CD44与抗乳腺癌药物耐药性的关系

细胞黏附分子CD44抗原与乳腺癌化疗耐药密切相关.其高表达能显著增强乳腺癌侵袭能力.CD44主要通过影响细胞转化生长因子-β(TGF-β)表达来促进乳腺癌细胞对三苯氧胺产生耐药性,而对erbB-2信号通路的调节是CD44影响乳腺癌曲妥珠单抗耐药的重要方式.通过诱导多药耐药相关蛋白(MRP)2上调及对拓扑异构酶Ⅱ的抑制,CD44加强了乳腺癌对蒽环类药物的耐药.而对sur-vivn蛋白及多药耐药基因的调节增强了乳腺癌对紫杉类药物的耐药性.     

蛋白tau表达与乳腺癌紫杉类新辅助化疗敏感性的关系

目的:探讨原发性乳腺癌组织中tau蛋白的表达与乳腺癌紫杉类药物新辅助化疗敏感性的关系.方法:应用免疫组化法对113例原发性乳腺癌患者术前穿刺样本进行tau蛋白表达水平的检测,分析其与紫杉类药物化疗敏感性的关系.结果:乳腺癌组织中tau蛋白表达的阳性率为24.78%(28/113);紫杉类药物新辅助化疗后,达到病理完全缓解(pCR)的患者40例,存在残留癌的患者73例.pCR组tau蛋白阳性率为12.50%(5/40),残留癌组tau蛋白阳性率为31.51%(23/73),两者之间差异有统计学意义,χ2=5.008,P=0.025.结论:tau蛋白表达水平与乳腺癌紫杉类药物化疗敏感性呈负相关,检测tau蛋白表达状态对预测乳腺癌紫杉类药物新辅助化疗的敏感性可能具有一定的指导意义.     

紫杉类药物耐药的相关分子生物学指标

耐药是影响紫杉类药物临床疗效的重要因素.回顾与紫杉类耐药相关的分子生物学指标,并从多药耐药(MDR)机制、微管、凋亡因子、细胞周期蛋白监控、HER-2、BRCA-1、BRCA-2、紫杉醇耐药相关基因-3等方面分别加以阐述.     

紫杉类药物耐药的相关分子生物学指标

耐药是影响紫杉类药物临床疗效的重要因素。回顾与紫杉类耐药相关的分子生物学指标，并从多药耐药(MDR)机制、微管、凋亡因子、细胞周期蛋白监控、HER—2、BRCA—1、BRCA-2、紫衫醇耐药相关基因—3等方面分别加以阐述。     

晚期乳腺癌紫杉类耐药及其新型抗微管治疗

紫杉类药物原发性或继发性耐药已成为不可避免的棘手难题.伊沙匹隆对经多线治疗包括紫杉类耐药的乳腺癌患者有效.艾日布林用于治疗接受过二线以上化疗的晚期乳腺癌患者.新型抗微管药物有望成为既往接受过紫杉类药物标准化疗的晚期乳腺癌患者的有效方案.     

血小板反应蛋白1与紫杉醇耐药机制的研究

血小板反应蛋白l(TSPl)因其抗血管生成及诱导凋亡的作用而被人们广泛关注.近期研究表明,TSPl与紫杉烷类的耐药有着紧密的关系,TSPl表达下调会导致肿瘤细胞对紫杉醇的敏感性降低,而TSPl的下调可能是由一种新发现的紫杉醇耐药基因l(Txrl)介导的,这为临床解决紫杉烷类耐药问题提供了新的研究方向.     

