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Seminars in Radiation Oncology Oct 2014The incidence of glioblastoma (GBM) has been increasing over the past several decades with majority of this increase occurring in patients older than 70 years. In spite... (Review)
Review
The incidence of glioblastoma (GBM) has been increasing over the past several decades with majority of this increase occurring in patients older than 70 years. In spite of the growing body of evidence in this area, it is still unclear as to the optimal management of elderly patients with GBM. The elderly are a heterogeneous population with a range of comorbid conditions, and functional, cognitive, and physiological changes, and ideally treatment decisions should be made in the context of a comprehensive geriatric assessment. Patients with a poor performance status or assessed as "frail" might be considered for less aggressive therapy such as hypofractionated radiotherapy or single-agent temozolomide, whereas those with a good functional status may still benefit from maximum resection followed by combined radiation and chemotherapy. Recent randomized trials suggest molecular markers such as O(6)-methylguanine-DNA-methyltransferase promoter methylation testing could help guide these decisions, particularly when considering monotherapy with temozolomide vs radiotherapy. Ongoing studies seek to clarify the role of concurrent treatment in this population. Clinical judgment and discussion with patients and families, weighing all the options, are necessary in each case. Ultimately, patients and the neuro-oncology community should be encouraged to participate in clinical trials focused specifically on caring for the elderly patient with GBM.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Disease Management; Glioma; Humans; Temozolomide
PubMed: 25219813
DOI: 10.1016/j.semradonc.2014.06.004 -
Neurological Research Feb 2015This review article summarizes in vitro, in vivo, and clinical evidence pertaining to temozolomide (TMZ) and bevacizumab (BEV) efficacy and mechanism of action in... (Review)
Review
OBJECTIVE
This review article summarizes in vitro, in vivo, and clinical evidence pertaining to temozolomide (TMZ) and bevacizumab (BEV) efficacy and mechanism of action in gliomas.
METHODS
Relevant publications published before June 2013 in PubMed database were reviewed.
RESULTS
Temozolomide and BEV are current chemotherapeutic agents treating patients with high-grade glioma, including glioblastoma. In vitro and in vivo studies have proposed discordant cell death pathways for TMZ as either apoptosis or autophagy using different experimental setting details or cell lines. In addition, BEV may cause cell death through hypoxia-induced autophagy or unspecific indirect effects on cancer cells. The complexity of cancer cells in glioma has contributed to their resistance of both chemotherapies. In clinical trials, overall survival duration in glioma patients with recurrence (8-9 months) is lower than that in newly diagnosed patients (12-15 months).
CONCLUSION
Our collected data support the addition of radiotherapy, BEV, and other targeted agents to TMZ treatment, indicating prolonged survival duration in newly diagnosed patients. However, the optimal regimen for treating high-grade glioma cannot be concluded without more clinical trials.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Cell Death; Combined Modality Therapy; Dacarbazine; Glioma; Humans; Neoplasm Recurrence, Local; Temozolomide
PubMed: 25033940
DOI: 10.1179/1743132814Y.0000000423 -
Neuro-oncology Nov 2021
Topics: Antineoplastic Agents, Alkylating; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 34347098
DOI: 10.1093/neuonc/noab186 -
Cancer Research Feb 2017In the January 1, 2017, issue of , Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to... (Review)
Review
In the January 1, 2017, issue of , Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cytometric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and mismatch repair (MMR) status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard, does not accurately reflect the expression of MGMT. Also, genomics for MMR are warranted. Furthermore, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity. .
Topics: Antineoplastic Agents, Alkylating; DNA Methylation; DNA Mismatch Repair; DNA Modification Methylases; DNA Repair Enzymes; Dacarbazine; Humans; Neoplasms; Precision Medicine; Temozolomide; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays
PubMed: 28159862
DOI: 10.1158/0008-5472.CAN-16-2983 -
Cancer Medicine Mar 2023Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G phase of the...
BACKGROUND
Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G phase of the cell cycle under the influence of therapeutic drugs has been identified as an event associated with tumor dissemination. In the present study, we investigated the ability of chemotherapeutic agent dacarbazine to induce a transition of melanoma cells to the G phase as a mechanism of chemoresistance.
