速1.0 ml/min,检测波长210 nm,柱温30℃,进样量20μl。结果建立了简便可行的米铂白蛋白结合型纳米制剂样品前处理方法;建立并验证了HPLC方法,线性范围3.63~130.80μg/ml(r=0.9995);低、中、高3个浓度的平均回收率(n=3)分别为(99.46±0.24)%、(99.20±1.38)%、(98.30±0.26)%;日内、间精密度RSD分别为1.62%(n=6)和1.32%(n=6);流速在0.99~1.01 ml/min范围内变化时米铂峰面积的RSD为1.01%(n=9),柱温在28~32℃之间变化时米铂峰面积的RSD为1.14%(n=9)。结论本文建立的含量测定方法简便易行,专属性强,灵敏度高,耐用性好;可定量检测米铂白蛋白结合型纳米制剂中米铂的含量。     

放化同步治疗中老年局部晚期非小细胞肺癌时紫杉醇剂量选择的研究

目的探讨放化同步治疗中老年非小细胞肺癌（NSCLC）时紫杉醇剂量的选择。方法选择60例NSCLC患者,其中男性36例,女性24例;年龄55~65岁。随机分为A、B、C、D、E 5组,每组12例患者。所有患者先经过3个周期的诱导化学治疗,1个月后进行放化同步治疗。三维适形放射治疗在5~6周内完成,控制总剂量在60 Gy;化学治疗时使用紫杉醇,A组2次/周,每次10mg/m2;B组2次/周,每次15 mg/m2;C组2次/周,每次20 mg/m2;D组3次/周,每次10 mg/m2;E组3次/周,每次15 mg/m2,6周完成治疗。当任何一组患者在治疗期间出现半数以上的患者发生3度以上急性不良反应即停止该组试验。结果 A、B、D 3组出现3度以上不良反应的患者均未超过半数,完成所有治疗,近期总有效率分别为41.67%、75.00%、66.67%;C、E两组因出现3度以上不良反应的患者超过半数而停止试验。结论在诱导化疗后使用放化同步治疗中老年局部晚期NSCLC患者时紫杉醇最佳使用剂量的选择为每周30 mg/m2,可根据患者具体身体状况调整每次给药剂量和给药次数,并于5~6周完成治疗。     

紫杉醇脂质体联合铂类治疗晚期食管癌疗效与安全性系统评价

目的系统评价紫杉醇脂质体联合铂类治疗晚期食管癌的疗效和安全性。方法利用计算机检索PubMed,Embase,Cochrane Library,Web of Science,CNKI,VIP,WanFang Data等数据库,收集有关临床试验,检索时间为自建库至2019年7月。根据纳入和排除标准独立进行文献筛选、资料提取及质量评价。对于单臂试验采用StataSE 11.0软件合并效应量,采用RevMan 5.3软件对随机对照试验(RCT)进行Meta分析。结果共纳入13篇文献,其中6篇为紫杉醇脂质体(研究组)与紫杉醇(对照组)的RCT,另外7篇为紫杉醇脂质体单臂试验,共有患者713例。单臂试验中,研究组的合并客观缓解率为46%,95%CI(0.40,0.52);RCT中,研究组的客观缓解率与对照组相当[RR=1.08,95%CI(0.87,1.35),P=0.50],但研究组的呼吸困难、肌肉痛、恶心呕吐、皮肤潮红等不良反应发生率明显低于对照组(P<0.05)。结论紫杉醇脂质体与普通紫杉醇在治疗晚期食管癌的疗效类似,但前者不良反应明显减少。     

