Glioma Multiforme Research Articles

PREWARMING IN PATIENTS UNDERGOING ELECTIVE NEUROSURGERY: CRITICALLY APPRAISED TOPIC

Summary: Clinical setting: A 20-year-old patient with a diagnosis of glioma multiforme, will be taken to a scheduled craniotomy for resection of his tumor. No medical or surgical pathological history. On physical examination, a patient with normal vital signs, without neurological focus. His neoplasm was excised by craniotomy under general anesthesia, with warm-up for 30 minutes and active intraoperative warm-up, without complications. He was transferred to the ICU for neurological surveillance. Discharge 7 days after surgery without complications. Clinical problem: In adults who will undergo programmed neurosurgery, does warm-up decrease in-hospital mortality? Objetives: Perform a Critically Appraised Topic (CAT) to (I) analyze existing research related to warming in patients undergoing neurosurgery, and (II) apply the results to the clinical setting. Methods: A systematic search was carried out in 3 databases in search of publications about the clinical problem in adults over 18 years of age. Results: Three studies met the inclusion criteria. The evidence about the usefulness of warming in reducing episodes of hypothermia during the intraoperative period is highlighted, however, no study was found that evaluated the outcomes of warming in the postoperative period. Conclusion: Warming up for at least 10 minutes is a useful measure to increase comfort and reduce hypothermic episodes. The prevention of hypothermic episodes during the perioperative period has been shown to be useful for reducing multiple complications including mortality. However, the usefulness of postoperative warming in neurosurgery is unknown, despite this its use is recommended due to its causal relationship with the decrease in perioperative hypothermia for at least a period of 10 minutes and to continue it even during induction.

Evaluation of the effect of fluorescein sodium-guided under yellow 560nm surgical microscope filter in surgery for high grade gliomas: Preliminary results in a series of 27 patients

Objective: The importance of a complete resection of high‑grade gliomas (HGGs) has been highlighted in scientific literature, in order to limit tumor recurrence and above all to improve disease‑free survival rates. Several fluorescent biomarkers have been tested to improve intraoperative identification of residual tumor. The fluorescein sodium (FS) are now starting to play an important role in glioma surgery. Under the YELLOW 560nm surgical microscope filter, low-dose FS (5mg/kg) as a fluorescent dye helps in visualization of tumor tissue. Our study provides preliminary results in investigating the safety and efficacy of this technique in patients with HGGs. Subject and method: A prospective, uncontrolled study of 27 patients with HGGs underwent FS-guided resection under YELLOW 560nm surgical microscope filter. We have analyzed the clinical features, size, tumor location, extent of tumor resection, pathologic of HGGs, patient status (Karnofsky Performance Scale) and FS side effects. Result: 7/27 patients (25.9%) were glioma grade III and 20/27 patients (74.1%) were glioma multiforme (GBM). With YELLOW 560nm surgical microscope filter (PENTERO 900 surgical microscope), FS-guided gross total resection (GTR) was achieved in 74.1% and subtotal resection (STR) in 11.1%. No side effects of FS were reported. Conclusion: FS-guided resection of HGGs under the YELLOW 560nm surgical microscope filter was effective and safe.

MiR-674-5p Suppresses the Proliferation and Migration of Glioma Cells by Targeting Cul4b.

Glioma multiforme (GBM) is the most common malignant primary brain tumors. Despite the considerable advances in GBM treatment, it is still one of the most lethal forms of brain tumor. New clinical biomarkers and therapeutic targets are immediately required. MicroRNAs (miRNAs) are a class of small, evolutionarily conserved noncoding RNAs and have emerged as the key regulators of many cancers. Here in this study, we showed that miR-674-5p was probably an important regulator of glioma cell growth. After the transfection with miR-674-5p mimic or inhibitor, we found that the expression level of miR-674-5p was negatively related with cell proliferation and migration in C6 cells. Based on the prediction of the target genes of miR-674-5p on the website, we chose Cullin 4B (Cul4b), a gene upregulated in GBM, and proved that it was a target of miR-674-5p. In addition, we explored the role of miR-674-5p in glioma growth in vivo. Taken together, the present study indicated that miR-674-5p suppressed glioma cell proliferation and migration by targeting Cul4b.

A Short-Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections.

