CCND1表达沉默促进胶质母细胞瘤细胞株对替莫唑胺的敏感性

目的 利用已构建的CCND1表达沉默及过表达的人源性胶质母细胞瘤细胞株SHG-44,筛选能够与CCND1协同抑制胶质母细胞瘤细胞增殖的化学治疗药物.方法 用蛋白质印迹法检测CCND1表达沉默及过表达的人源性胶质母细胞瘤细胞株SHG-44中多药耐药基因MDR1的表达产物P-糖蛋白(P-gp)及凋亡因子Bcl-2、Caspase-3的表达.使用卡莫司汀(BCNU)、洛莫司汀(CCNU)、替莫唑胺(TMZ)3种化学治疗药物分别处理CCND1过表达或表达沉默的SHG-44细胞,筛选能够与CCND1表达沉默协同抑制肿瘤细胞生长的化学治疗药物,并在人源性胶质母细胞瘤细胞株系U251中进一步验证.结果 蛋白质印迹结果示CCND1表达沉默能够下调P-gp、Bcl-2的表达,上调Caspase-3的表达(P均＜0.01).BCNU (0.05、0.25 μg/mL)、CCNU(20、80 μg/mL)处理CCND1过表达或表达沉默的SHG-44细胞的第2、3、4、5天时,细胞生长曲线的差异均无统计学意义;而在药物处理后细胞培养的第4、5天,CCND1表达沉默SHG-44细胞的生长受到TMZ(9.1μg/mL)的抑制作用较亲代SHG-44细胞强(P＜0.05).U251细胞实验证实CCND1表达沉默促进TMZ的化学治疗敏感性.结论 CCND1表达沉默联合TMZ较两者单独作用能更有效地抑制人源性胶质母细胞瘤细胞株SHG-44的增殖,提示CCND1可能参与TMZ化学治疗耐药机制.     

贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤的疗效分析

目的:评价贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤的疗效及不良事件。方法:回顾性分析20例接受过贝伐珠单抗联合替莫唑胺剂量密度方案治疗的复发胶质瘤患者的临床资料并进行生存随访。依据RANO标准评价客观疗效，应用Kaplan-Meier 法进行生存分析，不良事件评价依据CTCAE 4.0版标准。结果:20例复发胶质瘤患者的临床获益率和客观反映率可达到85%和60%，中位PFS和中位OS分别为3个月（1.5~11个月）和6.5个月（3~15个月）。主要不良事件为高血压。结论:贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤安全有效，且耐受性良好。     

恶性脑胶质瘤术后两种同步放化疗的疗效对比

目的比较两种同步放化疗方案在恶性脑胶质瘤术后中的临床疗效。方法选取2016年1月-2017年12月我院行手术治疗的94例恶性胶质瘤患者,按随机数字表法分为A组(47例)和B组(47例),A组予以三维适行放疗与司莫司汀化疗,B组予以三维适行放疗与替莫唑胺化疗,比较不同组患者近期缓解率、远期生存率和不良反应等情况。结果B组患者近期缓解率较A组升高(P<0.05);B组治疗6个月时生存率比较差异无统计学意义(P>0.05),治疗1年时B组患者生存率较A组患者提高(P<0.05);B组患者治疗期间乏力、肾毒性、消化系统和骨髓抑制等不良反应发生率均明显低于A组(P<0.05)。结论与三维适行放疗与司莫司汀化疗相比,三维适行放疗与替莫唑胺化疗更有助于提高恶性胶质瘤术后患者近远期疗效以及减少不良反应发生率。     

3-O-Acetyl-11-keto-β-boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma

Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%–15% of all brain tumors. 3-O-Acetyl-11-keto-β-boswellic acid (AKBA), one of the most active ingredients of gum resin from Boswellia carteri Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.     

Pharmacokinetics,safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

BackgroundThe poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.MethodsPreclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.ResultsOlaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m² daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.ConclusionOlaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.     

影响术后接受替莫唑胺联合放疗治疗的脑胶质瘤患者的预后风险因素分析

目的替莫唑胺同步放疗可以显著提高术后脑胶质瘤患者的生存期,改善患者生存质量。本研究旨在探索影响术后接受替莫唑胺联合放疗治疗的脑胶质瘤患者的预后风险因素。方法本研究从2010年1月至2018年6月回顾性收集175例手术切除后接受替莫唑胺联合放疗辅助治疗的脑胶质瘤患者。收集患者资料及治疗情况病例记录,后期随访患者的预后生存情况。分析入组患者的无进展生存期(PFS)和总生存期(OS)数据。构建Cox多变量模型分析影响患者OS的风险因素。结果纳入研究的175例患者均可评估预后,175例患者的中位PFS为6.4个月(95%CI:5.62~7.18),中位OS为13.6个月(95%CI:11.08~16.12)。Cox模型当中对OS具有独立影响意义的变量为年龄(OR=1.45,P=0.025),ECOG评分(OR=1.77,P=0.011),WHO分级(OR=2.11,P=0.003)和手术范围(OR=1.85,P=0.009)。不良反应均为1~2级,未发现3级以上不良反应。结论替莫唑胺联合放疗的方案在术后脑胶质瘤患者中具有相应的疗效及安全性。患者的年龄、ECOG评分、WHO分级和手术切除程度是影响患者预后的风险因素。