贝伐珠单抗单药及联合化疗对子宫内膜癌Ishikawa细胞增殖和凋亡的影响

目的： 探究贝伐珠单抗单药及联合紫杉醇加卡铂给药,对子宫内膜癌Ishikawa细胞增殖和凋亡的影响。方法： 体外培养Ishikawa细胞,MTT法检测贝伐珠单抗（Bev）、紫杉醇（T）、卡铂（C）抑制Ishikawa细胞增殖能力的变化,并计算半数抑制浓度（IC₅₀）。以不同浓度的Bev将实验设为4组,分别为A组：对照组;B组：低浓度组（Bev 2.5 mg·mL^-1）;C组：中浓度（Bev 5.5 mg·mL^-1）;D组：高浓度组（Bev 11 mg·mL^-1）。采用MTT法在24,48,72 h分别检测A、B、C、D 4组对Ishikawa细胞抑制增殖的作用。同时实验根据IC₅₀值还将不同浓度的Bev联合紫杉醇、卡铂分为4组,分别为a组（Bev 5.5 mg·mL^-1）;b组（Bev 2.5 mg·mL^-1+卡铂7.0 mg·mL^-1+紫杉醇10 μg·mL^-1）;c组（Bev 5.5 mg·mL^-1+卡铂7.0 mg·mL^-1+紫杉醇10 μg·mL^-1）;d组（Bev 11 mg·mL^-1+卡铂7.0 mg·mL^-1+紫杉醇10 μg·mL^-1）采用MTT法检测对Ishikawa细胞的抑制增殖作用;用Annexin V-FITC/PI双染,流式细胞仪分析48 h贝伐珠单抗A、B、C、D四组对Ishikawa细胞凋亡的影响。结果： MTT法测定出A、B、C、D 4组药物对Ishikawa细胞体外增殖抑制作用显著,并随着剂量的增大、时间的延长,抑制作用也明显增强;MTT法显示不同浓度Bev联合紫杉醇、卡铂,a、b、c、d 4个组均显著抑制Ishikawa细胞的增殖,与a组相比,Bev（5.5 mg·mL^-1）+紫杉醇、卡铂组对Ishikawa细胞有显著抑制增殖作用（P<0.05）,Bev（11 mg·mL^-1）+紫杉醇、卡铂组对Ishikawa细胞表现出更为显著的抑制增殖作用（P<0.01）;通过流式细胞仪检测48 h后A、B、C、D 4组均能诱导细胞的凋亡,且随着剂量增加作用也增强。与对照组比较,差异均有统计学意义（P<0.05）。结论： 贝伐珠单抗单药及联合卡铂和紫杉醇给药,均能在体外抑制人子宫内膜癌细胞株Ishikawa细胞增殖反应,且呈剂量和时间依赖性。     

Taxotere resistance in SUIT Taxotere resistance in pancreatic carcinoma cell line SUIT 2 and its sublines

AIM: To investigate the specific mechanisms of intrinsic and acquired resistance to taxotere (TXT) in pancreatic adenocarcinoma (PAC). METHODS: MTT assay was used to detect the sensitivity of PAC cell line SUIT-2 and its sublines (S-007, S-013, S-020, S-028 and TXT selected SUIT-2 cell line, S2/TXT) to TXT. Mdr1 (P-gp), multidrug resistance associated protein (MRP), lung resistance protein (LRP) and beta-tubulin isotype gene expressions were detected by RT-PCR. The functionality of P-gp and MRP was tested using their specific blocker verapamil (Ver) and indomethacin (IMC), respectively. The transporter activity of P-gp was also confirmed by Rhodamine 123 accumulation assay. RESULTS: S-020 and S2/TXT were found to be significantly resistant to TXT(19 and 9.5-fold to their parental cell line SUIT-2, respectively). RT-PCR demonstrated strong expression of Mdr1 in these two cell lines, but weaker expression or no expression in other cells lines. MRP and LRP expressions were found in most of these cell lines. The TXT-resistance in S2-020 and S2/TXT could be reversed almost completely by Ver, but not by IMC. Flow cytometry showed that Ver increased the accumulation of Rhodamine-123 in these two cell lines. Compared with S-020 and SUIT-2, the levels of beta-tubulin isotype II, III expressions in S-2/TXT were increased remarkably. CONCLUSION: The both intrinsic and acquired TXT-related drug resistance in these PAC cell lines is mainly mediated by P-gp, but had no relationship to MRP and LRP expressions. The increases of beta-tubulin isotype II, III might be collateral changes that occur when the SUIT-2 cells are treated with TXT.