Nanomedicine-based combination therapies for overcoming temozolomide resistance in glioblastomas

Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.

Mechanism of NURP1 in temozolomide resistance in hypoxiatreated glioma cells via the KDM3A/TFEB axis

Temozolomide(TMZ)resistance is a major obstacle in glioma treatment.Nuclear protein-1(NUPR1)is a regulator of glioma progression.This study investigated the mechanism of NUPR1 in TMZ resistance in hypoxiatreated glioma cells and its mechanism in modulating autophagy.We treated TMZ-resistant cells U251-TMZ and T98G-TMZ to normoxia or hypoxia and silenced NUPR1 in hypoxia-treated U251-TMZ and T98G-TMZ cells to assess cell viability,proliferation,apoptosis,LC3-II/LC3-I and p62 expressions,and autophagic flux under different concentrations of TMZ.We found that hypoxia upregulated NUPR1 expression and autophagy while NUPR1 silencing suppressed hypoxia-induced TMZ resistance and autophagy in glioma cells.We also investigated the interaction between NUPR1 and lysine demethylase 3A(KDM3A),as well as the enrichments of KDM3A and H3 lysine 9 dimethylation(H3K9me2)in the transcription factor EB(TFEB)promoter region.Our results suggest that hypoxia-induced NUPR1 promotes TFEB transcription by binding to KDM3A and reducing H3K9me2 levels,thereby augmenting glioma cell autophagy and TMZ resistance.Moreover,the overexpression of KDM3A or TFEB promoted glioma cell autophagy.In a xenograft tumor model,silencing NUPR1 suppressed TMZ resistance in glioma cells in vivo.Overall,our findings highlight a mechanism by which NUPR1 enhances glioma cell autophagy and TMZ resistance via the KDM3A/TFEB axis.

A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance

Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.

TMZ@ZIF-8纳米粒的制备、表征及体内外抗肿瘤研究

目的制备沸石咪唑骨架(ZIF)-8纳米粒(NPs)负载替莫唑胺(TMZ)(简称TMZ@ZIF-8 NPs)药物递送系统,以增加药物在病灶的富集和抗脑胶质瘤效果。方法采用室温溶液反应法制备ZIF-8 NPs后,再采用浸渍法制备TMZ@ZIF-8 NPs药物递送系统。进行透射电镜、激光粒度及傅里叶变换红外光谱等表征和溶出实验,并进行体外及体内抗肿瘤活性实验。结果TMZ@ZIF-8 NPs制备成功,粒径为(126.23±7.92)nm,载药率为(28.79±1.26)%,72 h累积溶出速率为(72.36±3.62)%。体外抗肿瘤活性实验结果显示,ZIF-8 NPs的相对细胞存活率一直保持在90%以上;与游离的TMZ相比,TMZ@ZIF-8 NPs对C6细胞的生长、增殖表现出更优的抑制作用、更高的被摄取能力和更好的促凋亡效果。体内抗肿瘤活性实验结果显示,ZIF-8 NPs在大鼠脑部不富集,TMZ在脑部富集效果并不显著,而TMZ@ZIF-8 NPs在脑部富集效果显著。结论ZIF-8 NPs可有效负载TMZ,制备成功的TMZ@ZIF-8可提高TMZ摄取能力及抗脑胶质瘤效果。

PDT通过氧化应激增加TMZ对胶质瘤U251细胞的抑制

目的多重耐药性(multiple drug resistance,MDR)仍在替莫唑胺(temozolomide,TMZ)治疗胶质瘤过程中不可避免的出现,成为胶质瘤预后不佳和局部侵袭复发的重要原因。本研究旨在观察光动力疗法(photodynamic therapy,PDT)是否能增加人胶质瘤细胞U251对TMZ的化疗敏感度,并深入探讨其增敏机制。方法人源胶质瘤细胞U251进行常规体外培养,根据处理方法分为5组,即对照(control)组、TMZ组、PDT组、TMZ+激光(TMZ+Laser)组和PDT+TMZ组,应用CCK-8观察U251细胞活性、Transwell小室观察细胞侵袭能力、免疫荧光观察细胞内活性氧(reactive oxygen species,ROS)及线粒体膜电位(mitochondrial membrane potential,MMP)水平,结果数据用GraphPad Prism软件统计分析。结果CCK-8实验表明在TMZ处理后8h,即产生了U251细胞对TMZ的治疗抵抗。PDT协同应用于TMZ处理8h的U251细胞后,PDT+TMZ组光密度(OD)值、侵袭细胞数量、MMP水平与control组和TMZ组比较均降低,而ROS升高,进一步分析表明,ROS和MMP水平呈负相关(r=-0.559,P<0.05)。结论PDT通过提高TMZ作用后的胶质瘤U251细胞内的ROS总量,加强了对U251细胞增殖和侵袭能力的抑制,延缓了MDR的发生。

