Quality-adjusted survival analysis of first-line treatment of hormone-receptor-positive HER2+ metastatic breast cancer with letrozole alone or in combination with lapatinib

Abstract

Aim:

Compare first-line lapatinib plus letrozole (L?+?Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2?+?metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period.     

Anti-tumor effect of local injectable hydrogel-loaded endostatin alone and in combination with radiotherapy for lung cancer

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. In vitro, ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. In vivo, ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.     

雷帕霉素对肾小管上皮细胞增殖和凋亡的影响

目的 探讨雷帕霉素对肾小管上皮细胞增殖和凋亡的影响。方法 体外培养肾小管上皮细胞(HK-2细胞),选择100, 200, 400, 800 ng/ml雷帕霉素作用于HK-2细胞24、48、72h。利用 MTT实验分析雷帕霉素对HK-2细胞增殖的影响,并计算各浓度及不同时间的增殖抑制率优化雷帕霉素作用的浓度和时间;选择最佳的作用浓度和作用时间处理HK-2细胞,通过流式细胞分析技术,分析雷帕霉素对HK-2细胞的凋亡的影响。结果 MTT实验显示不同浓度的雷帕霉素,对增殖有抑制作用,且表现浓度依赖性和时间依赖性;RAPA可以促进HK-2细胞的凋亡。结论 通过HK-2细胞模型研究,发现雷帕霉素可抑制肾小管上皮细胞增殖、促进细胞凋亡。     

Delivery systems of ceramide in targeted cancer therapy: ceramide alone or in combination with other anti-tumor agents

ABSTRACT

Introduction: Ceramide is a bioactive lipid which functions as a tumor suppressor, regulating processes such as cell proliferation, differentiation, senescence and apoptosis. However, several challenges need to be overcome in order to realize the therapeutic potential of such a bioactive lipid combination regimen, including the hydrophobic and hemolytic nature of the lipids.

Areas covered: In this review, we briefly describe the biological function of ceramide, then the delivery systems that have been developed to improve the pharmacology of ceramide have been summarized. In addition, combination therapies based on these delivery systems to reveal the interactions between therapeutic drugs and ceramide were also highlighted. Furthermore, future perspective before the extension of ceramide’s applications in cancer treatment will also be discussed.

Expert opinion: Although ceramide has attracted tremendous attention in targeted cancer treatment, its levels are usually suppressed by over-expression of ceramide-metabolizing enzymes or down-regulation of ceramide-generating enzymes. Thus, finding ways to increase ceramide by exogenous treatment in cancer cells is desired. Therefore, translating these bioactive lipids into clinical usage requires a variety of methods, and appropriately designed delivery systems may play the direct and important role in this process.     

双去甲氧基姜黄素对小鼠乳腺癌的抗肿瘤作用及机制

目的　本研究旨在研究双去甲氧基姜黄素（bisdesmethoxycurcumin,BDMC）对小鼠乳腺癌的影响及机制。方法　采用小鼠乳腺癌4T1细胞,分为Control组及不同剂量（3、9、27 μM）BDMC组,通过CCK8法检测BDMC对小鼠乳腺癌4T1细胞增殖的影响,TUNEL染色检测BDMC对4T1细胞凋亡的影响,Western blot检测BDMC对4T1细胞Bax、Bcl-2及cleaved caspase-3表达的影响;采用4T1乳腺癌荷瘤小鼠模型,分为Control组及不同剂量（10、30 mg/kg）BDMC组,检测BDMC对小鼠肿瘤体积及体质量的影响,Western blot检测BDMC对乳腺癌小鼠肿瘤组织Bax、Bcl-2及cleaved caspase-3表达的影响。采用单因素方差分析。结果　与Control组相比,9、27 μM BDMC均能明显抑制4T1细胞增殖（均P<0.01）,促进其凋亡（均P<0.01）,同时上调细胞Bax/Bcl-2比值及cleaved caspase-3表达（均P<0.01）;10、30 mg/kg BDMC均能明显抑制乳腺癌小鼠肿瘤体积的增长（均P<0.05）,同时明显上调肿瘤组织Bax/Bcl-2比值及cleaved caspase-3表达（均P<0.05）,但对体质量无明显影响。结论　BDMC对乳腺癌小鼠模型具有明显的抗肿瘤作用,其机制与激活线粒体凋亡通路有关。     

