乳腺癌内分泌治疗耐药相关信号通路的研究进展

内分泌治疗在乳腺癌综合治疗中占有重要的地位,但原发性与继发性耐药是当前内分泌治疗面临的难题.研究证明,雌激素受体通路与各种因子信号通路的交叉效应是导致乳腺癌内分泌耐药的主要机制之一,针对各种通路的靶向治疗药物也成为了热点.许多临床试验结果表明靶向阻断这些信号通路的药物联合内分泌治疗药物可显著提高患者的生存率.本文根据PubMed检索获取相关资料,就近年来与乳腺癌内分泌耐药相关的信号通路及治疗策略研究进展进行综述.     

乳腺癌内分泌治疗耐药机制的研究进展

内分泌治疗是雌激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗面临的难题。耐药机制主要包括:ER表达缺失或表观遗传修饰;共调因子表达失衡;雌激素受体通路与生长因子受体（growth factor receptor,GFR）通路的交叉效应;特异性miRNA表达改变;乳腺癌上皮间质转化（EMT）等。根据PubMed检索获取相关资料,就近年来雌激素受体阳性乳腺癌内分泌耐药机制及治疗策略研究进展进行综述。     

乳腺癌内分泌治疗耐药相关机制的研究进展

内分泌治疗作为雌激素受体（estrogen receptor,ER）阳性乳腺癌的主要治疗方案被广泛应用。他莫西芬（tamoxifen,Tam）是乳腺癌内分泌治疗最常用的药物,它通过与雌激素竞争性结合ERα来降低雌激素的生物学活性,抑制细胞的增殖,从而治疗乳腺癌。然而,肿瘤细胞所表现出的原发性或获得性的他莫西芬耐药使得其临床应用受到了限制,寻找克服他莫西芬耐药的治疗策略已经刻不容缓。目前为止,他莫西芬耐药的相关机制已部分明确,但仍需进一步研究。有证据表明ERα、生长因子受体信号通路及microRNA的表达异常等多种机制均与他莫西芬耐药有关。本文对他莫西芬耐药的相关机制进行了具体分析,以期为ER阳性乳腺癌的治疗提供新思路。     

乳腺癌内分泌耐药机制及治疗对策的研究进展

内分泌治疗在激素受体阳性乳腺癌患者的治疗中占重要地位,但耐药的产生为内分泌治疗增加了难度。近年来,内分泌耐药发生的机制是研究的热点问题,已有研究证实内分泌耐药的发生与生长因子受体、磷脂酰肌醇3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白信号通路、细胞周期蛋白依赖性激酶及组蛋白去乙酰化酶有关。目前,针对耐药相关信号通路中的各个分子靶点已经研发了众多的靶向药物。本文将针对内分泌耐药的不同机制以及逆转耐药的治疗进行综述。     

MAPK信号通路在ER阴性的乳腺癌ER再表达中的作用及其研究进展

雌激素受体（ER）的表达情况与乳腺癌的治疗和预后十分相关。雌激素受体阳性的患者应用内分泌治疗的有效率为50%-60%,而阴性者有效率低于10%。临床上,有30%-40%乳腺癌是雌激素受体阴性的。雌激素受体阴性的乳腺癌患者往往对内分泌治疗耐药,且手术复发率高。是否可以让ER再表达,使其对内分泌治疗有效从而提高乳腺癌患者的生存率成为了最近研究的热点。促分裂原活化蛋白激酶（MAPK）信号通路在细胞的生长和分化等过程中起重要作用,在许多癌症的发生、发展过程中也起关键作用。研究表明：在乳腺癌中,MAPK信号通路中的各个元件以及其上游的调控分子的表达上调,通常伴随的是ER的表达下调。使用MAPK通路中信号元件的抑制剂后,可以让ER阴性的乳腺癌细胞在转录和蛋白水平再表达出ER,并且再次表达的ER可以参与细胞的生长调控,从而对内分泌治疗敏感。这表明ER在乳腺癌细胞内的表达是可逆的,是动态的。同时这也给我们的临床治疗ER阴性的乳腺癌患者提供了一个新的治疗理念。     

PI3K/AKT/mTOR信号通路介导乳腺癌内分泌治疗耐药的研究进展

内分泌治疗在激素受体阳性乳腺癌患者中的地位越来越受到重视,可以明显改善患者预后.内分泌治疗耐药严重制约着其临床应用,但耐药机制仍不明确,目前认为多信号通路激活参与耐药形成,其中PI3K/AKT/mTOR信号通路在耐药机制中发挥重要作用.临床试验提示,在内分泌治疗的基础上阻断信号通路可以逆转耐药,研究结果令人鼓舞.本文对PI3K/AKT/mTOR信号通路在内分泌耐药机制中的作用进行综述.     