Transcriptomic analysis identifies the neuropeptide cortistatin (CORT) as an inhibitor of temozolomide (TMZ) resistance by suppressing the NF-kB-MGMT signaling axis in human glioma

Glioma is a common tumor originating in the brain that has a high mortality rate.Temozolomide(TMZ)is the first-line treatment for high-grade gliomas.However,a large pro-portion of gliomas are resistant to TMZ,posing a great challenge to their treatment.In the study,the specific functions and mechanism(s)by which cortistatin(CORT)regulates TMZ resis-tance and glioma progression were evaluated.The decreased expression of CoRT was detected in glioma tissues,and highly expressed CORT was associated with a better survival rate in pa-tients with glioma.CORT overexpression notably decreased the capacity of glioma cells to pro-liferate and migrate in vitro and to form tumors in vivo.CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT,p21,and Puma expression.Importantly,CORT overexpression reduced the resistance of gliomas to TMZ in vivo.CORT expression Was negatively correlated with MGMT expression in both glioma tissues and cells,and it was found that CORT inhibited NF-kB pathway activation in glioma cells,thereby inhibiting MGMT expression.In conclusion,CORT regulates glioma cell growth,migration,apoptosis,and TMZ resistance by weakening the activity of NF-kB/p65 and thereby regulating MGMT expression.The CORT/NF-kB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ.Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells,independent of its effects on TMZ resistance,providing evidence of novel therapeutic targets for glioma that should be evaluated infurther studies.

Temozolomide for treatment of brain metastases: A review of 21 clinical trials

Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.

Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells

Glioblastoma multiforme （GBM） is the most aggressive primary brain tumor in adults.Current therapy includes surgery,radiation and chemotherapy with temozolomide （TMZ）.Major determinants of clinical response to TMZ include methylation status of the O6-methylguanine-DNA methyltransferase （MGMT） promoter and mismatch repair （MMR） status.Though the MGMT promoter is methylated in 45% of cases,for the first nine months of follow-up,TMZ does not change survival outcome.Furthermore,MMR deficiency makes little contribution to clinical resistance,suggesting that there exist unrecognized mechanisms of resistance.We generated paired GBM cell lines whose resistance was attributed to neither MGMT nor MMR.We show that,responding to TMZ,these cells exhibit a decoupling of DNA damage response （DDR） from ongoing DNA damages.They display methylation-resistant synthesis in which ongoing DNA synthesis is not inhibited.They are also defective in the activation of the S and G2 phase checkpoint.DDR proteins ATM,Chk2,MDC1,NBS1 and gammaH2AX also fail to form discrete foci.These results demonstrate that failure of DDR may play an active role in chemoresistance to TMZ.DNA damages by TMZ are repaired by MMR proteins in a futile,reiterative process,which activates DDR signaling network that ultimately leads to the onset of cell death.GBM cells may survive genetic insults in the absence of DDR.We anticipate that our findings will lead to more studies that seek to further define the role of DDR in ultimately determining the fate of a tumor cell in response to TMZ and other DNA methylators.