HPLC法测定胃健宁胶囊中和厚朴酚及厚朴酚的含量

目的建立胃健宁胶囊中和厚朴酚及厚朴酚的检测方法。方法色谱条件为C18色谱柱;流动相:乙腈-水-冰醋酸(60∶40∶1)(V∶V∶V);流速:1.000 mL·min-1;检测波长:294 nm。结果胃健宁胶囊中和厚朴酚在0.02⁰.32μg(r=0.999 6)范围内线性关系良好,平均回收率为96.58%,RSD为1.78%(n=9);厚朴酚在0.019 60.32μg(r=0.999 6)范围内线性关系良好,平均回收率为96.58%,RSD为1.78%(n=9);厚朴酚在0.019 6⁰.313 6μg(r=0.999 8)范围内线性关系良好,厚朴酚的平均回收率为97.29%,RSD为1.39%(n=9)。结论该方法简便,准确度高,可有效控制胃健宁胶囊的质量。     

Anti-tumor effect of electrotherapy alone or in combination with interleukin-2 in mice with sarcoma and melanoma tumors.

Electrotherapy with direct current (DC) was performed on two murine tumor models, fibrosarcoma SA-1 and melanoma B16. Three Pt/Ir cathodes were inserted directly into the subcutaneous tumors and two anodes subcutaneously in the vicinity of the tumor. Significant tumor growth delay was achieved after electrotherapy and was dependent on DC intensity (0.6, 1.0, 1.4 and 1.8 mA). Melanoma B16 tumors were more sensitive to electrotherapy than SA-1 tumors. In order to enhance the antitumor effect of electrotherapy, combined treatment with interleukin-2 (IL-2) was performed. When both therapies were combined significant tumor growth delay and also higher curability rate was achieved. The results imply that electrotherapy can be an effective antitumor therapy and that the effects can be enhanced with additional IL-2 therapy.     

Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for hormone receptor positive(HR+) and HER2+ advanced or metastatic breast cancer(MBC)

Abstract

Background:

Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit.     

Synergistic anti-cancer activity of the combination of dihydroartemisinin and doxorubicin in breast cancer cells

BackgroundDihydroartemisinin (DHA) exhibits potent anti-malarial and anti-cancer activities. This study aimed to investigate the anti-proliferative effects of a combination of DHA and doxorubicin (DOX) on human breast cancer cells.MethodsMTT assay and the combination index (CI) were used to show the anti-proliferative effects and calculate the synergism potential, respectively. Flow cytometry assay was used to detect apoptosis and the intracellular accumulation of DOX. JC-1 staining was used to determine the mitochondrial membrane potential. Western blot analysis was used to detect the protein expression of some apoptosis-related molecules.ResultsAsynergistic anti-proliferative effect was found, and the enhanced anti-cancer activity was observed to be accompanied by the prompt onset of apoptosis in MCF-7 cells. The combinative treatment remarkably decreased the mitochondrial membrane potential and activated caspase cascades more than the mono-treatment. Pretreatment with DHAalso did not influence the accumulation of DOX in MCF-7 cells.ConclusionThis study presented a new opportunity to enhance the effectiveness of future treatment regimens of breast cancer using DOX.     