METHODS
We used the flow cytometry to analyze cell distribution within cell cycle phases after dacarbazine treatment as well as to identifyG -positive cells population. Transcriptome profiling was provided to determine genes associated with dacarbazine resistance. We evaluated the activity of β-galactosidase in cells treated with dacarbazine by substrate hydrolysis. Cell adhesion strength was measured by centrifugal assay application with subsequent staining of adhesive cells with Ki-67 monoclonal antibodies. Ability of melanoma cells to metabolize dacarbazine was determined by expressional analysis of CYP1A1, CYP1A2, CYP2E1 followed by CYP1A1 protein level evaluation by the ELISA method.
RESULTS
The present study determined that dacarbazine treatment of melanoma cells could induce an increase in the percentage of cells in G phase without alterations of β-galactosidase positive cells which corresponded to the fraction of the senescent cells. Transcriptomic profiling of cells under dacarbazine induction of G -positive cells percentage revealed that 'VEGFA-VEGFR2 signaling pathway' and 'Cell cycle' signaling were mostly enriched by dysregulated genes. 'Focal adhesion' signaling was also found to be triggered by dacarbazine. In melanoma cells treated with dacarbazine, an increase in G -positive cells among adherent cells was found.
CONCLUSIONS
Dacarbazine induces the alteration in a percentage of melanoma cells residing in G phase of a cell cycle. The altered adhesive phenotype of cancer cells under transition in the G phase may refer to a specific intercellular communication pattern of quiescent/senescent cancer cells.
Topics: Humans; Cell Line, Tumor; Melanoma; Dacarbazine; Cell Cycle; Cell Division
PubMed: 36533319
DOI: 10.1002/cam4.5510 -
CNS Oncology 2015Gliosarcoma (GS) is a malignant, uncommon variant of high-grade glioma comprised of infiltrative glial and atypical sarcomatous cells, identified in adult and pediatric... (Review)
Review
Gliosarcoma (GS) is a malignant, uncommon variant of high-grade glioma comprised of infiltrative glial and atypical sarcomatous cells, identified in adult and pediatric populations. GS has been subcategorized into primary (de novo) and secondary tumors, with the latter typically arising in the setting of prior glioblastoma. Due to its rarity, the pathogenesis, epidemiology and optimal therapy of GS have been based on small retrospective cohort studies, with treatment presently utilizing regimens established for other high-grade gliomas, including combination of resection, radiotherapy and temozolomide-based chemotherapy. As more information is gathered about GS molecular profiles, novel treatment strategies may be developed to improve outcomes of GS patients. Here we summarize results of GS management with focus on the temozolomide era.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; Disease Management; Gliosarcoma; Humans; Temozolomide
PubMed: 25905568
DOI: 10.2217/cns.14.61 -
CNS Oncology 2015Anaplastic oligodendrogliomas (AOs) are rare brain tumors responsive to chemotherapy with procarbazine, lomustine (CCNU) and vincristine (PCV), especially when harboring... (Review)
Review
Anaplastic oligodendrogliomas (AOs) are rare brain tumors responsive to chemotherapy with procarbazine, lomustine (CCNU) and vincristine (PCV), especially when harboring 1p19q codeletion. However, with the emergence of temozolomide as an easier to administer and less toxic alternative regimen, PCV fell out of favor. Now, long-term results of two Phase III studies conceived in the 1990s, Radiation Therapy Oncology Group (RTOG) 9402 and European Organisation for Research and Treatment of Cancer (EORTC) 26951, resurrected debate about the potential role of PCV. No adequately powered prospective trial has compared chemotherapy alone with PCV versus temozolomide for newly diagnosed 1p19q codeleted AOs. Available data suggest responses may be both more frequent and more durable with PCV, and survival may be longer. Which regimen is 'better', therefore, depends on the importance of different metrics (i.e., toxicity, complexity, efficacy), and await definitive results from the important ongoing and recently redesigned CODEL international Phase III trial.
Topics: Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Dacarbazine; Humans; Lomustine; Oligodendroglioma; Procarbazine; Temozolomide; Treatment Outcome; Vincristine
PubMed: 26544062
DOI: 10.2217/cns.15.36 -
CNS & Neurological Disorders Drug... 2023Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the... (Review)
Review
BACKGROUND
Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable.