Downregulation of SNRPG induces cell cycle arrest and sensitizes human glioblastoma cells to temozolomide by targeting Myc through a p53-dependent signaling pathway

Objective:Temozolomide(TMZ)is commonly used for glioblastoma multiforme(GBM)chemotherapy.However,drug resistance limits its therapeutic effect in GBM treatment.RNA-binding proteins(RBPs)have vital roles in posttranscriptional events.While disturbance of RBP-RNA network activity is potentially associated with cancer development,the precise mechanisms are not fully known.The SNRPG gene,encoding small nuclear ribonucleoprotein polypeptide G,was recently found to be related to cancer incidence,but its exact function has yet to be elucidated.Methods:SNRPG knockdown was achieved via short hairpin RNAs.Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG.Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues.Results:The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53.In addition,the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent.Furthermore,SNRPG was increased in TMZ-resistant GBM cells,and downregulation of SNRPG potentially sensitized resistant cells to TMZ,suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.Our data confirmed that SNRPG suppression sensitizes GBM cells to TMZ by targeting Myc via the p53 signaling cascade.Conclusions:These results indicated that SNRPG is a probable molecular target of GBM and suggested that suppressing SNRPG in resistant GBM cells might be a substantially beneficial method for overcoming essential drug resistance.

Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells

O6-methylguanine DNA methyltransferase(MGMT) can remove DNA alkylation adducts, thereby repairing damaged DNA and contributing to the drug resistance of gliomas to alkylating agents. In addition, glioma stem-like cells(GSCs) have been demonstrated to be involved in the recurrence and treatment resistance of gliomas. In this study, we aimed to investigate MGMT expression and regulatory mechanisms in GSCs and the association of MGMT with temozolomide(TMZ) sensitivity. GSCs were enriched from one MGMT-positive cell line(SF-767) and 7 MGMT-negative cell lines(U251, SKMG-4, SKMG-1, SF295, U87, MGR1, and MGR2) through serum-free clone culture. GSCs from the U251G, SKMG-4G, SF295G, and SKMG-1G cell lines became MGMT-positive, but those from the U87G, MGR1G, and MGR2G cell lines remained MGMT-negative. However, all the GSCs and their parental glioma cell lines were positive for nuclear factor-κB(NF-κB). In addition, GSCs were more resistant to TMZ than their parental glioma cell lines(P < 0.05). However, there was no significant difference in the 50% inhibition concentration(IC50) of TMZ between MGMT-positive and MGMT-negative GSCs(P > 0.05). When we treated the MGMT-positive GSCs with TMZ plus MG-132(an NF-κB inhibitor), the antitumor activity was significantly enhanced compared to that of GSCs treated with TMZ alone(P < 0.05). Furthermore, we found that MGMT expression decreased through the down-regulation of NF-κB expression by MG-132. Our results show that MG-132 may inhibit NF-κB expression and further decrease MGMT expression, resulting in a synergistic effect on MGMT-positive GSCs. These results indicate that enhanced MGMT expression contributes to TMZ resistance in MGMT-positive GSCs.

Inhibition of Ciliogenesis Enhances the Cellular Sensitivity to Temozolomide and Ionizing Radiation in Human Glioblastoma Cells

Objective To investigate the function of primary cilia in regulating the cellular response to temozolomide(TMZ)and ionizing radiation(IR)in glioblastoma(GBM).Methods GBM cells were treated with TMZ or X-ray/carbon ion.The primary cilia were examined by immunostaining with Arl13 b andγ-tubulin,and the cellular resistance ability was measured by cell viability assay or survival fraction assay.Combining with cilia ablation by IFT88 depletion or chloral hydrate and induction by lithium chloride,the autophagy was measured by acridine orange staining assay.The DNA damage repair ability was estimated by the kinetic curve ofγH2 AX foci,and the DNAdependent protein kinase(DNA-PK)activation was detected by immunostaining assay.Results Primary cilia were frequently preserved in GBM,and the induction of ciliogenesis decreased cell proliferation.TMZ and IR promoted ciliogenesis in dose-and time-dependent manners,and the suppression of ciliogenesis significantly enhanced the cellular sensitivity to TMZ and IR.The inhibition of ciliogenesis elevated the lethal effects of TMZ and IR via the impairment of autophagy and DNA damage repair.The interference of ciliogenesis reduced DNA-PK activation,and the knockdown of DNA-PK led to cilium formation and elongation.Conclusion Primary cilia play a vital role in regulating the cellular sensitivity to TMZ and IR in GBM cells through mediating autophagy and DNA damage repair.

