替莫唑胺在胶质母细胞瘤化疗中的自噬作用研究进展

原发性恶性脑肿瘤相对少见,然而却是最致命的癌症之一.胶质母细胞瘤是最常见的恶性胶质瘤,预后最差,对促凋亡的化疗抵抗.目前广泛使用的化疗药替莫唑胺(TMZ)对抵抗促凋亡化疗的胶质母细胞瘤患者有确实的治疗效果,延长了患者的生存时间,主要是通过自噬这种肿瘤抑制机制实现的.本文就国内外对TMZ在胶质母细胞瘤化疗中的自噬作用研究进展综述如下.     

P57对U87胶质母细胞瘤细胞系增殖的抑制作用及对替莫唑胺化疗损伤的抵抗作用

目的 探讨替莫唑胺(TMZ)短期化疗下P57在胶质母细胞瘤细胞增殖抑制中的作用和机制. 方法 通过Western blotting检测P57和核增殖抗原(Ki-67)在TMZ短期化疗后U87细胞中的表达情况;通过Western blotting和免疫组化染色比较原发性和复发性(经TMZ治疗)胶质母细胞瘤临床标本中P57的表达差异;通过干扰P57的表达,检测TMZ短期化疗下和撤药后U87细胞凋亡、细胞周期和细胞活力的变化. 结果 TMZ短期化疗后,U87细胞中P57蛋白表达量明显升高,而Ki-67表达量明显下降;胶质母细胞瘤临床标本中复发性肿瘤的P57表达量高于原发性肿瘤;干扰P57表达后周期素依赖性激酶2(Cdk2)的表达量增加,表现为TMZ对U87细胞的增殖抑制作用减弱,但细胞凋亡率明显升高(未干扰细胞凋亡率为12.83％±1.40％,干扰组细胞凋亡率为31.00％±3.48％);此外,撤药后,与对照组相比,P57干扰组U87细胞发生明显细胞周期阻滞和细胞活力下降. 结论 TMZ短期化疗下,U87细胞通过上调P57表达及下调Cdk2表达抑制肿瘤细胞增殖,同时通过抑制细胞周期进程以降低化疗损伤.     

精确放疗同步替莫唑胺治疗胶质母细胞瘤疗效初探

目的 探讨精确放疗同步替莫唑胺化疗对多形性胶质母细胞瘤的临床疗效.方法 回顾性分析2009年7月至2010年12月北京世纪坛医院收治的54例多形性胶质母细胞瘤,术后接受精确放疗(三维适形或调强放疗)同步替莫唑胺化疗,随后接受替莫唑胺辅助化疗.结果 全组共21例死亡,均死于肿瘤复发.全组1年总生存率为79.6％,1年无进展生存率为48.7％.32例出现复发,其中原位复发为16例.卡氏评分(KPS≥70分)组1年总生存率显著高于卡氏评分(KPS＜ 70分)组(86.8％与50.8％,P=0.005).全切或近全切除组1年总生存率高于部分切除组(84.4％与70.5％,P=0.067).仅2例出现3度以上不良反应(骨髓抑制).结论 精确放疗同步替莫唑胺化疗是多形性胶质母细胞瘤安全有效的治疗模式,卡氏评分和手术切除肿瘤的程度是影响生存的重要因素.     

替莫唑胺治疗胶质母细胞瘤的长期疗效评价

目的 以卡莫司汀(BCNU)为对照,观察替莫唑胺(TMZ)对胶质母细胞瘤化疗的疗效,并探讨O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)的表达对胶质母细胞瘤预后的影响. 方法 天津市环湖医院神经外科自2004年1月至2009年1月使用化疗药物治疗胶质母细胞瘤患者283例,其中应用TMZ 97例(TMZ组),BCNU 186例(BCNU组),免疫组织化学染色检测手术切除的肿瘤组织中MGMT的表达,对患者进行随访并比较2组患者的生存率、客观有效率和并发症的发生. 结果 TMZ组患者累积生存率高于BCNU组,差异有统计学意义(x2=27.944,P=0.000);TMZ组、BCNU组患者的客观有效率分别是75.26％(73/97)和45.16％(84/186),差异有统计学意义(x2=24.753,P=0.000);与BCNU组比较,TMZ组白细胞减少症的发生率较低,差异有统计学意义(x2=15.681,P=0.000). 结论 TMZ治疗胶质母细胞瘤疗效较BCNU显著,副作用小,耐受性好,是一种理想的胶质母细胞瘤术后化疗药物.     