TUBB3和MAPT预测非小细胞肺癌对紫杉类药物敏感性的研究

目的 探讨Ⅲ型β-微管蛋白（TUBB3）和微管相关蛋白tau（MAPT）在非小细胞肺癌（NSCLC）组织中的表达水平及其对紫杉类化疗药物敏感性的预测价值。 方法 收集55例未经化疗的不能手术的转移性或复发晚期NSCLC患者的肿瘤组织标本,一线治疗均采用铂类联合紫杉类双药化疗方案,2个周期后评估疗效,将完全缓解和部分缓解的患者归为敏感组,疾病稳定的患者归为次敏感组,疾病进展的患者归为耐药组。采用逆转录-聚合酶链反应检测3组TUBB3和MAPT的mRNA水平,分析NSCLC组织中TUBB3和MAPT mRNA的相关性,采用免疫组织化学法检测3组TUBB3和MAPT的蛋白表达情况。 结果 在55例NSCLC组织中,TUBB3和MAPT mRNA在3组均有不同程度的表达,且两者蛋白均定位在细胞质内。敏感组、次敏感组及耐药组的TUBB3 mRNA水平分别为0.12±0.13、0.17±0.24和0.51±0.19,MAPT mRNA水平分别为0.09±0.05、0.14±0.09和0.46±0.21,TUBB3阳性表达率分别为22.22％（4／18）、20.00％（5／20）和70.59％（12／17）,MAPT阳性表达率分别为16.67％（3／18）、25.00％（4／20）和52.94％（9／17）;耐药组的TUBB3和MAPT mRNA水平及阳性率均高于其余两组（P＜0.05）,且敏感组和次敏感组的以上差异均无统计学意义（P＞0.05）。TUBB3和MAPT的mRNA水平呈正相关（r=0.219,P=0.047）。 结论 TUBB3和MAPT的mRNA和蛋白表达与紫杉类药物的敏感性有关,高表达者提示对紫杉类药物耐药,联合检测TUBB3和MAPT可能对紫杉类药物化疗敏感性具有较好的预测价值。     

染色体不稳定性与肿瘤的研究新进展

染色体不稳定性定义为持续获得或丢失整条染色体或染色体片段,是基因组不稳定性的主要原因.多数实体瘤具有此特征性表现.染色体不稳定性与紫杉烷类药物固有耐药,与实体瘤中的获得性多重耐药和较差预后具有相关性.目前证据显示,铂类药物比如卡铂对染色体不稳定性肿瘤特异性敏感.     

卡培他滨联合长春瑞滨治疗转移性乳腺癌的临床进展

蒽环类与紫杉类药物是目前乳腺癌化疗的基石,但由于肿瘤异质性,蒽环类与紫杉类药物治疗乳腺癌取得巨大进步的同时,耐药和复发转移有着日趋增多的态势,成为乳腺癌临床治疗的新难题.目前研究发现,卡培他滨与长春瑞滨无论作为一线治疗,还是作为既往蒽环类、紫杉类药物治疗失败的乳腺癌患者的二线治疗,疗效均满意,不良反应可以耐受,是一种有效可行的治疗手段.     

ERCC1、RRM1及BRCA1在非小细胞肺癌中表达及其临床意义

化疗是肺癌治疗的主要手段,耐药是影响化疗疗效的重要因素.近年来的研究表明,肿瘤细胞DNA修复的异常及其相关基因的表达异常使肿瘤对药物产生耐药是影响药效的一个重要因素.以下对肺癌常用化疗药物铂类、吉西他滨、紫杉类药物疗效相关的分子标志如ERCC1、RRM1、BRCA1等近年来的研究进展进行综述.     

Molecular basis for the development of novel taxanes in the treatment of metastatic breast cancer

The identification of taxanes proved to be a significant advance in the treatment of breast cancer. First-generation taxanes achieved 35% to 55% response rates for women not previously treated with anthracyclines and exceeded 20% for anthracycline-resistant disease. Consequently, taxanes were established as a standard of care in metastatic disease. Subsequent research evaluated taxane monotherapy and combination therapy with other cytotoxic agents, as well as optimal dose and administration schedules to maximize efficacy while minimizing toxicities. Clinical trials suggested the optimal administration schedule and dose for paclitaxel was 80 mg/m² weekly, and this weekly schedule is commonly used. However, the solvents required for administration of first-generation taxanes are associated with significant toxicities and undermined clinical efficacy. These factors motivated development of taxane formulations that would enhance the therapeutic index and minimize toxicities. This article reviews the rationale for development of novel taxane formulations and emerging research regarding new formulations including oral taxanes, paclitaxel poliglumex, and vitamin E-based paclitaxel emulsion.     

Rationale and use of epirubicin-based therapy in the adjuvant setting

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin- cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease     

Taxanes for breast cancer: an evidence-based review of randomized phase II and phase III trials

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early-or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin-cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.     

