骨肉瘤化疗耐药的研究进展

0引言 骨肉瘤为临床最常见的原发恶性骨肿瘤,好发于青少年.目前的治疗是新辅助化疗保护下的保肢治疗,因此化疗的敏感性对其预后有着重要的影响,而耐药是临床化疗失败常见的原因.     

骨肉瘤化疗耐药分子机制的相关研究进展

骨肉瘤是最常见的骨原发性恶性肿瘤之一,好发于儿童及青少年。术前和术后化疗结合手术治疗是目前骨肉瘤的主要治疗方法。但肿瘤多药耐药是骨肉瘤发生局部复发、远处转移及治疗失败的重要原因。明确骨肉瘤化疗的耐药机制,逆转骨肉瘤耐药,降低骨肉瘤患者复发转移率对临床治疗有重要意义。本文将对骨肉瘤化疗耐药作一综述。     

MiRNA靶向调控骨肉瘤耐药机制的研究进展

摘 要：MicroRNAs (miRNAs)是一类长度为22～25个核苷酸的非编码小分子RNA,具有高度的保守性、时序性和特异性。MiRNAs参与调节多种生物活动和病理过程,包括肿瘤的形成和发展。骨肉瘤是一种具有很强转移性及侵袭性的恶性肿瘤,目前骨肉瘤的治疗仍以手术及化疗为主,然而肿瘤细胞对化疗药物的耐药性是骨肉瘤治疗及预后所面临的主要问题。近年来,研究发现miRNA可调控肿瘤细胞的多种位置靶点基因,降低甚至逆转肿瘤细胞对化疗药物的抗性,对miRNA的研究可能成为改变骨肉瘤耐药机制新的治疗方向。该文对miRNA调控骨肉瘤的耐药机制作一综述。     

骨肉瘤化疗耐药与自噬的研究进展

骨肉瘤是起源于间叶组织的恶性肿瘤,多发生于儿童和青少年,是最常见的原发于骨的恶性肿瘤,好发于股骨远端和胫骨近端.单纯依靠手术治疗效果差,容易复发和转移.化疗和手术的结合是骨肉瘤的重要治疗手段,而多药耐药的发生是导致骨肉瘤化疗失败的主要原因之一.自噬对化疗耐药的影响主要认为其是骨肿瘤细胞逃避凋亡的一种重要机制,抑制自噬则可以显著提高肿瘤细胞对化疗药物的敏感性.本文主要探讨骨肉瘤化疗耐药与自噬相关因子的关系、相关机制和最新研究.     

microRNAs与ABC转运蛋白介导的肿瘤多药耐药研究进展

目的回顾ABC转运蛋白与肿瘤耐药的研究现状,探讨miRNA在逆转肿瘤耐药过程中的作用机制。方法应用PubMed和CNKI期刊全文数据库检索系统,检索2010-01-01-2014-05-20的相关文献,以"ABC转运蛋白、miRNA和多药耐药"为关键词。纳入标准:1)ABC转运蛋白的表达水平与肿瘤耐药;2)miRNA对ABC转运蛋白表达水平的调控;3)miRNA对肿瘤细胞药物敏感性的影响,根据纳入标准符合分析的文献34篇。结果大多数癌症患者使用一种化疗药物治疗后,肿瘤细胞可能因为种种原因,不仅对该药产生耐药,而且对多种结构不同和作用机制完全不同的其他药物也产生交叉耐药。研究表明,在多药耐药导致肿瘤化疗失败的众多原因中,ABC转运蛋白过表达是导致肿瘤多药耐药的主要原因之一。在耐药肿瘤细胞当中高表达的ABC转运蛋白主要有乳腺癌耐药蛋白ABCG2,多药耐药相关蛋白ABCC1,P-糖蛋白ABCB1,这些蛋白采用ATP水解的能量将细胞内药物泵出细胞外,从而降低细胞内药物的浓度,使细胞产生耐药性。miRNA能与ABC转运蛋白mRNA的3′UTR结合,使mRNA降解或抑制其翻译,导致目标蛋白的表达受到抑制,从而增加肿瘤细胞的药物敏感性,逆转由ABC转运蛋白过表达引起的肿瘤多药耐药。结论 miRNA可以逆转由ABC转运蛋白家族高表达所引起的肿瘤耐药,这为肿瘤多药耐药的研究提供了新的思路。     