The chemistry and short lifetimes of metal-based anti-cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1 L2 ], where L1 is N-(salicylideneaminato)-N'-(2-hydroxyethyl)ethane-1,2-diamine and L2 is 3,5-di-tert-butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8-fold less toxic. 1 was 12-fold more toxic than cisplatin in T98g cells and 6-fold more toxic in T98g cells than in a non-cancer human cell line, HFF-1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal-binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

A Short‐Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections

AbstractThe chemistry and short lifetimes of metal‐based anti‐cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1L2], where L1 is N‐(salicylideneaminato)‐N′‐(2‐hydroxyethyl)ethane‐1,2‐diamine and L2 is 3,5‐di‐tert‐butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8‐fold less toxic. 1 was 12‐fold more toxic than cisplatin in T98g cells and 6‐fold more toxic in T98g cells than in a non‐cancer human cell line, HFF‐1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal‐binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

Peptide Nanosponges Designed for the Delivery of Perillyl Alcohol to Glioma Cells.

Peptide nanosponges of low polydispersity are spontaneously formed from trigonal supramolecular building blocks in aqueous buffers, which feature cationic and/or anionic oligopeptides (n = 5-20) and a hydrophobic unit. In contrast to classical liposomes/vesicles, nanosponges feature interwoven hydrophilic and hydrophobic nanodomains and are readily taken up by mammalian cells. Perillyl alcohol is known to be a simple, but effective small molecule drug against glioma multiforme. However, its efficacy is limited by a poor bioavailability. In order to make perillyl alcohol bioavailable, two nanosponges consisting of 10 aspartates, to which perillyl alcohol is attached by means of an ester bond, and 20 lysines or arginines (type (D-POH)10K20 and (D-POH)10R20) were synthesized, purified, and characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). These nanosponges were then tested in cell cultures of murine glioma cells (GL26) and murine neural progenitor cells (NPC) because the latter was previously utilized in cell-based cancer therapy. The two nanosponges exhibited significantly different biophysical properties (size distribution and ζ potentials). Consequently, different efficacies in killing GL26 and NPC were observed in serum-containing culture media. The results from these experiments confirmed that the type (D-POH)10K20 nanosponge is a promising candidate for the (cell-mediated) cytotherapy of glioblastoma.

Protein kinase D2: a versatile player in cancer biology.

Protein kinase D2 (PKD2) is a serine/threonine kinase that belongs to the PKD family of calcium-calmodulin kinases, which comprises three isoforms: PKD1, PKD2, and PKD3. PKD2 is activated by many stimuli including growth factors, phorbol esters, and G-protein-coupled receptor agonists. PKD2 participation to uncontrolled growth, survival, neovascularization, metastasis, and invasion has been documented in various tumor types including pancreatic, colorectal, gastric, hepatic, lung, prostate, and breast cancer, as well as glioma multiforme and leukemia. This review discusses the versatile functions of PKD2 from the perspective of cancer hallmarks as described by Hanahan and Weinberg. The PKD2 status, signaling pathways affected in different tumor types and the molecular mechanisms that lead to tumorigenesis and tumor progression are presented. The latest developments of small-molecule inhibitors selective for PKD/PKD2, as well as the need for further chemotherapies that prevent, slow down, or eliminate tumors are also discussed in this review.

Role of Merlin/NF2 inactivation in tumor biology.

Merlin ((Moesin-ezrin-radixin-like protein, also known as schwannomin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. Loss of function mutations or deletions in NF2 cause Neurofibromatosis type 2 (NF2), a multiple tumor forming disease of the nervous system. NF2 is characterized by the development of bilateral vestibular schwannomas. Patients with NF2 can also develop schwannomas on other cranial and peripheral nerves, as well as meningiomas and ependymomas. The only potential treatment is surgery/radiosurgery which often results in loss of function of the involved nerve. There is an urgent need for chemotherapies that slow or eliminate tumors and prevent their formation in NF2 patients. Interestingly NF2 mutations and merlin inactivation also occur in spontaneous schwannomas and meningiomas, as well as other types of cancer including mesothelioma, glioma multiforme, breast, colorectal, skin, clear cell renal cell carcinoma, hepatic and prostate cancer. Except for malignant mesotheliomas, the role of NF2 mutation or inactivation has not received much attention in cancer, and NF2 might be relevant for prognosis and future chemotherapeutic approaches.This review discusses the influence of merlin loss of function in NF2-related tumors and common human cancers. We additionally discuss the NF2 gene status and merlin signaling pathways affected in the different tumor types and the molecular mechanisms that lead to tumorigenesis, progression and pharmacological resistance.