高效液相色谱法测定加味藿香正气丸中厚朴酚与和厚朴酚的含量

目的 建立加味藿香正气丸中厚朴酚与和厚朴酚含量测定的高效液相色谱（HPLC）分析方法.方法 采用 Agilent ZORBAX SB-C18（4.6 mm×150.0 mm,5 μm）色谱柱,流动相为甲醇-水（70∶30）,检测波长为294 nm,流速为1.0 mL/min,进样量10 μL,柱温25 ℃.结果 厚朴酚与和厚朴酚的线性范围分别为0.113 0～1.130 0 μg[相关系数（r）=0.999 99,n=6]和0.061 5～0.615 0 μg（r=0.999 98,n=6）;平均回收率分别为98.4%[相对标准偏差（RSD）=0.98%,n=9]和98.8%（RSD=0.54%,n=9）.结论 HPLC法测定加味藿香正气丸中厚朴酚与和厚朴酚的含量,操作简便、准确、重现性好,可作为该药品质量控制的方法.     

HPLC法测定藿香正气口服液中橙皮苷、和厚朴酚、厚朴酚的含量

目的用HPLC法进行藿香正气口服液中几种有效成分的含量测定方法。方法采用DiamonsilTMC18柱（250×4.6mm,5μm）,以甲醇-水梯度洗脱,检测波长283nm,流速1mL.min-1,柱温25℃。结果橙皮苷、和厚朴酚、厚朴酚线性范围分别在0.1311～2.622μg、0.1728～3.4568μg、0.1751～3.5020μg。结论该测定方法简便可行,可用于藿香正气口服液中几种有效成分的含量测定。     

HER2蛋白在乳腺癌靶向治疗中的作用及意义

近年来,分子生物学在医学领域得到了充分的发展,分子靶向治疗成为治疗肿瘤的一个新方向。酪氨酸激酶受体家族调控着细胞增殖、分化以及凋亡,与肿瘤的发生与发展密切相关,是一个较为理想的特异性靶点。约有30%的乳腺癌患者出现了人表皮生长因子受体2（HER2）过表达,而HER2受体的活化直接导致了其下游的PI3K/AKT和丝裂原活化蛋白激酶（MAPK）通路被激活,而通过靶向HER2过表达的细胞对肿瘤进行控制成为了一种新的乳腺癌的治疗手段。     

HPLC测定拈痛丸中厚朴酚与和厚朴酚的含量

目的 建立拈痛丸中厚朴酚与和厚朴酚含量的测定方法.方法 采用RP-HPLC法,色谱柱为DiamonsidTM-C18柱,甲醇-水-磷酸(68:32:0.1)为流动相;流速1.0 ml·min-1;检测波长294 nm;柱温30℃.结果 厚朴酚的平均回收率为97.7%,RSD=1.78%(n=6);和厚朴酚的平均回收率为100.9%,RSD=1.97%(n=6).结论 所建方法可用于拈痛丸中厚朴酚与和厚朴酚的含量测定.     

苦参碱对人乳腺癌细胞MCF-7增殖、凋亡的影响

目的探讨苦参碱对人乳腺癌细胞MCF-7的增殖、凋亡的影响。方法实验组MCF-7细胞加入苦参碱溶液,对照组加入等量培养液。MTT比色法检测苦参碱对MCF-7细胞的生长抑制率;镜下观察细胞形态学变化;流式细胞术检测MCF-7细胞Bax、Bcl-2蛋白表达。结果与对照组比较,实验组苦参碱呈时间、剂量依赖性明显抑制MCF-7细胞生长,诱导MCF-7细胞凋亡,上调Bax蛋白表达,下调Bcl-2蛋白表达。结论苦参碱对MCF-7细胞具有明显的生长抑制和促凋亡作用,与上调Bax和下调Bcl-2表达有关。     

