Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. Methods: The treatment schedule was 150–200 mg/m² per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas. Received: 24 October 1996 / Accepted 5 February 1997     

FK228 augmented temozolomide sensitivity in human glioma cells by blocking PI3K/AKT/mTOR signal pathways

Temozolomide is a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM). Romidepsin (FK228), a histone deacetylase inhibitor, is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, combination of the two drugs in glioma remains largely unknown. In the present study, we evaluated the combinatory effects of FK228 with TMZ in glioma, and its molecular mechanisms responsible for these effects. Glioma cell lines were treated with TMZ, FK228 or the combination of drugs. The resistance effect including cytotoxicity and apoptosis was determined in glioma cells, respectively. We further evaluated the effects of FK228 in the PI3K/Akt-signaling pathway in vitro. Mice engrafted with 5 × 10⁶ LN382 cells were treated with TMZ, FK228 or the combination of two drugs, and tumor weights and volumes were measured, respectively. FK228 enhanced the cytotoxic effects of TMZ in glioma cells compared to vehicle-treated controls or each drug alone. The combination of FK228 and TMZ-induced apoptosis was demonstrated by increased expression of cleaved-Caspase 3, Bax, cleaved-PARP, and decreased Bcl-2 expression. Furthermore, the expression of key components of the PI3K/Akt-signaling pathway showed that combination of FK228 and TMZ block PI3K/Akt pathways in vitro. This block effect was also confirmed in vivo in mice models. Mice treated with both FK228 and TMZ drugs showed significantly reduced tumor weights and volumes, compared to each drug alone. Our results suggested that FK228 augmented temozolomide sensitivity in human glioma cells partially by blocking PI3K/AKT/mTOR signal pathways. It thus may provide a promising target for improving the therapeutic outcome of TMZ-resistant gliomas, although further studies will be needed.     

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.     

A pediatric case of anaplastic astrocytoma with a gliomatosis cerebri; the growth pattern and changes in serum VEGF-121 levels after bevacizumab treatment

Gliomatosis cerebri (GC) is a rare diffusely infiltrating glial neoplasm that carries a poor prognosis. Because tumors are undetectable in most patients at early-stage of the onset, a useful diagnostic method is expected. We compared serum vascular endothelial growth factor (VEGF)-121 levels in patients with GC or glioblastoma and controls. VEGF-121 levels were significantly higher in one patient with GC and patients with glioblastoma than in controls. VEGF-121 levels decreased in a patient with GC after bevacizumab-based therapy. Thus, VEGF-121 may be useful for diagnosing GC, its disease-monitoring and understanding its etiology.     

Clinical study of apatinib plus temozolomide for the treatment of recurrent high-grade gliomas

ObjectivesRecurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma.Patients and methodsEighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m²/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions.ResultsFrom the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%).ConclusionApatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.     

替莫唑胺对 Livin基因过表达的胶质瘤TJ905细胞及其干细胞增殖活性的影响

目的分析替莫唑胺（TMZ）干预Livin基因过表达的胶质瘤TJ905细胞及其干细胞模型后对细胞增殖活性的影响,以及对胶质瘤TJ905细胞和TJ905干细胞中Livin、Caspase-3/7的作用机制。 方法使用免疫磁珠方法从胶质瘤TJ905细胞系中分选出CD133阳性胶质瘤干细胞,采用慢病毒过表达技术建立Livin过表达的细胞模型,使用不同浓度（0、25、50、100、200、400 μmol/L）的TMZ干预细胞模型48 h,采用CCK-8、流式细胞术、反转录PCR检测药物干预后细胞增殖活性、细胞周期及Livin、Caspase-3/7基因的表达量。 结果（1）胶质瘤TJ905细胞中Livin基因表达量明显高于同源TJ905干细胞,差异有统计学意义（P<0.05）;（2）TMZ能抑制胶质瘤TJ905细胞及其干细胞的增殖活性,降低增殖速度,并且随药物浓度的增加抑制作用逐渐增强;（3）TMZ能抑制Livin基因的表达,诱导Caspase-3/7的表达,并且随药物浓度的增加抑制作用逐渐增强,差异有统计学意义（P<0.05）;（4）Livin基因转染后胶质瘤干细胞细胞周期G0/G1增加明显,而TJ905细胞周期则是G2/M期少量增加;TMZ干预细胞模型后,TJ905干细胞过表达组在S、G2/M停滞,对照组则是在S期停滞;TJ905细胞过表达组在S期停滞,对照组G2/M则是低浓度诱导停滞,随药物浓度增加其诱导作用减弱,差异均有统计学意义（P<0.05）。 结论TMZ可以通过抑制Livin基因的表达、诱导Caspase-3/7的表达、调控细胞周期变化来降低细胞增殖活性,促进细胞凋亡。     

Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: A 6 year single institutional experience

Objectives

Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Surgery and radiotherapy constitute the cornerstones for the therapeutic management of GBM. The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. Despite the progress in neurosurgery, radiotherapy and oncology, the prognosis still results poor.In order to reduce the long time of standard treatment, maintaining or improving the clinical results, in our institute we have investigated the effects of hypo-fractionated radiation therapy for patients with GBM.