Development of LC–MS method for analysis of paclitaxel-inhibited growth and enhanced therapeutic response in human glioblastoma cells

Abstract Glioma stem cells are considered responsible for drug resistance and glioma relapse resulting in poor prognosis in glioblastoma multiforme. SU3 glioma cell is a highly invasive glioma stem cell line from the patients with glioblastoma multifrome. It is of great significance to study the efficacy and molecular mechanism for anticancer drug effects on SU3 glioma cells. In this work, we develop a liquid chromatography–mass spectrometry (LC–MS) method for direct analysis of the role of drugs (paclitaxel) on SU3 glioma cells at the molecular level. We use the specific fluorescence dyes to evaluate cell viability, the levels of ROS and GSH when the cells were treated with drugs. In addition, the LC–MS platform was successfully employed to detect the amount of 6-O-methylguanine, demonstrating that it is effective to induce cell apoptosis and enhance the cytotoxic response of SU3 glioma cells. The analytical linear equals are Y = 9.49 × 105X + 2.42 × 104 for 6-O-methylguanine (R2 = 0.9998) and Y = 4.72 × 104X + 2.21 × 103 (R2 = 0.9996) for 7-methylguanine. Thus, the combination of cell-specific fluorescence dyes and LC–MS method enables us to reveal the molecular mechanism of paclitaxel-inhibited growth and enhanced therapeutic response in the chemotherapy for glioma multiforme.

Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: a prospective combination of ABT-737 and TMZ for treating glioma.

Bcl2L12 as a new member of the Bcl2 family, which contains a BH2 domain and shares a lower amino acid similarity with other Bcl2 family proteins. Bcl2L12 is reported to be involved in apoptosis regulation, but this role remains controversial in different cancer type. Temozolomide (TMZ) is currently used to intervene glioma multiforme (GBM), but an acquired chemotherapeutic resistance maybe occurred due to undesired autophagy. Previous studies uncovered that Bcl2L12 may interact with Bcl-xL and may harbor a BH3-like domain. Therefore, we investigated whether this BH3-like domain is responsible for the Bcl2L12 anti-apoptotic property. Moreover, we tested whether ABT-737, a BH3 mimetic agent, can be combined with TMZ to treat GBM. We aligned Bcl2L12 with Bcl2 family members, compared interacting pattern of BH3 domain and their protein 3D structure. We identified that Bcl2L12 interacts with Bcl-xL and Bcl2 in yeast two-hybrid system. Bcl2L12192-220 was a minimal region for Bcl2L12-Bcl-xL interaction. Five-point mutations with respect to hydrophobic and charge residues were generated to test whether they are the key residue of BH3-like domain. Our data showed that both h1 (L213) and h2 residue (L217) are essential for Bcl2L12 interacting with Bcl2 family proteins. Ectopically expressed h1 or h2 mutant in U87MG cell line resulted in reactivation of cleaved-PARP, caspase-3 and cytochrome c releasing compared to Bcl2L12 wt group. Implementing ABT-737 combined with TMZ provided a superior effect on apoptosis induction in Bcl2L12 wt group, which effectively reactivated apoptotic markers. Altogether, our findings indicated that Bcl2L12 retains a BH3-like domain, which is important for the Bcl2L12 anti-apoptotic property and TMZ-induced autophagy. Our results basically support the idea of using ABT-737 to counteract the anti-apoptotic role of Bcl2L12 and sensitize drug response of the GBM cells to TMZ.