肿瘤治疗电场联合替莫唑胺化疗与单独使用替莫唑胺化疗对胶质母细胞瘤临床疗效比较的Meta分析

目的 探讨单独使用替莫唑胺（TMZ）与替莫唑胺联合肿瘤治疗电场（TTF）治疗胶质母细胞瘤安全性和疗效的比较。方法 检索Pubmed、Cochrance、Embase、Ovid、Scopus、Web of Science、中国知网、万方数据知识服务平台、维普中文期刊数据库、中国生物医学文献服务系统数据库、谷歌学术自建库至2020年4月5日的文献,筛选TMZ和TTF+TMZ进行疗效比较的随机对照研究,按照纳入和排除标准,把总体生存率（OS）和无进展生存期（PFS）作为结局指标,最后使用Review Manager进行统计分析。结果 最终纳入4篇研究,共1091例患者,其中单纯TMZ组381例,TTF+TMZ组710例。TTF+TMZ组的平均OS （26.9个月）和平均PFS （14.7个月）,优于单纯TMZ组的平均OS （12.63个月）和平均PFS （5个月）（P<0.01）。结论 TTF+TMZ治疗GBM的有效性优于单纯使用TMZ的患者。     

转录因子FOXC1影响胶质母细胞瘤对替莫唑胺的化疗耐药性

目的 探讨转录因子FOXC1对胶质母细胞瘤(GBM)患者替莫唑胺(TMZ)化疗耐药性的影响.方法 收集30例GBM患者的原发GBM组织(初次手术切除)、复发GBM组织(患者初次手术后经标准TMZ化疗方案治疗后复发并再次手术),分别采用qPCR实验、Western Blot实验对比30例GBM患者原发GBM组织与复发GB...     

C1QBP调节线粒体功能介导胶质母细胞瘤对替莫唑胺耐受作用研究

目的 探讨C1QBP通过调节线粒体功能介导胶质母细胞瘤(GBM)对替莫唑胺(TMZ)的耐受作用。方法 采用MTT法检测GBM细胞系U251及耐受TMZ细胞系U251(U251/TMZ)半抑制指数,采用免疫荧光实验、Western Blot检测U251及U251/TMZ中C1QBP的表达水平,C1QBP过表达转染构建U251/TMZ+OE-C1QBP组,实时荧光定量PCR(qRT-PCR)检测各组C1QBP的mRNA表达水平,MTT法检测U251/TMZ+OE-C1QBP组半抑制指数,流式检测仪检测各组细胞凋亡水平,荧光显微镜下观察线粒体膜电位变化情况。结果 相比较U251细胞系,U251/TMZ细胞系的半抑制指数以及C1QBP的蛋白表达水平要更高,而转染后的U251/TMZ+OE-C1QBP细胞系的半抑制指数最高,U251、U251/TMZ、U251/TMZ+OE-C1QBP三组细胞系中C1QBP的mRNA表达水平依次增高,细胞凋亡水平依次降低,同时线粒体膜电位表达越来越强。结论 C1QBP的表达水平与GBM对TMZ的耐药性有关,随着C1QBP表达水平的增高,线粒体膜电位即功能增强,同...     

TNP-470联合化疗抑制胶质母细胞瘤的实验研究

目的 探讨TNP-470联合化疗药物卡氮芥(BCNU)对人U-251胶质母细胞瘤细胞裸鼠皮下移植瘤生长的作用.方法 将人U-251胶质母细胞瘤细胞株注射至裸鼠皮下,第7天荷瘤裸鼠随机分为4组:TNP-470治疗组、BCNU治疗组、TNP-470和BCNU联合治疗组、对照组.测体质量及肿瘤大小,以山羊抗小鼠CD105多克隆抗体免疫组化染色计数肿瘤微血管密度(MVD).结果 治疗后第21天联合治疗组移植瘤体积[(108.93±17.63)mm3]明显小于TNP-470治疗组[(576.10±114.29)mm3]及BCNU治疗组[(473.01±48.04)mm3](P均＜0.01);各治疗组移植瘤体积均小于对照组[(1512.61±470.25)mm3](P均＜0.01);TNP-470治疗组与BCNU治疗组间移植瘤体积差异无统计学意义(P＞0.05).治疗后第21天联合治疗组的抑瘤率(92.80%±11.37%)显著高于TNP-470治疗组(61.91%±6.29%)和BCNU治疗组(68.73%±9.65%)(P均＜0.01),TNP-470治疗组与BCNU治疗组间抑瘤率无统计学意义(P＞0.05).联合治疗组移植瘤MVD[(4.23 4±0.83)个/视野]明显低于TNP470治疗组[(5.70±0.85)个/视野]和BCNU治疗组[(8.60±0.87)个/视野](P均＜0.05);TNP-470治疗组移植瘤MVD显著低于BCNU治疗组(P＜0.05);各治疗组移植瘤MVD均较对照组[(11.32±1.50)个/视野]显著降低(P均＜0.05).结论 TNP-470联合化疗药物BCNU对人U-251胶质母细胞瘤细胞裸鼠皮下移植瘤的生长有显著抑制作用.     