Aromatase inhibitors and other novel agents in breast cancer treatment

Thirty years after the introduction of tamoxifen, which was expanded from palliation of metastatic cancer to recent application for chemoprevention, the primacy of this drug as the mainline pharmacological intervention is currently being challenged by the third generation aromatase inhibitors and inactivators. In contrast to the oestrogen receptor blockade provided by tamoxifen, aromatase inhibitors result in deprivation of oestrogens in postmenopausal women both through paracrine/intracrine and endocrine modulation. Experimental evidence has shown a significant (97-99%) reduction of in vivo aromatase activity and an equal or sometimes better antitumour activity compared with megestrol acetate when these drugs are used as second-line treatment for metastatic breast cancer. Recent pivotal studies in first-line settings comparing tamoxifen for metastatic breast cancer and preliminary results from the neoadjuvant trials demonstrate that third generation aromatase inhibitors are superior to tamoxifen. With a better understanding of local tissue production of oestrogen through oestrone sulfatase, which hydrolyses oestrone sulfate to oestrone, and 17-beta-hydroxysteroid dehydrogenase Type 1, which in turn catalyses the reduction of oestrone to oestradiol, more powerful tactics for oestrogen starvation of cancer may be realised in future.     

山楂酸与顺铂合用对肺癌A549细胞增殖、凋亡的影响

目的探讨山楂酸与顺铂合用对肺癌细胞A549增殖及凋亡产生的影响。方法将人的肺癌细胞系A549经过药物干预(山楂酸、顺铂),并将干预后的肺癌细胞通过MTT实验,分析细胞增殖能力变化,通过流式细胞技术,分析细胞的凋亡水平变化。通过Western blot分析细胞中XIAP、Survivin的表达水平变化。结果山楂酸和顺铂合用后,A549细胞的增殖率显著降低,凋亡水平显著提高;荧光电子显微镜下观察到凋亡细胞明显增加,核碎裂明显,细胞大片脱落;Western blot结果显示,山楂酸和顺铂合用,显著下调XIAP、Survivin的蛋白表达量。结论山楂酸和顺铂合用抑制肺癌细胞的增殖,促进肺癌细胞的凋亡,并下调细胞中凋亡抑制相关指标XIAP、Survivin的表达水平。     

姜黄素对前列腺癌PC-3细胞增殖的抑制作用

目的研究姜黄素对PC-3细胞增殖活性的影响。方法以不同浓度(10、20、40、60、80μmol/L)的姜黄素及顺铂作用于体外培养的PC-3细胞24h,以中效浓度(40μmol/L)的姜黄素及顺铂作用于体外培养的PC-3细胞4、12、24、48、72h,后用MTT法检测在不同浓度及时间作用下PC-3细胞的抑制率,应用流式细胞仪检测PC-3细胞周期的变化。结果姜黄素对PC-3细胞的增殖抑制作用与顺铂相似(P>0.05),具有剂量时间依赖性,并随着药物浓度及时间的增加,抑制率逐渐增高,流式细胞仪检测显示:姜黄素和顺铂组都能使PC-3细胞生长明显阻滞于G2/M期,两组比较差异无统计学意义(P>0.05)。各实验组与空白对照组比较均有显著性差异(P<0.05)。结论姜黄素可以明显抑制PC-3细胞的增殖,在临床治疗前列腺癌方面有着良好的应用前景。     

Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated.The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide ± celecoxib following different incubation schedules were analyzed.We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions.Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase.These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule.     

液相微萃取／后萃取-高效液相色谱法测定厚朴及其制剂中厚朴酚与和厚朴酚的含量

本文采用液相微萃取／后萃取（LPME／BE）与高效液相色谱联用法萃取并测定了中药厚朴及其制剂-藿香正气口服液和香砂养胃丸中厚朴酚与和厚朴酚的含量。优化了萃取效率影响因素，萃取溶剂、供相与接受相、转速及萃取时间。厚朴酚与和厚朴酚的线性范围分别为1．56—156μg/mL和1．10—110μg／mL；检测限（S／N=3）分别为0．10ug/mL和0.07μg/mL，回收率范围为98.3％-105．1％，RSD〈2．5％。