Inhibitory effects of everolimus in combination with paclitaxel on adriamycin-resistant breast cancer cell line MDA-MB-231

ObjectiveWe aimed to evaluate the therapeutic effects of paclitaxel in combination with mTOR inhibitor everolimus on adriamycin-resistant breast cancer cell line MDA-MB-231 (MDA-MB-231/ADR).Materials and methodsMDA-MB-231/ADR cells were treated with different concentrations of paclitaxel and everolimus. The IC₅₀ values after 48 h of treatment were measured by the MTT assay. The apoptosis rate and cell cycle were detected by flow cytometry. The protein expressions of Akt, PI3K, mTOR, p-pI3K, p-AKT and p-mTOR were detected by Western blot.ResultsWhen paclitaxel at ≥1.56 μg/ml was used, the growth of MDA-MB-231/ADR cells was inhibited more significantly than that of control group (P < 0.05). After treatment with ≥6.25 μg/ml everolimus, the cell growth was also suppressed more significantly (P < 0.05). The IC₅₀ values of everolimus and paclitaxel were 32.50 μg/ml and 7.80 μg/ml, respectively. The inhibition rate of paclitaxel plus everolimus was significantly enhanced with increasing paclitaxel concentration (P < 0.001). After treatment with 7.80 μg/ml paclitaxel, the two drugs had best synergistic inhibitory effects on proliferation. Compared with drugs alone, the combination significantly promoted apoptosis (P < 0.001). The paclitaxel + everolimus group had significantly more cells in the G0-G1 phase than those of control and individual drug groups (P < 0.001). Everolimus significantly decreased mTOR and p-mTOR expressions compared with those of control group (P < 0.001). Compared with everolimus alone, the combination reduced the expressions more significantly (P < 0.05). Paclitaxel decreased the expression levels of PI3K, p-PI3K and p-AKT. Compared with paclitaxel alone, the combination significantly promoted the reduction of PI3K, p-PI3K and p-AKT expressions (P < 0.05).ConclusionEverolimus can enhance the effect of paclitaxel on MDA-MB-231/ADR cells, inhibit cell proliferation, induce apoptosis and arrest cell cycle in the G1 phase mainly by down-regulating the expressions of key proteins in the mTOR signaling pathway.     

经口明视下阿霉素治疗复发性三叉神经痛的临床观察

目的：探讨经口明视下阿霉素治疗复发性三叉神经痛(第Ⅱ、Ⅲ支)的疗效。方法：选择复发性三叉神经痛(第Ⅱ、Ⅲ支)患者40例，全部患者均接受过无水酒精注射治疗或开颅手术。局麻监护下，经口内解剖，分离出三叉神经第Ⅱ、Ⅲ支，微量注射器直视下注入阿霉素3mg。结果：39例患者术后1周内三叉神经痛症状不同程度减轻，其中72．5％(29／40)在术后24h内疼痛减轻，25％(10／40)在术后1周内疼痛减轻，无效2．5％(1／40)。术后2年内有3例复发，复发率为7．5％(3／40)，复发患者症状均较前减轻，发作次数及持续时间均较前减少。结论：经口明视下阿霉素治疗复发性三叉神经痛是一种安全、有效的方法。     

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.     

