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Oncotarget Jun 2017More than 40 years ago, we discovered that novel transplantation antigens can be induced in vivo or in vitro by treating murine leukemia with dacarbazine. Years later,... (Review)
Review
More than 40 years ago, we discovered that novel transplantation antigens can be induced in vivo or in vitro by treating murine leukemia with dacarbazine. Years later, this phenomenon that we called "Chemical Xenogenization" (CX) and more recently, "Drug-Induced Xenogenization" (DIX), was reproduced by Thierry Boon with a mutagenic/carcinogenic compound (i.e. N-methyl-N'-nitro-N-nitrosoguanidine). In both cases, the molecular bases of DIX rely on mutagenesis induced by methyl adducts to oxygen-6 of DNA guanine. In the present review we illustrate the main DIX-related immune-pharmacodynamic properties of triazene compounds of clinical use (i.e. dacarbazine and temozolomide).In recent years, tumor immunotherapy has come back to the stage with the discovery of immune checkpoint inhibitors (ICpI) that show an extraordinary immune-enhancing activity. Here we illustrate the salient biochemical features of some of the most interesting ICpI and the up-to-day status of their clinical use. Moreover, we illustrate the literature showing the direct relationship between somatic mutation burden and susceptibility of cancer cells to host's immune responses.When DIX was discovered, we were not able to satisfactorily exploit the possible presence of triazene-induced neoantigens in malignant cells since no device was available to adequately enhance host's immune responses in clinical settings. Today, ICpI show unprecedented efficacy in terms of survival times, especially when elevated mutation load is associated with cancer cells. Therefore, in the future, mutation-dependent neoantigens obtained by appropriate pharmacological intervention appear to disclose a novel approach for enhancing the therapeutic efficacy of ICpI in cancer patients.
Topics: Animals; DNA Repair; Humans; Immunogenetics; Immunotherapy; Mice; Molecular Targeted Therapy; Neoplasms; Triazenes
PubMed: 28404974
DOI: 10.18632/oncotarget.16335 -
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 -
British Journal of Cancer Mar 2016Glioblastoma is a unique model of non-metastasising disease that kills the vast majority of patients through local growth, despite surgery and local irradiation.... (Review)
Review
Glioblastoma is a unique model of non-metastasising disease that kills the vast majority of patients through local growth, despite surgery and local irradiation. Glioblastoma cells are resistant to apoptotic stimuli, and their death occurs through autophagy. This review aims to critically present our knowledge regarding the autophagic response of glioblastoma cells to radiation and temozolomide (TMZ) and to delineate eventual research directions to follow, in the quest of improving the curability of this incurable, as yet, disease. Radiation and TMZ interfere with the autophagic machinery, but whether cell response is driven to autophagy flux acceleration or blockage is disputable and may depend on both cell individuality and radiotherapy fractionation or TMZ schedules. Potent agents that block autophagy at an early phase of initiation or at a late phase of autolysosomal fusion are available aside to agents that induce functional autophagy, or even demethylating agents that may unblock the function of autophagy-initiating genes in a subset of tumours. All these create a maze, which if properly investigated can open new insights for the application of novel radio- and chemosensitising policies, exploiting the autophagic pathways that glioblastomas use to escape death.
Topics: Antineoplastic Agents, Alkylating; Apoptosis; Autophagy; Brain Neoplasms; Dacarbazine; Glioblastoma; Humans; Radiation-Sensitizing Agents; Radiotherapy; Temozolomide
PubMed: 26889975
DOI: 10.1038/bjc.2016.19 -
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 -
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 -
Pediatric Blood & Cancer Jan 2023Irinotecan and temozolomide achieve objective responses in patients with Ewing sarcoma that recurs after initial therapy. Optimal dose schedules have not been defined.... (Review)
Review
Irinotecan and temozolomide achieve objective responses in patients with Ewing sarcoma that recurs after initial therapy. Optimal dose schedules have not been defined. We reviewed published series of patients treated with irinotecan and temozolomide for Ewing sarcoma that recurred after initial therapy. We compared objective response rates for patients who received 5-day irinotecan treatment schedules to response rates for patients who achieved 10-day irinotecan treatment schedules. Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%). Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%). In the treatment of recurrent Ewing sarcoma, investigators should consider the use of a 10-day schedule for administration of irinotecan.
Topics: Humans; Irinotecan; Sarcoma, Ewing; Temozolomide; Camptothecin; Dacarbazine; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Neuroectodermal Tumors, Primitive, Peripheral
PubMed: 36184748
DOI: 10.1002/pbc.30005 -
Neuro-oncology Aug 2014
Review
Topics: Brain Neoplasms; Clinical Trials as Topic; Dacarbazine; Humans; Medical Oncology; Temozolomide
PubMed: 24944226
DOI: 10.1093/neuonc/nou108 -
Current Neuropharmacology 2021Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together... (Review)
Review
Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Humans; Nanotechnology; Temozolomide
PubMed: 32589560
DOI: 10.2174/1570159X18666200626204005 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Carcinogens; Humans; Neoplasms; Triazenes
PubMed: 21850142
DOI: No ID Found -
British Journal of Cancer Jan 2013Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy.
METHODS
We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias.
RESULTS
We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumour volume by 50.4% (41.8-58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias.
CONCLUSION
These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.
Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; Disease Models, Animal; Glioma; Mice; Rats; Survival Analysis; Temozolomide; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 23321511
DOI: 10.1038/bjc.2012.504