Temozolomide resistance in high grade gliomas

High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemotherapy. Alkylating agent temozolomide has been established as the standard chemotherapy while its resistance inevitable during treatment. This phenomenon seriously influences the prognosis of patients suffering from high grade gliomas. This review aims to elucidate temozolomide chemoresistance mechanisms through three chapters including O^6-methylguanine-DNA methyltransferase(MGMT) methylation, mismatch repair mutation and epigenetic regulation consisting of p21, chromatin and histone, Y-box binding protein-1 and micro RNAs.

Extended Daily Schedule of Temozolomide in Recurrent Glioblastoma: Single-Institution Report on a Series of 43 Patients

Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.

Adiponectin Supports Human Glioma Cells Survival against Temozolomide through Enhancement of Autophagic Response in Glioma Cells

Objective: To investigate the role of adiponectin in human glioma cell lines against the temozolomide and the molecular regulation mechanism. Methods: Human glioma cell lines U251 and U-87MG were cultured in Dulbecco’s modified eagle medium (DMEM) containing 4500 mg/L glucose. MTT was used to measure cell growth ratio. Western blot was used to detect the protein levels of autophagy-related protein (Beclin 1, LC3 I/II, p62) and phosphorylated AMPK (p-AMPK) in human glioma cell lines. After AICAR and Compound C were administered, the change of p-AMPK and the autophagy level were examined by western blot. Results: While adiponectin stimulates AMPK in phosphatase and up-regulates the level of autophagy, human glioma cell lines obtain more resistance against the temozolomide, which is facilitated by AICAR and weakened by Compound C. Conclusion: As an important adipokine, adiponectin can up-regulate the glioma cell autophagy by activating the AMPK signaling pathway which increases the resistance of glioma cells to temozolomide.

S-1 plus temozolomide as second-line treatment for neuroendocrine carcinoma of the breast:A case report

BACKGROUND Neuroendocrine carcinoma of the breast(NECB)is a rare type of malignant tumor.Due to the rarity of NECB,the relevant literature mostly comprises case reports.Available data on treatment options for NECB are very limited.CASE SUMMARY A 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography(CT)imaging.She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital.The patient initially presented with a painful lesion of the right breast.She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy.She was regularly followed every 3 mo after surgery.Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm×6.3 cm.Chest CT revealed masses in the anterior chest wall and lung.Core needle biopsy of the lesion revealed liver metastases of NECB.A bone scan showed right second anterior rib metastases.Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor.She stopped receiving endocrine therapy and then received etoposide and cisplatin(EP)chemotherapy as a firstline treatment regimen for six cycles at our hospital after liver,bone,and lung metastases.On October 2017,the chemotherapy regimen was changed to S-1(40mg twice daily,days 1-14)combined with temozolomide(200 mg once daily,days 10-14)(STEM)every 21 d as a second-line treatment regimen due to disease progression.Progression-free survival(PFS)and adverse effects after treatment were analyzed,and the efficacy of the STEM regimen was assessed using RECIST version 1.1.This patient achieved a partial response after using the STEM regimen,with a PFS of 23 mo.Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.CONCLUSION This case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB.STEM is still highly effective in patients who show disease progression with the EP regimen.More evidence is needed to prove the validity of STEM.

The efficacy of capecitabine and temozolomide against neuroendocrine carcinomas

Objective Neuroendocrine carcinomas(NECs) are resistant to currently available chemotherapy agents, and its therapeutic options are limited. Preclinical data have suggested synergy between capecitabine and temozolomide(CAPTEM). Therefore, we evaluated the efficacy and safety of CAPTEM in patients with metastatic NECs who have failed prior therapies.Methods A retrospective review was conducted on seven patients with metastatic NECs for whom platinum-based chemotherapies and hepatic chemoembolization failed. Patients received capecitabine(1000 mg twice daily on days 1-14) and temozolomide(150–200 mg/m^2 once daily on days 10–14) every 28 days. Tumor assessments were performed every two cycles.Results Among the seven patients treated, two achieved partial remission and four achieved stable disease. The total response rate was 29%, and the clinical benefit was 86%. Median progression-free survival was 10(range: 8–14) months. The most common toxicities were grade 1 and 2 neutropenia, grade 1 fatigue, and grade 1 and 2 hand-foot syndrome. No grade 4 toxicities or treatment-related deaths were observed.Conclusion Our study showed that the CAPTEM regimen is an effective and well-tolerated salvage option for NECs. Further prospective studies are warranted to evaluate optimal combinations of the CAPTEM regimen for NECs.