经肾动脉插管造影骨髓间充质干细胞移植对阿霉素肾病大鼠的影响

目的 探讨经颈动脉途径肾动脉插管造影骨髓间充质干细胞(MSCs)移植对慢性阿霉素肾病大鼠肾脏的影响,为临床干细胞移植治疗慢性肾脏病及其给药途径选择提供参考.方法 50只雄性SD大鼠作为实验动物.36只采用经尾静脉注射阿霉素制作慢性肾病大鼠模型,造模后随机分为3组(每组12只):(1)阿霉素肾衰模型对照组(ADR组);(2)MSCs移植组(A组),取MSCs悬浮液经肾动脉插管造影输入大鼠右肾;(3)生理盐水组(B组),以A组同样方法将生理盐水输入大鼠右肾.2只用于骨髓MSCs的制备.其余12只作为空白对照组(N组).干细胞移植后第1天和第7天分别测定各组大鼠肾功能(尿素氮、肌酐)和血红蛋白含量,第7天光镜下观察各组大鼠肾脏病理改变.结果 (1) ADR组、A组、B组与N组比较血尿素氮、肌酐明显升高(P＜0.05),血红蛋白含量显著降低(P＜0.05).(2)第1天,与ADR组比较,A组、B组血尿素氮、肌酐和血红蛋白含量无统计学差异(P均＞0.05);第7天时,与ADR组比较,B组血尿素氮、肌酐和血红蛋白含量无统计学差异(P均＞0.05),A组血尿素氮、肌酐明显降低(P均＜0.05),血红蛋白含量明显升高(P＜0.05).(3)光镜下大鼠肾脏病理改变,B组肾小球、肾小管、肾间质损伤程度与ADR组相当,A组肾间质炎症改变程度轻且范围小.结论 移植MSCs有利于慢性阿霉素肾病大鼠肾脏损伤的修复,经颈动脉肾动脉插管造影是可行的途径.     

Treatment of hepatoma with liposome-encapsulated adriamycin administered into hepatic artery of rats

AIM: To observe the therapeutic effects of liposome-encapsulated adriamycin (LADM) on hepatoma in comparison with adriamycin solution (FADM) and adriamycin plus blank liposome (ADM BL) administered into the hepatic artery of rats. METHODS: LADM was prepared by pH gradient-driven method. Normal saline, FADM (2 mg/kg), ADM BL (2 mg/kg), and LADM (2 mg/kg) were injected via the hepatic artery in rats bearing liver W256 carcinosarcoma, which were divided into four groups randomly. The therapeutic effects were evaluated in terms of survival time, tumor enlargement ratio, and tumor necrosis degree. The difference was determined with ANOVA and Dunnett test and log rank test. RESULTS: Compared to FADM or ADM BL, LADM produced a more significant tumor inhibition (tumor volume ratio: 1.243±0.523 vs 1.883±0.708, 1.847±0.661, P < 0.01), and more extensive tumor necrosis. The increased life span was prolonged significantly in rats receiving LADM compared with FADM or ADM BL (231.48 vs 74.66, 94.70) (P < 0.05). CONCLUSION: The anticancer efficacies of adriamycin on hepatoma can be strongly improved by liposomal encapsulation through hepatic arterial administration.     

阿霉素诱导心源性水肿动物模型的建立及相关防治药物的研究进展

阿霉素是一种有效的抗癌药物,但具有一定心脏毒性,因此可以使用阿霉素诱导建立心源性水肿动物模型.选用的实验动物主要为大鼠,造模方法为腹腔注射和尾静脉注射.阿霉素诱导心源性水肿的机制主要与氧化应激作用、钙含量过负荷、细胞凋亡、线粒体损伤等有关.根据其作用机制,防治药物在自由基清除剂、钙拮抗剂、细胞凋亡抑制剂、线粒体保护剂等方面的应用取得较大进展,为治疗心源性水肿提供了科学依据.     

Multidisciplinary treatment strategy for locally advanced gastric cancer: A systematic review