生长因子信号通路与乳腺癌内分泌耐药的研究进展

肿瘤细胞对内分泌治疗的主要药物他莫昔芬耐药已成为乳腺癌治疗中的一个严重问题。大量研究结果显示,生长因子及其下游的Ras-Raf-Mek-MAPK和PI3K-Akt通路过度表达与乳腺癌内分泌治疗耐药密切相关。15%~30%的乳腺癌患者HER-2基因通过点突变扩增或过表达,与乳腺癌对各种治疗产生抗性和预后不良密切相关。生长因子可通过基因组和非基因组机制使乳腺癌细胞对雌激素的敏感性增加,极低的雌激素水平也可刺激乳腺癌细胞的增殖。雌激素消除后获得性耐药的高敏状态的共同特征是ERα表达增强、MAPK和PI3K信号活性增强。生长因子信号途径的过表达也可下调ERα的表达和功能,致使乳腺癌细胞对雌激素的非依赖性和对抗雌激素治疗的耐药。因此,靶向生长因子家族及其下游的信号传导通路关键酶类的药物,可以有效地杀灭内分泌耐药的肿瘤细胞。体外研究已发现,吉非替尼可以延迟乳腺癌细胞对雌激素消除的耐药,同时也可显著抑制对他莫昔芬耐药的乳腺癌细胞的增殖。对靶向Ras-Raf-Mek-MAPK途径的法尼基转移酶抑制剂R115777的Ⅱ期临床研究显示,其对内分泌治疗失败的乳腺癌的有效率为24%。临床前研究发现,靶向PI3K-Akt途径的CCI779可以杀灭ER 的耐药乳腺癌细胞。但由于细胞的信号传导通路是一个相互交联的复杂网络,推测联合用药和靶向多位点的药物也许具有更好的疗效。     

晚期雌激素受体阳性乳腺癌的治疗进展

针对晚期雌激素受体阳性乳腺癌虽然主要使用内分泌、靶向等治疗方法，但内分泌治疗的耐药问题在临床上较常见。随着对CDK4/6、PI3K-Akt1-mTOR通路等治疗靶点和耐药机制的研究，晚期雌激素受体阳性乳腺癌的靶向治疗已成为研究热点，利用基因靶向治疗等也可能成为新的突破点，同时在如何针对不同患者选择最佳治疗方案、最佳治疗时间等问题上仍存在挑战。本文将就晚期雌激素受体阳性乳腺癌的治疗进展进行综述。      

MicroRNA在乳腺癌内分泌耐药中的研究新进展

内分泌治疗可显著改善雌激素受体阳性的乳腺癌患者的无病生存期和总生存期,但内分泌耐药是导致治疗失败的重要原因。微小RNA（microRNA,miRNA）是肿瘤研究领域中的热点,新近研究证实miRNA的表达变化是乳腺癌耐药机制之一。miRNA通过上调药物外排转运、抗凋亡蛋白、调节多药耐药信号传导网络等方式促成上皮 间质转化并形成肿瘤干细胞。miRNA亦可能通过调节雌激素受体α表达、受体酪氨酸激酶信号传导、细胞生存信号及细胞凋亡等途径引发耐药。miRNA可能成为激素受体阳性乳腺癌的预后因子、内分泌治疗疗效评估的预测因子以及新的靶点。     

乳腺癌内分泌耐药的临床研究进展

内分泌治疗是激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗的难题.雌激素受体通路与其他受体通路的交互效应是耐药机制之一.抑制磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)、表皮生长因子受体(EGFR)等分子通路逆转内分泌耐药的临床研究已取得一定的成果.     

光动力疗法联合相关治疗研究进展

目的:总结可增强光动力疗法(PDT)抗肿瘤免疫效应的相关治疗研究进展.方法:应用PubMed和CNKI数据库,以“光动力疗法、肿瘤、免疫疗法、靶向光敏剂、肿瘤疫苗和免疫抑制”等为关键词,检索2000-01—2011-08的相关文献.纳入标准:1)PDT联合的免疫疗法;2)靶向光敏剂;3)PDT光照剂量;4)PDT免疫抑制效应; 5)PDT肿瘤疫苗.排除重复研究与本研究无关的文献,符合分析的文献32篇.结果:PDT处理后对宿主免疫系统的影响极为复杂,既能促进抗肿瘤免疫,在某些情况下又能抑制免疫;PDT联合免疫佐剂、细胞因子或免疫细胞可有效增强PDT抗肿瘤免疫反应;疫抑制效应具有条件性,可通过制备靶向光敏剂、调节光照剂量和去除负向调节性免疫效应分子及调节性T细胞等多种途径减弱甚至去除这种生物效应;PDT处理后肿瘤细胞裂解物具有免疫刺激作用,可用作肿瘤疫苗.结论:联合免疫疗法或其他方法来增强PDT抗肿瘤免疫效应、拮抗免疫抑制效应,可显著提高PDT抗肿瘤疗效.     