The inhibitive effect of targeting epidermal growth factor receptor and vascular endothelial growth factor receptor-2 on transplanted human glioblastoma multiforme in nude mice

Objective To explore the inhibitive effect on transplanted human glioblastoma multiforme in the brain of nude mice after treatment of C225 targeting the epidermal growth factor receptor (EGFR)and DC101 targeting the vascular endothehal cell growth factor receptor(VEGFR2)alone and combined application.Methods Forty mice bearing xenografts were divided into 4 groups randoInly with 10 every group,then 4 groups of mice received i.P.injections of C225(50 mg/ks),DC101(40 mg/kg),C225+DC101 or PBS(0.1 ml/20g)respectively 4 times,once every 2 days.On the day 14 post-treatment,mice were sacrificed.Murine brains were removed and fixed in formalin,then tumor appearance and volume were obserred,meanwhile microvessel density,proliferation and apoptosis index were also detected bv immunohistochemical or TUNEL methods.Results Compared with the control group.tumor volume was decreased by 59.7%.microvessel density was decreased by 64.0%,KI-67 LI was decreased by 53.2%,and AI was increased by 66.7%in DC101 group(P＜0.05),but tumor invasiveness was increased:C225 could reduce tumor invasiveness,but had no effect on the volume,Ki-67 LI or AI of tumor (P＞0.05):Tumor volume was decreased by 62.9%(P＜0.05),microvessel density was decreased by 68.0%,Ki-67 LI was decreased by 56.4%and AI was increased by 75%in C225+DC101 group(P＜0.05),invasiveness was also decreased significantly.Conclusion DC101 could inhabit the angiogenesis,and simultaneously could increase the tumor invasiveness,while the C225 could reduce tumor invasiveness.Combined of DC101 and C225 could significantly inhibit GBM tumor growth and reduce the capacity of tumor invasion as compared with DC101 or C255 used alone. Key words: EGFR; VEGFR-2; Molecular targeted tIlerapy; Glioma multiforme

Lack of Interactions between Breast Cancer Resistance Protein (BCRP/ABCG2) and Selected Antiepileptic Agents

Recent studies have indicated constitutive expression of efflux transporter, breast cancer resistance protein (BCRP, ABCG2), in endothelial cells of the blood-brain barrier (BBB). In epileptogenic brain tumors such as ganglioma, astrocytoma, anaplastic astrocytomas, or glioma multiforme, strong expression of BCRP in the microvasculature of the BBB was observed. Therefore it was hypothesized that this phenomenon could critically influence the bioavailability of drugs in these tumors and potentially contribute to the failure of antiepileptic treatment. The aim of this study was to test whether some commonly used antiepileptic drugs (AEDs) are substrates transported by human BCRP. In particular, we focused on phenobarbital, phenytoin, ethosuximide, primidone, valproate, carbamazepine, clonazepam, and lamotrigine. Furthermore, the inhibitory potency of these AEDs to BCRP was examined. To study substrate affinity of tested AEDs to BCRP, transport experiments were performed in epithelial BCRP-expressing MDCKII-BCRP and MDCKII-parent cell lines cultured on microporous membrane. For detection of inhibitory potency of AEDs to BCRP, accumulation assays were carried out in MEF3.8-BCRP cells with known BCRP substrates, BODIPY FL prazosin and mitoxantrone. No obvious interactions of tested AEDs with BCRP transporter were observed. Therefore these drugs in relevant therapeutic concentrations are neither substrates nor inhibitors of BCRP. Based on our in vitro data we can conclude that resistance to treatment with the tested AEDs probably is not caused by the overexpression of BCRP in the BBB of epileptogenic brain tumors.

Dendritic cell therapy with improved outcome in glioma multiforme—A case report

Malignant gliomas are the most devastating tumors in clinical practice and have poorest survival. Immunological treatment of such patients may likely increase the survival and quality of life. Dendritic cells (DCs), most potent antigen presenting cells in combination with oral chemotherapeutic agents may be tried for patients giving consent to such treatment. We have successfully combined the two therapies in an adult male patient who was on downhill course after being operated on once with post operation chemotherapy and radiotherapy for glioma in the left parietal area. He received five dendritic cell therapy vaccines in combination with oral chemotherapy and responded dramatically having near normal quality of life for an additional five months with this regime, increasing the survival after operation to 11 months. This therapy is continuing with radiological betterment of the lesion. The DCs are matured with antigen extracted from wax embedded tissue at 6th day of culture. We feel that the treatment can be given to more number of patients to establish its efficacy for the dreaded cancer glioblastoma multiforme.

Drug-polymer conjugates: potential for improved chemotherapy.

Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.

May Glioma Multiforme Be Hereditary?

May Glioma Multiforme Be Hereditary?