Improving the toxicity profile of chemotherapy for advanced ovarian cancer: a potential role for CT-2103

Significant progress has been made in the management of advanced ovarian cancer. Response rates to platinum-based chemotherapy are respectable; however, recurrence continues to be the rule rather than the exception. Chemotherapy is administered as initial treatment and for disease recurrence, often over a period of many years--thus ovarian cancer is considered a chronic disease by many oncologists. The importance of the taxanes in the treatment of ovarian cancer is well established. However, taxanes are associated with numerous toxicities, resulting in the need for alternative dosing strategies that produce fewer side effects, or the discovery of novel taxanes with equivalent anti-tumor activity, but a more favorable toxicity profile. Several taxanes are in development including CT-2103, a macromolecule consisting of paclitaxel conjugated to a biodegradable, water-soluble polymer of glutamic acid. Clinical data of CT-2103 as a single agent and in combination have demonstrated activity in previously treated ovarian cancer patients, both in platinum-sensitive and platinum-resistant disease. CT-2103 appears to be potentially associated with a more favorable toxicity profile relative to paclitaxel, and enhanced solubility allows for a 10-minute infusion. Ongoing trials employing this agent will focus on extending survival, optimizing quality of life, and defining a possible role for CT-2103 in the standard management of advanced ovarian cancer.     

The role of Tau protein in resistance to paclitaxel

Resistance to taxanes, related to limited efficacy of systemic therapy in cancer patients, is multifactorial. Among mechanisms of resistance to taxanes, those related to microtubule-associated proteins (MAP), including protein Tau, are of great importance. Protein Tau (50–64 kD) binds to beta-tubulin in the same place as paclitaxel. In preclinical studies, low expression of Tau in cancer cells was associated with increased sensitivity to paclitaxel. High expression of Tau protein in ER-positive breast cancers indicates resistance to taxane-containing chemotherapy and sensitivity to hormonal treatment. This article reviews current knowledge on predictive value of protein Tau in response to taxanes. Better understanding of its role may facilitate patients selection to this sort of treatment and lead to treatment optimization.     

Anthracyclines in the management of metastatic breast cancer: state of the art

Metastatic breast cancer is a heterogeneous disease and hence it is desirable to have a variety of treatment options to meet different treatment aims in individual patients. Anthracyclines are extremely effective single agents in the treatment of metastatic breast cancer, and combination therapy with anthracycline-containing regimens significantly improves response rates and progression-free survival, compared with non-anthracycline regimens. The addition of taxanes further increases the efficacy of anthracyclines as first-line therapy. Combination therapy with trastuzumab, taxanes and anthracyclines has been shown to produce significant improvements in survival, compared with taxanes and anthracyclines alone; however, trastuzumab is associated with significant cardiotoxicity, and augments the cardiotoxicity associated with anthracycline-based regimens. New anthracycline formulations such as non-pegylated liposomal doxorubicin (NPLD) have an important role in the treatment of metastatic breast cancer. NPLD is as effective as conventional doxorubicin formulations, and can be combined with trastuzumab with acceptable toxicity. However, a number of questions remain as to how anthracycline therapy can be optimised. Ultimately, the choice of regimen will require a balance between efficacy and the impact of treatment on the patient's quality of life.     

Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer

The use of taxanes in early breast cancer is increasing. However, there are few mature studies of taxanes in this setting, and their role is uncertain. Our systematic review of randomised trials of adjuvant or neoadjuvant systemic therapy identified ten reported trials comparing a taxane-containing group with a non-taxane-containing control group in women with early breast cancer. Four of five neoadjuvant trials showed higher rates of complete response with taxanes, although differences were not significant. All five adjuvant trials showed improvements in disease-free survival with taxanes, and these improvements were significant in three trials and independent of oestrogen-receptor status. Two trials showed a significant improvement in overall survival. These results support the use of adjuvant taxanes in women with early breast cancer and involved lymph nodes. Longer follow-up of these trials and results from continuing trials are needed to clarify the best use of taxanes in early breast cancer.     

Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest

Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.     

The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells

Introduction

Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.

Methods

The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.

Results

mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-β-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.

Conclusions

Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.