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International Journal of Molecular... Mar 2018Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation... (Review)
Review
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified. Using an animal model, it was shown that autophagy is required for GBM development. Temozolomide (TMZ) is the key drug in GBM chemotherapy and it was reported to induce senescence, autophagy and apoptosis in GBM. In some GBM cells, TMZ induces small toxicity despite its significant concentration and GBM cells can be intrinsically resistant to apoptosis. Resveratrol, a natural compound, was shown to potentiate anticancer effect of TMZ in GBM cells through the abrogation G2-arrest and mitotic catastrophe resulting in senescence of GBM cells. Autophagy is the key player in TMZ resistance in GBM. TMZ can induce apoptosis due to selective inhibition of autophagy, in which autophagic vehicles accumulate as their fusion with lysosomes is blocked. Modulation of autophagic action of TMZ with autophagy inhibitors can result in opposite outcomes, depending on the step targeted in autophagic flux. Studies on relationships between senescence, autophagy and apoptosis can open new therapeutic perspectives in GBM.
Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Autophagy; Brain Neoplasms; Cellular Senescence; DNA Damage; Dacarbazine; Disease Models, Animal; Glioblastoma; Humans; Mice; Resveratrol; Stilbenes; Temozolomide
PubMed: 29562589
DOI: 10.3390/ijms19030889 -
International Journal of Oncology Sep 2022Gliomas are a primary types of intracranial malignancies and are characterized by a poor prognosis due to aggressive recurrence profiles. Temozolomide (TMZ) is an... (Review)
Review
Gliomas are a primary types of intracranial malignancies and are characterized by a poor prognosis due to aggressive recurrence profiles. Temozolomide (TMZ) is an auxiliary alkylating agent that is extensively used in conjunction with surgical resection and forms the mainstay of clinical treatment strategies for gliomas. However, the frequent occurrence of TMZ resistance in clinical practice limits its therapeutic efficacy. Accumulating evidence has demonstrated that long non‑coding RNAs (lncRNAs) can play key and varied roles in glioma progression. lncRNAs have been reported to inhibit glioma progression by targeting various signaling pathways. In addition, the differential expression of lncRNAs has also been found to mediate the resistance of glioma to several chemotherapeutic agents, particularly to TMZ. The present review article therefore summarizes the findings of previous studies in an aim to report the significance and function of lncRNAs in regulating the chemoresistance of gliomas. The present review may provide further insight into the clinical treatment of gliomas.
Topics: Cell Line, Tumor; Dacarbazine; Glioma; Humans; RNA, Long Noncoding; Temozolomide
PubMed: 35796022
DOI: 10.3892/ijo.2022.5391 -
CNS Oncology Jan 2017Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance... (Review)
Review
Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.
Topics: Algorithms; Antineoplastic Agents, Alkylating; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Female; Follow-Up Studies; Glioblastoma; Humans; Magnetic Field Therapy; Magnetic Resonance Imaging; Male; Practice Guidelines as Topic; Temozolomide
PubMed: 27628854
DOI: 10.2217/cns-2016-0032 -
Neuroscience Bulletin Jun 2018In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two... (Review)
Review
In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.
Topics: Animals; Brain Neoplasms; Dacarbazine; Down-Regulation; Glioma; Humans; PPAR gamma; Temozolomide; Wnt Signaling Pathway
PubMed: 29582250
DOI: 10.1007/s12264-018-0219-5 -
Oncology (Williston Park, N.Y.) Jun 2017Managing elderly patients with glioblastoma presents a unique set of challenges, including a scarcity of available data, which limits evidence-based recommendations.... (Review)
Review
Managing elderly patients with glioblastoma presents a unique set of challenges, including a scarcity of available data, which limits evidence-based recommendations. Nearly half of patients with a new diagnosis of glioblastoma are over 65 years of age, a common cutoff point in the medical literature for identifying an elderly population. The current standard of care for glioblastoma patients younger than 70 years of age with satisfactory performance status is maximal safe resection, followed by radiation therapy of 60 Gy (delivered in 30 fractions over a 6-week period) with concurrent temozolomide chemotherapy, followed by adjuvant temozolomide. There is no consensus recommendation regarding the best available treatment for patients over age 70 with glioblastoma; however, multiple studies have shown molecular characterization of glioblastoma in this group-particularly MGMT promoter methylation status-to be valuable in treatment decision making. Results of the phase III CE6 study by the Canadian Cancer Trials Group challenge the existing treatment paradigms for glioblastoma in the elderly. This review discusses best practices for the treatment of glioblastoma in patients older than 65 years, and highlights management concerns in caring for this particular patient population.