OBJECTIVE
The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide.
METHODS
The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines.
DESCRIPTION
One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy.
CONCLUSION
This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.
Topics: Humans; Temozolomide; Glioblastoma; O(6)-Methylguanine-DNA Methyltransferase; Dacarbazine; Antineoplastic Agents, Alkylating; DNA; Cell Line, Tumor; Brain Neoplasms
PubMed: 35379142
DOI: 10.2174/1871527321666220404180944 -
International Journal of Molecular... Mar 2022Melanoma is a drug-resistant cancer, representing a serious challenge in cancer treatment. Dacarbazine (DTIC) is the standard drug in metastatic melanoma treatment,...
Melanoma is a drug-resistant cancer, representing a serious challenge in cancer treatment. Dacarbazine (DTIC) is the standard drug in metastatic melanoma treatment, despite the poor results. Hyperthermia has been proven to potentiate chemotherapy. Hence, this work analyzed the combined action of hyperthermia and DTIC on A375 and MNT-1 cell lines. First, temperatures between 40 °C and 45 °C were tested. The effect of DTIC on cell viability was also investigated after exposures of 24, 48, and 72 h. Then, cells were exposed to 43 °C and to the respective DTIC IC10 or IC20 of each time exposure. Overall, hyperthermia reduced cell viability, however, 45 °C caused an excessive cell death (>90%). Combinational treatment revealed that hyperthermia potentiates DTIC’s effect, but it is dependent on the concentration and temperature used. Also, it has different mechanisms from the treatments alone, delaying A375 cells at the G2/M phase and MNT-1 cells at the S and G2/M phases. Intracellular reactive oxygen species (ROS) levels increased after treatment with hyperthermia, but the combined treatment showed no additional differences. Also, hyperthermia highly increased the number of A375 early apoptotic cells. These results suggest that combining hyperthermia and DTIC should be more explored to improve melanoma treatment.
Topics: Cell Line, Tumor; Cell Survival; Dacarbazine; Humans; Hyperthermia, Induced; Melanoma; Reactive Oxygen Species
PubMed: 35408947
DOI: 10.3390/ijms23073586 -
Best Practice & Research. Clinical... Dec 2022Survival for patients with aggressive pituitary tumours (APT) and pituitary carcinomas (PC) has significantly improved following the increasing use of temozolomide (TMZ)... (Review)
Review
Survival for patients with aggressive pituitary tumours (APT) and pituitary carcinomas (PC) has significantly improved following the increasing use of temozolomide (TMZ) since the first reports of response in 2006. TMZ was established as first line chemotherapy for APT/PC in the 2018 ESE guidelines on the management of APT/PC. There is no controversy over its use as salvage therapy however there is increasing interest in exploring TMZ use earlier in the treatment algorithm for APT/PC. Overall response rates as reported in systematic reviews are around 40% but stable disease in another 25% illustrates the clinical effectiveness of TMZ. Response is higher among functional compared to non-functional tumours. Where maximal radiation thresholds have not been reached in a patient, combination radiotherapy and TMZ appears more effective. Whether combination TMZ and capecitabine (CAPTEM) offers increased benefit remains uncertain particularly given added toxicity. O6-methyl guanine DNA methyl transferase (MGMT) status is important in determining response to treatment, although examination via immunohistochemistry versus PCR-based promoter-methylation analysis remains somewhat controversial. Optimal duration of TMZ treatment has still not been determined although longer treatment courses have been associated with increased progression-free survival. Treatment options following disease progression after TMZ remain unclear but include a second course of TMZ, immunotherapy and targeted oncological agents such as bevacizumab and lapatinib as well as peptide receptor radionuclide treatment (PRRT). An experienced pituitary multidisciplinary team is essential to all management decisions in patients with APT/PC.
Topics: Humans; Temozolomide; Pituitary Neoplasms; Dacarbazine; Antineoplastic Agents, Alkylating; Systematic Reviews as Topic
PubMed: 36274026
DOI: 10.1016/j.beem.2022.101713