放化疗同步与单纯放疗治疗胶质母细胞瘤的疗效比较

目的 比较单纯放疗(RT)与放疗加替莫唑胺(RT-TMZ)治疗胶质母细胞瘤的局控率、生存率及不良反应.方法 对60例首次术后的胶质母细胞瘤随机分为接受单纯放疗、放疗加每天持续的替莫唑胺治疗以及6个周期的替莫唑胺辅助治疗.每组30例.主要研究目标为整体生存率.结果 RT-TMZ组与RT组总有效率分别为53.3%和26.6%;1年累计局部复发率分别为63.3%和90.0%,1年无复发生存率分别为36.7%和10.0%,1年生存率分别为56.7%和16.7%(P<0.05).RT-TMZ组常见不良反应是恶心,呕吐,白细胞和血小板下降,但仅限于Ⅰ～Ⅱ度.结论 在提高局控率、延缓肿瘤复发与提高患者无瘤生存期方面RT-TMZ组要优于RT组,而不良反应方面两组反应均较轻微.     

胶质母细胞瘤术后甲氨蝶呤间质化疗同步放化疗临床观察

目的观察间质化疗在胶质母细胞瘤患者救治中的作用。方法 90例胶质母细胞患者分为间质化疗组(A组)42例,术后仅进行常规放化疗治疗(B组)48例,对2组患者肿瘤复发时间、中位生存时间及3 a存活率进行分析。结果 A组肿瘤复发时间(13.61±3.83)月、中位生存时间2.10(1.35～2.70)a;B组肿瘤复发时间(10.31±2.20)月,中位生存时间1.55(1.30～2.10)a,差异均有统计学意义(P0.05)。结论间质化疗在胶质母细胞瘤中的治疗效果优于常规放化疗治疗。     

Efficacy of temozolomide as adjuvant chemotherapy after postsurgical radiotherapy alone for glioblastomas

Objectives

The aim of this study was to assess the efficacy of adjuvant TMZ chemotherapy for newly diagnosed GBM patients who were treated with surgery followed by radiotherapy alone.

Material and methods

Between January 2003 and April 2005, 59 consecutive GBM patients underwent radiation therapy after surgical resection and subsequently received TMZ chemotherapy. For the comparative analysis, we selected 60 clinically matched GBM patients who underwent radiotherapy followed by nitrosourea-based chemotherapy (NUBC), at the same institution between June 1995 and April 2005. The study cohort was divided into two groups, those with adjuvant TMZ treatment and with NUBC.

Results

59 patients with adjuvant TMZ treatment were assigned to the treatment group and 60 patients with NUBC to the control group. The median overall survival for the treatment group was 18.2 months (95% CI, 11.7–24.7 months), compared with the survival of 14.5 months (95% CI, 11.2–17.7 months) for the control group (p = 0.019). The progression-free survival for the treatment group was 5.6 months (95% CI, 4.4–6.7 months), while the control group showed progression-free survival of 3.3 months (95% CT, 3.2–6.0 months) (p = 0.030). Uni- and multivariate analysis revealed that extent of surgical resection, age ≥55 years and postoperative KPS were significantly associated with survival.

Conclusion

Adjuvant TMZ chemotherapy provided a clinically relevant benefit of survival, as compared with NUBC. Thus, we suggest that adjuvant TMZ chemotherapy may be effective even for patients who did not receive concomitant chemoradiotherapy for GBM.     

胶质瘤中P170、MGMT、TOPⅡ和GST-π的蛋白表达与化疗药物敏感性的研究

目的 探讨人脑胶质瘤组织中P170、MGMT、TOPⅡ和GST-π的蛋白表达与临床化疗药物敏感性的关系.方法 应用单克隆抗体、免疫组化技术S-P法,对52例低级别(Ⅱ级)和56例高级别(Ⅲ～Ⅳ级)胶质瘤病人组织标本行上述4种指标检测,并分析其术后化疗药物的敏感性.结果 胶质瘤组织中P170、MGMT、TOPⅡ和GST-π的表达在低级别和高级别胶质瘤之间有统计学意义(P<0.01),病人术后化疗药物敏感性分析结果显示:大部分P170、TOPⅡ高表达的患者用化疗药物更为有效.结论 胶质瘤组织中P170、MGMT、TOPⅡ和GST-π的表达高低可指导临床选择化疗药物.     