BackgroundMultidisciplinary management of patients with locally advanced gastric cancer (LAGC) remains unstandardized worldwide. We performed a systemic review to summarize the advancements, regional differences, and current recommended multidisciplinary treatment strategies for LAGC.MethodsEligible studies were identified through a comprehensive search of PubMed, Web of Science, Cochrane Library databases and Embase. Phase 3 randomized controlled trials which investigated survival of patients with LAGC who underwent gastrectomy with pre-/perioperative, postoperative chemotherapy, or chemoradiotherapy were included.ResultsIn total, we identified 11 studies of pre-/perioperative chemotherapy, 38 of postoperative chemotherapy, and 14 of chemoradiotherapy. In Europe and the USA, the current standard of care is perioperative chemotherapy for patients with LAGC using the regimen of 5-FU, folinic acid, oxaliplatin and docetaxel (FLOT). In Eastern Asia, upfront gastrectomy and postoperative chemotherapy is commonly used. The S-1 monotherapy or a regimen of capecitabine and oxaliplatin (CapOx) are used for patients with stage II disease, and the CapOx regimen or the S-1 plus docetaxel regimen are recommended for those with stage III Gastric cancer (GC). The addition of postoperative radiotherapy to peri- or postoperative chemotherapy is currently not recommended. Additionally, clinical trials testing targeted therapy and immunotherapy are increasingly performed worldwide.ConclusionsRecent clinical trials showed a survival benefit of peri-over postoperative chemotherapy and chemoradiotherapy. As such, this strategy may have a potential as a global standard for patients with LAGC. Outcome of the ongoing clinical trials is expected to establish the global standard of multidisciplinary treatment strategy in patients with LAGC.     

Role of Ticlopidine on Adriamycin-Induced Nephropathy

The effect of ticlopidine on rats with adriamycin nephropathy was observed during 26 weeks. In the ticlopidine-treated nephrotic animals (TNG), proteinuria was less than in the untreated nephrotic animals (NG), but this difference was significant only at week 6 (TNG = 47.27 ± 16.52 versus NG = 100.08 ± 13.83 mg/24h, p < 0.01) and week 26 (TNG =157.00 ± 28.73 versus NG = 217.00 ± 21.73 mg/24h, p < 0.01) after ADR injection. NG presented severe tubulointerstitial abnormalities with a tubulointerstitial lesion index of 3+. No diffience in glomerular lesions was observed among the groups (NG median = 6%. TNG median = 4% and TCG median = 2%). The tubulointerstitial lesion index of TNG was less intense (median = 2+) but not different from those of the control groups (CG median = 1+; TCG median = 0+) nor NG (median = 3+). We concluded that the treatment with ticlopidine produced some partially beneficial effects but did not prevent the devdopment of adriamycin-induced nephropathy.     

实验性心力衰竭大鼠模型的建立及评价

目的建立实验性心力衰竭大鼠模型,并对其进行评价。方法35只雄性Wistar大鼠随机分两组:正常对照组(CON组,n=10)和心力衰竭模型组(CHF组,n=25),CHF组采用阿霉素2.5 mg/kg尾静脉注射,每周一次,连续10 w,建立CHF大鼠模型。12 w时采用超声和血流动力学检测评价其心功能,放免法检测血浆肿瘤坏死因子-α、血管紧张素Ⅱ及醛固酮水平,氯胺T法检测羟脯氨酸及胶原含量,苦味酸天狼星红染色进行左室胶原特异染色及定量分析,计算胶原容积分数(CVF),并进行HE染色,观察其组织学变化。结果CHF组大鼠死亡率为40%(10/25),CON组无死亡。与CON组相比,CHF组大鼠左室舒张末期内径(LVEDD)及收缩末期内径(LVESD)增加,心功能明显下降,表现为左室短轴缩短率(FS)、二尖瓣环收缩期长轴方向峰值运动速度(Vs)、左室内压最大上升速率( dp/dtmax)、左室内压最大下降速率(-dp/dtmax)明显降低,左室舒张末期压(LVEDP)升高(P<0.01);CHF组血浆肿瘤坏死因子-α、血管紧张素Ⅱ及醛固酮水平升高(P<0.01),心肌羟脯氨酸及胶原含量较CON组增加(P<0.01);苦味酸天狼星红染色显示CHF组左室胶原明显增加,胶原容积分数(CVF)明显增高(P<0.01);病理学结果证实符合心肌病样改变。结论阿霉素多次小剂量静脉注射能导致大鼠发生心脏间质纤维化及心脏舒缩功能降低,可成功建立实验性心力衰竭大鼠模型。