环状RNA-微小RNA轴在骨肉瘤化疗耐药中的研究进展

环状RNA(circRNA)是一种具有稳定、保守、表达特异等特性的内源性共价闭合RNA,可作为微小RNA(miRNA)的分子海绵,影响下游靶基因的表达,从而调控疾病的发生和发展.在骨肉瘤耐药细胞中一些特定的circRNA出现异常表达,并可通过circRNA-miRNA轴进一步调控骨肉瘤的发生发展及转移、耐药等过程.鉴于circRNA-miRNA轴与骨肉瘤化疗耐药机制的紧密关系,有望作为抗肿瘤耐药的靶标,这在临床治疗中具有重要的研究价值.本文对近几年circRNA-miRNA轴在骨肉瘤化疗耐药中的研究进展进行综述.     

中医药逆转大肠癌耐药的实验研究进展

0引言 在世界范围内,大肠癌的发病率男女均处于恶性肿瘤的第3位,在我国,大肠癌的发病率亦呈上升态势,居恶性肿瘤的第4位[1].虽然目前该病仍以手术治疗为主,但术后5年生存率却一直停留在50%左右[2].对于手术后及失去手术机会或术后复发的肠癌,化疗是重要的治疗手段.但在化疗药物不断更新的今天,疗效仍不理想.     

恶性卵巢肿瘤化疗耐药机制及逆转的研究进展

恶性卵巢肿瘤是妇科恶性肿瘤患者死亡的主要原因之一 ,当今恶性卵巢肿瘤治疗中 ,化学治疗是重要手段之一 ,然而长期困扰临床医生的是恶性卵巢肿瘤耐药细胞的出现。恶性卵巢肿瘤细胞对抗肿瘤药物的内在性和获得性多药耐药 (multidrugresistance,MDR)是导致化疗失败的重要原因。多药耐药指肿瘤细胞不仅对一种化疗药物耐药 ,而且对结构和作用机制不同的其他药物也同时产生耐药。研究恶性卵巢肿瘤细胞的耐药机制、寻找克服耐药增敏的有效途径具有重要临床意义。近年来 ,对恶性卵巢肿瘤患者化疗敏感基因和耐药基因 (drug sensitivegeneanddrug …     

影响ⅡB期骨肉瘤术前化疗疗效的多因素分析

目的探讨和分析相关因素在影响骨肉瘤术前化疗疗效中的意义。方法分析40例骨肉瘤患者的性别、年龄、部位、病程、肿瘤体积、AKP和LDH、化疗前骨肉瘤Pgp表达、化疗方案、化疗后白细胞和淋巴细胞最低值以及X线类型等因素的特点,行多因素Logistic回归分析上述因素对TCNR的影响。结果40例中24例的TCNR＞90%（60%）;通过单因素分析及多因素非条件Logistic回归分析发现肿瘤体积、化疗后AKP、白细胞最低值及化疗方案与TCNR有相关性（P=0.020,P=0.024,P=0.034,P=0.034）,并得出了相关回归方程。结论肿瘤体积、化疗后AKP、化疗后白细胞最低值和化疗方案是影响骨肉瘤术前化疗疗效的最主要因素。肿瘤体积大及化疗后AKP水平高是术前化疗疗效差的危险因素;化疗后白细胞下降的程度可以间接反映术前化疗疗效;DIA方案的疗效优于MMIA方案。     

Ezrin蛋白在骨肉瘤中的表达及其意义

目的：探讨Ezrin蛋白在化疗前、后骨肉瘤组织中的表达及其与骨肉瘤临床病理特征的关系。方法:通过免疫组织化学方法检测51例化疗前、后骨肉瘤组织、11例骨样骨瘤和7例骨母细胞瘤及8例反应性新生骨组织中Ezrin蛋白的表达, 并结合临床资料进行相关分析。结果:Ezrin蛋白在反应性新生骨病例中缺乏表达,在骨样骨瘤、骨母细胞瘤及骨肉瘤中阳性表达率分别为9.09%、14.29%、56.86%。 骨肉瘤组织中Ezrin蛋白的阳性表达率明显高于骨样骨瘤、骨母细胞瘤及反应性新生骨组织,差异具有统计学意义(P<0.005); 化疗后骨肉瘤Ezrin蛋白表达降低或消失（P=0.015）,其表达与肿瘤坏死率不存在相关性;化疗后 Ezrin蛋白阳性表达率在骨肉瘤肺转移组明显高于无肺转移组（P=0.029）。2年内死亡患者Ezrin蛋白阳性表达率明显高于存活2年以上者（P=0.028）。结论:Ezrin蛋白在骨肉瘤中的表达明显高于骨良性肿瘤,可能成为良、恶性成骨肿瘤鉴别诊断有益的辅助指标。Ezrin蛋白与骨肉瘤患者转移及预后密切相关。化疗可降低骨肉瘤组织中Ezrin蛋白的表达,可在一定程度上反映术前化疗的疗效。     