Impact of p53 status to response of temozolomide in low MGMT expression glioblastomas: preliminary results

OBJECTIVE: This study was designed to assess the clinical outcomes of MGMT low expression glioblastomas with different p53 statuses to the treatment of temozolomide capsule chemotherapy. METHODS: In this retrospective study, glioblastomas with low MGMT expression receiving surgical resection, radiotherapy and temozolomide capsule chemotherapy were divided into high and low mutant p53 expression groups. Patient age, gender, KPS score and extent of resection were analysed between the two groups by t-test and Fisher's exact test, respectively. Correlation between p53 status and control of tumor growth was analysed by survival analysis. RESULTS: In total, 30 patients were included in the study. No statistically significant differences in age, gender, KPS score or extent of resection existed between the two groups. Patients with both low mutant p53 expression and low MGMT had much longer progression-free survival time to temozolomide capsule than those with high mutant p53 expression and low MGMT (p<0.05) Overall survival time did not reach statistical significance between the two groups. CONCLUSION: p53 in addition to MGMT plays a role in chemotherapy resistance to temozolomide. Glioblastoma patients with both low MGMT and low mutant p53 expression have higher progression-free survival time and may have longer term prognosis compared with those patients with both low MGMT and high mutant p53 expression.     

Hypofractionated intensity modulated radiotherapy with temozolomide in newly diagnosed glioblastoma multiforme

We conducted a phase I study to determine (a) the maximum tolerated dose of peri-radiation therapy temozolomide (TMZ) and (b) the safety of a selected hypofractionated intensity modulated radiation therapy (HIMRT) regimen in glioblastoma multiforme (GBM) patients. Patients with histological diagnosis of GBM, Karnofsky performance status (KPS) ⩾ 60 and adequate bone marrow function were eligible for the study. All patients received peri-radiation TMZ; 1 week before the beginning of radiation therapy (RT), 1 week after RT and for 3 weeks during RT. Standard 75 mg/m²/day dose was administered to all patients 1 week post-RT. Dose escalation was commenced at level I: 50 mg/m²/day, level II: 65 mg/m²/day and level III: 75 mg/m²/day for 4 weeks. HIMRT was delivered at 52.5 Gy in 15 fractions to the contrast enhancing lesion (or surgical cavity) plus the surrounding edema plus a 2 cm margin. Six men and three women with a median age of 67 years (range, 44–81) and a median KPS of 80 (range, 80–90) were enrolled. Three patients were accrued at each TMZ dose level. Median follow-up was 10 months (range, 1–15). Median progression free survival was 3.9 months (95% confidence interval [CI]: 0.9–7.4; range, 0.9–9.9 months) and the overall survival 12.7 months (95% CI: 2.5–17.6; range, 2.5–20.7 months). Time spent in a KPS ⩾70 was 8.1 months (95% CI: 2.4–15.6; range, 2.4–16 months). No instance of irreversible grade 3 or higher acute toxicity was noted. HIMRT at 52.5 Gy in 15 fractions with peri-RT TMZ at a maximum tolerated dose of 75 mg/m²/day for 5 weeks is well tolerated and is able to abate treatment time for these patients.     

Marked response of gliomatosis cerebri to temozolomide and whole brain radiotherapy

Gliomatosis cerebri (GC) represents an unfortunate, rare variant of glioma with a very poor prognosis. Given this lesion's rarity, little information exists on appropriate treatment options. The diffuse, infiltrative nature of GC precludes any surgical resection and limits therapy. Because of the improved survival seen with the use of temozolomide (TMZ) in malignant glioma, a rigorous systematic review of the published literature was performed to ascertain the benefit of TMZ in GC. We identified all GC cases in the literature where there was enough information to ascertain a clear response to a specific chemoradiotherapeutic treatment. In addition to our experience with a recent case, we have identified 61 patients with GC in the published literature who demonstrated a positive radiographic or clinic response after treatment. Statistical analysis of survival was performed by Kaplan-Meier analysis. A positive radiographic and clinical response was seen in patients ranging in age from 4 to 84 years. Overall median survival in patients diagnosed with GC who demonstrated a response after treatment was 25 months, with 1- and 2-year survival rates of 89% and 55%, respectively. The most common treatment regimens for responders included TMZ alone (26.2%), external whole-brain radiotherapy (WBRT) (26.2%), and concomitant TMZ and WBRT (20%). Our patient was treated with concomitant TMZ (150 mg/m(2)/day over 5 days) and WBRT (50 Gy) and has remained with a complete radiographic response after 36 months. In conclusion, patients with GC confirmed by surgical biopsy should be aggressively treated with concomitant TMZ and WBRT, as marked responses have been seen, and this appears to offer overall survival benefit.     

Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy

Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1–5, 200 mg/m² orally) and PLD (day 1, 40 mg/m² intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41–72%). The median time to progression was 6.2 months (95% CI, 5.6–8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7–15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar–plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.