Combination therapy of long-term tumor treating fields with temozolomide and bevacizumab prolongs survival in multifocal glioblastoma diagnosed patient: a case report

The multifocal glioblastomas (GBM) are tumors with multiple discrete areas of contrast enhancing tumors which have considerably poorer prognosis than solitary GBM. Median overall survival of diagnosed patients almost twice as less than solitary presentation. We present a case report of multifocal GBM. A 72-year old right-handed male was evaluated at the Neuro-Oncology Clinic of Baylor Scott and White Hospital (Central Division). Patient presented at this hospital because of persistent progressive headaches, confusion, and an incident of fall. Physical evaluation revealed neurological impairments. Brain magnetic resonance imaging (MRI) revealed heterogeneous contrast enhancing lesions with associated vasogenic oedema. Patient underwent a stereotactic biopsy analysis of the larger lesion and pathology evaluation concluded an isocitrate dehydrogenase 1 and 2 wild type GBM with unmethylated O-6-methylguanine- DNA methyltransferase. Treatment remedies: Patient received 4 weeks concurrent radiation therapy along with combination of temozolomide at dose of 75 mg/m^2 followed adjuvant temozolomide for 10 cycles with bevacizumab at 10 mg/kg every 2 weeks and Optune treatment. Post treatment evaluation: Repeat MRIs showed near complete resolution of the tumors at 26 months of treatment along with improvement of neurological status. Conclusion: Due to limitations of surgical manipulations in multifocal GBM diagnosed patients, combinational chemo and radiation therapy is the treatment of choice for most cases. Using additional novel treatment with non-invasive therapeutic device proven to be effective is another excellent approach to the established practice. Therefore, combination therapy of Optune plus temozolomide and bevacizumab might be a promising remedy for newly diagnosed multifocal glioblastomas.

Efficacy of Temozolomide Combined with Whole Brain Radiotherapy in the Treatment of Cerebral Metastases from Lung Cancer

[Objectives] To observe the clinical efficacy,adverse reaction and survival time of temozolomide combined with whole brain radiotherapy in the treatment of lung cancer. [Methods] A total of 43 patients with lung cancer and cerebral metastases were reviewed and analyzed. Three-dimensional conformal radiotherapy(3D-CRT) technique was used to perform whole brain radiotherapy,one time a day and5 times a week. At the same time of radiotherapy,temozolomide chemotherapy was performed,150 mg/( m2·d),continuous oral administration of 5 d,every 28 days were a cycle( those patients who continue receiving temozolomide chemotherapy did not receive other related antitumor therapy,such as systemic chemotherapy and molecular targeted therapy,etc.),and drugs were administered for 4-6 cycles according to tolerance of patients. Kaplan-Meier method was used to calculate the survival rate. [Results]The objective response rate of 43 patients was79. 0%(34/43),in which CR was 6/43,PR was 28/43,and 9 cases had PD. By December 31,2016,7 patients in 43 cases died,one patient died of cerebral hernia due to intracranial lesions and 6 patients died of failure of other important organs due to metastasis. The OS and PFS of the whole group of patients in one year were 49. 1% and 56. 9% respectively. The adverse reactions were mild and the patients could tolerate such treatment. [Conclusions] Temozolomide combined with whole brain radiotherapy in the treatment of lung cancer with cerebral metastases has excellent clinical efficacy,while patients can tolerate such treatment.

Temozolomide chemotherapy based on MGMT protein expression for patients with malignant gliomas:a report of 40 cases

Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods A total of 40 patients with pathologically confirmed malignant gliomas were enrolled. All patients had pretreated with radiotherapy and had assessable lesions.