骨肉瘤新辅助化疗,保肢手术疗效分析

报告骨肉瘤新辅助化疗，保肢手术的初步成绩。收治５６例四肢骨肉瘤。其中３５例接受了不同的化疗方案，在此基础上，２２例接受了肿瘤广泛边缘切除，假体置换手术。结果显示：化疗组的３年和５年生存率分别达５４％和４０％，优于非化疗组；新辅助化疗疗效优于辅助化疗；保肢术和根治性手术比较，生存率无明显差别。作者认为：在有效新辅助化疗基础上保肢手术是四肢骨肉瘤较为理想的治疗方法。     

PSC833逆转人骨肉瘤细胞系多药耐药性的研究

目的 探讨PSC833对骨肉瘤耐药细胞系U2OS/DOX和SaOS/DOX的逆转作用及其机制。方法 用MTT法和细胞计数法测定PSC833逆转MDR的活性;用流式细胞仪观察PSC833对细胞内Rh123积聚和外排的影响;用免疫荧光技术定量检测逆转剂对P-gp表达水平的影响。结果 PSC833对DOX敏感系U2OS和SaOS无明显作用。PSC833能显著增加DOX对U2OS/DOX和SaOS/DOX的细胞毒性作用,逆转效果明显强于VPL和CSA,且存在剂量依赖关系。PSC833能减少耐药细胞系内Rh123的外排,增加Rh123的积聚,而对P-gp的表达水平没有明显影响。结论 PSC833能逆转U2OS/DOX和SaOS/DOX的MDR,其效果明显优于VPL和CSA,逆转机理在于抑制耐药系细胞膜上P-gp的功能,而对P-gp的表达水平没有影响。     

骨肉瘤软组织肿块骨化程度与患者临床病理特征的相关性

目的 探讨骨肉瘤软组织肿块骨化程度与患者临床病理特征的相关性.方法 回顾性分析有软组织肿块的普通型骨肉瘤患者临床资料,包括Enneking分期、化疗敏感度、总生存期和转移出现后的生存时间.影像学评估软组织肿块内成骨情况,病理形态学上评估骨样基质占比.结果 本研究共纳入符合要求的189例患者.Enneking ⅢB期患者...     

Predictors of Chemotherapy Induced Adverse Events in Pediatric Osteosarcoma Patients

Objective: To investigate the prevalence of chemotherapy-induced adverse events and the associated risk factors in pediatric patients with osteosarcoma. Methods: This retrospective cross-sectional study enrolled 90 pediatric osteosarcoma patients (with 1,017 chemotherapy cycles) treated at Srinagarind Medical Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, between January 1, 2008 and December 31, 2018. The prevalence of major adverse events and a correlation between baseline characteristics and adverse events were analyzed using a generalized estimating equation model. Result: The prevalence of adverse events in 90 pediatric osteosarcoma patients (with 1,017 chemotherapy cycles) was determined as chemotherapy-induced nausea and vomiting (29.2%; n=296), hepatotoxicity (21.2%; n=215), anemia (70.69%; n=719), neutropenia (26.65%; n=271), and thrombocytopenia (13.65%; n=139). Factors associated with chemotherapy-induced hepatotoxicity included methotrexate dose ≥ 12 g/m2 (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.22–1.39; P<0.001), plasma concentration of methotrexate at 72 hours >0.1 μM (OR 1.22; 95% CI 1.19–1.25; P<0.001), and pre-hydration rate ≤ 125 mL/m2/h (OR 1.10; 95% CI 1.07–1.12; P<0.001). Conclusion: Major adverse events are becoming more common in pediatric osteosarcoma patients, and risk factors include larger chemotherapy doses, higher plasma methotrexate concentrations, and a slower pre-hydration rate. The outcomes of the study could aid in the better treatment of toxicity in children with osteosarcoma.     