Topics: Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemotherapy, Adjuvant; Dacarbazine; Disease Management; Glioblastoma; Humans; Neurosurgical Procedures; Prognosis; Radiotherapy; Temozolomide
PubMed: 28620898
DOI: No ID Found -
Cancer Treatment and Research 2015There is no generally agreed upon standard of care treatment for elderly patients (age ≥70 years) with glioblastoma (GBM). Treatment options range from supportive care... (Review)
Review
There is no generally agreed upon standard of care treatment for elderly patients (age ≥70 years) with glioblastoma (GBM). Treatment options range from supportive care only, radiation therapy (RT) only (most often given in a shortened hypofractionated schedule), temozolomide (TMZ) chemotherapy only, and the combination RT + TMZ, followed by post-RT TMZ as is the current standard of care for younger good performance patients with newly diagnosed GBM.
Topics: Aged; Brain Neoplasms; Combined Modality Therapy; DNA Modification Methylases; DNA Repair Enzymes; Dacarbazine; Glioblastoma; Humans; Isocitrate Dehydrogenase; Temozolomide; Tumor Suppressor Proteins
PubMed: 25468231
DOI: 10.1007/978-3-319-12048-5_10 -
Neuro-oncology Oct 2016Pituitary adenomas are benign intracranial neoplasms that are frequently well-controlled with standard treatments that include surgical resection, radiotherapy, and... (Review)
Review
Pituitary adenomas are benign intracranial neoplasms that are frequently well-controlled with standard treatments that include surgical resection, radiotherapy, and agents that modulate hormonal excess. Unfortunately, a subset of patients remains uncontrolled or develops complications from these interventions. For these patients, chemotherapy is an additional treatment option that could improve outcomes. Temozolomide is an oral chemotherapy with a favorable side-effect profile that has shown activity against pituitary adenomas. Its non-overlapping toxicity and ability to induce rapid tumor regression renders it a potentially important adjunctive treatment. In patients with tumors that cannot be optimally addressed with standard treatments, there may be a role for early initiation of temozolomide.
Topics: Adenoma; Antineoplastic Agents; Dacarbazine; Humans; Pituitary Neoplasms; Temozolomide
PubMed: 27106409
DOI: 10.1093/neuonc/now059 -
Expert Opinion on Pharmacotherapy Jun 2016Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the... (Review)
Review
INTRODUCTION
Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the established standard of care with temozolomide-based radiotherapy are urgently needed.
AREAS COVERED
We reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015.
EXPERT OPINION
In the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease. Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering 'tumor-treating fields' in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma.
Topics: Bevacizumab; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Glioblastoma; Humans; Neovascularization, Pathologic; Snake Venoms; Temozolomide
PubMed: 27052640
DOI: 10.1080/14656566.2016.1176146 -
Journal of Clinical Pharmacology Nov 2016
Topics: Antineoplastic Agents, Alkylating; Dacarbazine; Humans; Liver Cirrhosis; Male; Middle Aged; Temozolomide
PubMed: 27094014
DOI: 10.1002/jcph.753 -
Cancer Medicine Nov 2017Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging... (Review)
Review
Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.
Topics: Adolescent; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dacarbazine; Humans; Medulloblastoma; Molecular Targeted Therapy; Smoothened Receptor; Temozolomide
PubMed: 28980418
DOI: 10.1002/cam4.1171