High-intensity therapy versus low-intensity therapy in advanced breast cancer patients

The aim of this study was to evaluate the significance of response to the first two cycles of FEC (5-fluorouracil, 4-epirubicin, cyclophosphamide) in patients with advanced breast cancer. A total of 99 patients entered the study. They showed either high risk criteria and were previously untreated or showed low risk criteria and were pretreated by hormonal therapies. Eighty-two patients were evaluable. In 22 (27%) who had disease progression despite two cycles of FEC, further therapeutic attempts proved ineffective, the median survival being 2.8 months. The remaining patients responded either by stable disease (SD, n = 29; 35%), by partial or by complete remission (PR, CR, n = 31; 38%). These 60 patients were randomized to two regimes of maintenance therapy: FEC every 3 weeks or LMF (leukeran, methotrexate, 5-fluorouracil) every 6 weeks. The subsequent course of the disease was not different in both arms. It was neither influenced by the quality of early response, i.e. SD, PR, CR, nor by the intensity of chemotherapy. The prognostic impact of early response to two cycles of FEC proved to be higher than other prognostic parameters in the patients examined. Thus, early response may serve as a valid guide to adapt maintenance chemotherapy in individual patients with advanced breast cancer.     

多发性骨髓瘤固定周期治疗和连续治疗的研究进展

多发性骨髓瘤(MM)占血液系统恶性肿瘤的13％,常发生于老年人群.新药物和治疗方法的引入使患者的生存期显著延长,但是患者在不同治疗阶段仍会复发.有研究证实,在行自体造血干细胞移植的患者中,应用来那度胺、硼替佐米或硼替佐米联合方案巩固治疗,可提高标危或高危患者的无疾病进展生存期;在不适合移植的患者中,应用来那度胺联合地塞米松方案连续治疗的患者,比应用美法仑联合泼尼松、沙利度胺方案固定周期治疗的患者生存期长,优化治疗方案是目前合适的选择.文章对移植后及不适合移植患者的固定周期治疗和连续治疗的效果进行介绍.     

Data handling in radiation therapy in the age of image-guided radiation therapy

Image-guided radiation therapy (IGRT) in the modern sense includes large volumetric image sets and high-resolution planar images. In addition to the issue of the sheer size of the data under consideration in IGRT is the critical need for the data to be available in the necessary situation in a timely and reliable fashion. Standards exist for the format of much of the data needed to perform IGRT, but the information workflow is not "standardized" (formal or ad hoc) and details of the use of the standards are only recently being constrained to ensure interoperability. Depending on the interpretation of the scope of IGRT or the desired workflow of the IGRT system, not all of the information that needs to be exchanged between systems is yet standardized nor is the means to exchange the information. The organization of the different types of data needed for IGRT for easy navigation is addressed by commercially available products from multiple vendors; however, this is also an area in which standards and consistency in the clinical environment are catching up to the market. The critical questions a clinician needs answers to include the following: (1) What kinds of data will I need to store and communicate between the pieces of my IGRT system? (2) How much storage will I need to address the volumes of data produced? (3) How long do I need to store (and be able to access) the data? (4) How will the pieces of my IGRT system communicate the necessary information between them (what standards or technical frameworks apply and do the pieces conform or adhere to them)? (5) What are the time constraints on getting information from "where it is" to "where it needs to be"? and (6) Is my IGRT system as a whole capable of providing me with the workflow necessary for my clinical environment or, alternatively, what do the providers of my IGRT system need to do to enable my required workflow? The body of this article examines these issues in greater detail to enable clinicians and clinical support personnel to frame the questions in a practical manner and develop answers that assist in the successful deployment of IGRT.     