Transmembrane Protein 166 Expression in Esophageal Squamous Cell Carcinoma in Xinjiang,China

Objective: Transmembrane protein 166 (TMEM166) expression in esophageal squamous cell carcinoma(ESCC) and remote normal esophageal tissues was examined to assess any role in tumour biology. Methods:TMEM166 mRNA expression in 36 cases with ESCC (36 tumour samples, 36 remote normal esophageal tissuesamples) was detected by RT-PCR. TMEM166 protein expression was analysed in paraffin-embedded tissuesamples from the same cases by immunohistochemistry. Results: Semi-quantitative analysis showed TMEM166mRNA expression in ESCCs to be significantly lower than in remote normal esophageal tissues (0.759±0.713 vs.2.622±1.690, P=0.014). TMEM166 protein expression was also significantly reduced (69.4% vs. 94.4%, P<0.01).Conclusion: TMEM166 mRNA and protein expression demonstrated significant reduction in ESCCs comparedwith remote esophageal tissues, albeit with no correlation with tumour size, differentiation, stage, and lymphnode metastasis, suggesting a role in regulating autophagic and apoptotic processes in the ESCC.     

High Expression of Lung Resistance Protein mRNA at Diagnosis Predicts Poor Early Response to Induction Chemotherapy in Childhood Acute Lymphoblastic Leukemia

Background: Treatment failure in leukemia is due to either pharmacokinetic resistance or cell resistanceto drugs. Materials and Methods: Gene expression of multiple drug resistance protein (MDR-1), multidrugresistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7healthy controls by real time PCR. The expression was scored as negative, weak, moderate and strong. Results:The male female ratio of cases was 2.75:1 and the mean age was 5.2 years. Some 26/45 (58%) were in standardrisk, 17/45(38%) intermediate and 2/45 (4%) in high risk categorie, 42/45 (93%) being B-ALL and recurrenttranslocations being noted in 5/45 (11.0%). Rapid early response (RER) at day 14 was seen in 37/45 (82.3%)and slow early response (SER) in 8/45 (17.7%) cases. Positive expression of MDR-1, LRP and MRP was notedin 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15(53.3%) cases respectively. Dual or more gene positivity was noted in 17/45 (38%) cases. 46.5 % (7/15) of LRPpositive cases at day 14 were in RER as compared to 100% (30/30) of LRP negative cases (p<0.05). All 8 (100%)LRP positive cases in SER had strong LRP expression (p=<0.05). Moreover, only 53.3% of LRP positive caseswere in haematological remission at day 30 as compared to 100% of LRP negative cases (p=<0.05). Conclusions:Our study indicated that increased LRP expression at diagnosis in pediatric ALL predicts poor response to earlytreatment and hence can be used as a prognostic marker. However, larger prospective studies with longer followup are needed, to understand the clinical relevance of drug resistance proteins.     

Role of ABC transporters in cancer chemotherapy

Multidrug resistance(MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality.The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette(ABC) transporters,which can increase efflux of drugs from cancer cells,thereby decreasing intracellular drug concentration.Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs.This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.     

Snail及N-cadherin蛋白在骨肉瘤中的表达及其与预后的关系

目的观察Snail及N-cadherin蛋白在骨肉瘤中的表达,探讨其在骨肉瘤发生发展、浸润转移的作用及其与预后的关系。方法采用免疫组织化学SP法检测38例骨肉瘤组织、20例骨软骨瘤组织中Snail及N-cadherin蛋白的表达。结果(1)Snail、N-cadherin蛋白在骨肉瘤中表达均高于它们在骨软骨瘤组织中的表达,其差异有统计学意义(χ²=27.375,P<0.01;χ²=21.849,P<0.01);(2)Snail和N-cadherin蛋白与骨肉瘤的软组织浸润、Ennecking分期、肺转移有关(P<0.05), 而与性别、年龄、部位、Dahlin类型无关(P>0.05);Snail、N-cadherin蛋白在骨肉瘤中的表达呈正相关(r=0.421,P<0.05);(3)骨肉瘤中Snail、N-cadherin蛋白阳性患者生存率均明显低于阴性患者,其差异均有统计学意义(P<0.05)。结论骨肉瘤组织中Snail蛋白及N-cadherin蛋白的高表达,提示它对骨肉瘤的发生发展和浸润转移起重要作用并预示患者预后不良。