Patients and methods

Sixty-seven patients affected by GBM who had previously undergone surgical resection (total, subtotal or biopsy) were enrolled between October 2005 and December 2011 in a single institutional study of hypo-fractionated intensity modulated radiation therapy (IMRT) followed or not by adjuvant chemotherapy with TMZ (6–12 cycles). The most important eligibility criteria were: biopsy-proven GBM, KPS ≥ 60, age ≥ 18 years, no previous brain irradiation, informed consensus. Hypo-fractionated IMRT was delivered to a total dose of 25 Gy in 5 fractions prescribed to 70% isodose. Response to treatment, OS, PFS, toxicity and patterns of recurrence were evaluated, and sex, age, type of surgery, Karnofsky performance status, Recursive Partitioning Analysis (RPA) classification, time between surgery and initiation of radiotherapy were evaluated as potential prognostic factors for survival.

Results

All patients have completed the treatment protocol. Median age was 64.5 years (range 41–82 years) with 31 females (46%) and 36 males (54%). Median KPS at time of treatment was 80. The surgery was gross total in 38 patients and subtotal in 14 patients; 15 patients underwent only biopsy.No grade 3–4 acute or late neurotoxicity was observed. With median follow-up of 14.9 months, the median OS and PFS were 13.4 and 7.9 months, respectively.

Conclusions

The hypo-fractionated radiation therapy can be used for patients with GBM, resulting in favourable overall survival, low rates of toxicity and satisfying QoL. Future investigations are needed to determine the optimal fractionation for GBM.     

胶质母细胞瘤组织RBM8A表达与病人预后及替莫唑胺化疗敏感性的关系

目的 探讨胶质母细胞瘤（GBM）组织RNA结合基序8A（RBM8A）蛋白表达与病人预后及替莫唑胺（TMZ）化疗敏感性的关系。方法 选取2015年6月至2020年6月手术切除的GBM组织130例及颅脑损伤减压术中切取的非肿瘤脑组织20例（对照）,用免疫组化法检测组织RBM8A表达。术随访时间3~50个月,中位随访时间为12个月。结果 GBM组织RBM8A高表达率[86.15%（112/130）]明显高于对照组[20%（4/20）;P<0.05]。随访期间死亡98例,失访2例;多因素Cox回归分析显示,RBM8A高表达是GBM病人生存预后不良的独立危险因素（P<0.05）。生存曲线分析显示,RBM8A高表达GBM病人中位无复发生存时间和总生存时间均明显低于低表达病人（P<0.05）;RBM8A低表达GBM病人中,TMZ化疗病人无复发生存时间和总生存时间均明显高于未化疗病人（P<0.05）;TMZ化疗与RBM8A高表达GBM病人无复发生存时间和总生存时间无明显关系（P>0.05）。结论 GBM组织RBM8A呈高表达,与病人不良生存预后有关。检测RBM8A有助于评估GBM病人对TMZ化疗敏感性。     

Unraveling the cytotoxic potential of Temozolomide loaded into PLGA nanoparticles

Background

Nanotechnology has received great attention since a decade for the treatment of different varieties of cancer. However, there is a limited data available on the cytotoxic potential of Temozolomide (TMZ) formulations. In the current research work, an attempt has been made to understand the anti-metastatic effect of the drug after loading into PLGA nanoparticles against C6 glioma cells.Nanoparticles were prepared using solvent diffusion method and were characterized for size and morphology. Diffusion of the drug from the nanoparticles was studied by dialysis method. The designed nanoparticles were also assessed for cellular uptake using confocal microscopy and flow cytometry.

Results

PLGA nanoparticles caused a sustained release of the drug and showed a higher cellular uptake. The drug formulations also affected the cellular proliferation and motility.

Conclusion

PLGA coated nanoparticles prolong the activity of the loaded drug while retaining the anti-metastatic activity.