Adjuvant therapy in melanoma

Despite intensive research and numerous clinical trials on the adjuvant treatment of patients with high-risk cutaneous melanoma, the issue is still controversial. Early positive results from studies on adjuvant chemo- and immunotherapy were based on historical controls and could not be confirmed by prospective randomized trials. The effect of interleukin-2 in the adjuvant treatment of malignant melanoma is not yet clearly defined. Combined treatment modalities like bio-chemotherapy are still to be analyzed in controlled clinical trials, and results of new studies with active specific immunization (vaccination) will only be available within the next years. Only interferon alpha (IFN alpha) has shown reproducible superiority over observation for high-risk melanoma patients in large prospective randomized trials with respect to disease-free survival (DFS) and partially for overall survival (OS). These studies resulted in the approval of IFN alpha for the adjuvant treatment of malignant melanoma in many countries. Low-dose IFN has shown significant prolongation of DFS, but so far failed to improve OS. The question whether high-dose IFN has shown enough superiority over observation with respect to OS based on one negative and two positive trials to make it the standard therapy in stage IIb,c and stage III melanoma patients still remains unanswered. Results from intermediate-dose IFN alpha, pegylated IFN alpha, and modified high-dose interferon schedules are pending. In conclusion, interferon is the cornerstone of adjuvant therapy in high-risk melanoma today, but the optimal dosage and duration of treatment are still to be defined. Patients with high-risk malignant melanoma should preferentially be treated in prospective randomized multicenter trials to give more detailed data for treatment recommendations.     

Radiation therapy in craniopharyngiomas

Eighteen patients with cranipharyngiomas, who were studied and treated between 1970–1980, are presented. Each patient was treated with surgery and radiotherapy (50–60 Gy). Six patients were treated with radiotherapy because the tumor recurred after surgery. An extensive representation of the clinical symptomatology typical of this tumor was seen. In 3 patients an improvement in visual symptoms was demonstrated; in 11 the headaches and vomiting were controlled after treatment. The 18 treated patients are still alive without evidence of progression of the tumor, after a period of 2 to 12 years. Our experience supports the contention that conservative surgery coupled with radical radiotherapy remains the treatment of choice for the craniopharyngioma.     

肿瘤光动力疗法研究进展

光动力疗法(PDT)的治疗过程相对简单,目前仅有卟吩姆钠、盐酸氨基乙酰丙酸和间-四羟基二氢卟吩等少数几种光敏剂被批准应用于临床.激光因其单色性和高功率被认为是PDT的理想光源.PDT对表浅的小肿瘤病灶疗效高,除了轻微、短暂的皮肤光毒性外无明显的蓄积毒性.研究表明,如果选择合适的适应证,PDT可以作为治疗肿瘤的替代疗法.     

Jasmonates in cancer therapy

Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates increased the life span of EL-4 lymphoma-bearing mice, and exhibited selective cytotoxicity towards cancer cells while sparing normal blood lymphocytes, even when the latter were part of a mixed population of leukemic and normal cells drawn from the blood of chronic lymphocytic leukemia (CLL) patients. Jasmonates join a growing number of old and new cancer chemotherapeutic compounds of plant origin. Three mechanisms of action have been proposed to explain the anti-cancer activity of jasmonates. These include: (1) The bio-energetic mechanism-jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation; (2) The re-differentiation mechanism-jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity; (3) The reactive oxygen species (ROS)-mediated mechanism-jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Several similarities between the effects of jasmonates on plant and cancer cells have been recorded, suggesting that additional analysis of jasmonate effects in plant cells may contribute to a deeper understanding of the anti-cancer actions of these compounds. Those similarities include: induction of cell death, suppression of proliferation and cell cycle arrest, MAPK induction, ROS generation, and enhancement of heat-shock proteins (HSP) expression. Finally, jasmonates can induce death in drug-resistant cells. The drug resistance was conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonate family of novel anti-cancer agents presents new hope for the development of cancer therapeutics, which should attract further scientific and pharmaceutical interest.     

Supportive therapy in neuro-oncology

Patients with cerebral neoplasms often report pain or other kinds of symptoms which, even though not directly connected to the disease itself, can cause complications in the approach to therapy and worsen the quality of life of the patients. The therapies aimed at controlling these kinds of disturbances are referred to as supportive therapies as they do not cure the underlying disease. However, these therapies should not be underestimated, because, by controlling these disturbances, they are able not only to greatly improve the quality of life of the neuro-oncologic patients but also increase their survival. Based on this hypothesis, we will discuss and examine the drugs more frequently used for supportive therapy in neuro-oncologic patients. We assert, in fact, that the desire to offer neuro-oncologic patients better assistance guarantees not only adequate specialized input from the health operators involved, concerning the quality of life and the uniqueness of the 'person-patient', but also the ability to be able to listen to the patients, understand their choices and allow them to express their priorities.