-
Neuro-oncology Mar 2021
Topics: Brain Neoplasms; Dacarbazine; Humans; Oligodendroglioma; Temozolomide
PubMed: 33560350
DOI: 10.1093/neuonc/noab006 -
Molecular Biology Reports Oct 2014Temozolomide (TMZ) is an alkylating agent that is widely used in chemotherapy for cancer. A key mechanism of resistance to TMZ is the overexpression of... (Review)
Review
Temozolomide (TMZ) is an alkylating agent that is widely used in chemotherapy for cancer. A key mechanism of resistance to TMZ is the overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT). MGMT specifically repairs the DNA O(6)-methylation damage induced by TMZ and irreversibly inactivates TMZ. Regulation of MGMT expression and research regarding the mechanism of TMZ resistance will help rationalize the clinical use of TMZ. In this review, we provide an overview of recent advances in the field, with particular emphasis on MGMT structure, function, expression regulation, and the association between MGMT and resistance to TMZ.
Topics: Animals; Antineoplastic Agents, Alkylating; DNA Methylation; Dacarbazine; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Promoter Regions, Genetic; Research; Temozolomide
PubMed: 24990698
DOI: 10.1007/s11033-014-3549-z -
Current Opinion in Neurology Dec 2014Glioblastoma is the most common malignant brain tumor in adults and carries a particularly poor prognosis. Since 2005, state-of-the-art therapy consists of maximal well... (Review)
Review
PURPOSE OF REVIEW
Glioblastoma is the most common malignant brain tumor in adults and carries a particularly poor prognosis. Since 2005, state-of-the-art therapy consists of maximal well tolerated surgical resection followed by combined radiotherapy and chemotherapy with temozolomide. Over the past decade, further advances have been achieved in various disciplines, most prominently including antiangiogenic treatment with bevacizumab. Still, whether these therapeutic innovations have translated to the general population remains unclear.
RECENT FINDINGS
Population-based outcome and pattern of care (POC) studies have recently documented the rapid dissemination of the treatment standard to community practice across countries. This has resulted in a modest but significant increase in survival at the population level. However, the increase was significantly less marked in elderly patients in whom undertreatment is a concern. Other serious concerns address diverging POC between academic versus nonacademic centers, patients with high-income versus low-income, and racial and marital status disparities. With regard to bevacizumab treatment, there is still insufficient evidence of a beneficial impact on population-based survival, so far.
SUMMARY
Despite the rapid incorporation of the current standard treatment in clinical practice and the thereby achieved modest survival gain at the population-level, prevailing POC needs to be reconsidered and standardized, especially for elderly glioblastoma patients who bear a large disease burden and carry the worst prognosis. Future POC studies are urgently needed and would benefit from the systematic inclusion of quality-of-life data and molecular tumor markers, so that this information could be captured in population-based cancer registries.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Community Health Planning; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 25364955
DOI: 10.1097/WCO.0000000000000144 -
Carbohydrate Polymers Sep 2023The aim of this study was to investigate the anti-melanoma and anti-angiogenic effects of enoxaparin surface-coated dacarbazine-loaded chitosan nanoparticles...
The aim of this study was to investigate the anti-melanoma and anti-angiogenic effects of enoxaparin surface-coated dacarbazine-loaded chitosan nanoparticles (Enox-Dac-Chi NPs). The prepared Enox-Dac-Chi NPs had a particle size of 367.95 ± 1.84 nm, zeta potential of -7.12 ± 0.25 mV, efficiency of drug loading (DL%) of 73.90 ± 3.84 %, and attached enoxaparin percentage of 98.53 ± 0.96 %. Both drugs had extended-release profiles and approximately 96 % of enoxaparin and 67 % dacarbazine were released within 8 h. The Enox-Dac-Chi NPs with IC of 59.60 ± 1.25 μg/ml were the most cytotoxic against melanoma cancer cells compared with chitosan nanoparticles containing only dacarbazine (Dac-Chi NPs) and free dacarbazine. There was no significant difference between the cellular uptake of Chi NPs and enoxaparin coated Chi NPs (Enox-Chi NPs) in B16F10 cells. Enox-Chi NPs with an average anti-angiogenic score of 1.75 ± 0.125 had more anti-angiogenic effect than enoxaparin. The results showed that simultaneous delivery of dacarbazine and enoxaparin by chitosan nanoparticles can enhance the anti-melanoma effect of dacarbazine. Additionally, enoxaparin can prevent the melanoma metastasis by its anti-angiogenic activity. Thus, the designed nanoparticles can be introduced as effective drug delivery vehicles for the treatment and prevention of metastatic melanoma.
Topics: Humans; Enoxaparin; Dacarbazine; Chitosan; Drug Delivery Systems; Melanoma; Nanoparticles
PubMed: 37321735
DOI: 10.1016/j.carbpol.2023.121041 -
Molecular Pharmaceutics Jul 2024Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent...
Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.
Topics: Solubility; Crystallization; X-Ray Diffraction; Dacarbazine; Photolysis; Spectroscopy, Fourier Transform Infrared; Magnetic Resonance Spectroscopy; Calorimetry, Differential Scanning
PubMed: 38858241
DOI: 10.1021/acs.molpharmaceut.4c00393 -
Progress in Neurological Surgery 2018Alternating electric fields of intermediate frequencies, also known as Tumor Treating Fields (TTFields or TTF) is a novel anticancer treatment modality that disrupts... (Review)
Review
Alternating electric fields of intermediate frequencies, also known as Tumor Treating Fields (TTFields or TTF) is a novel anticancer treatment modality that disrupts tumor cell mitosis at the metaphase-anaphase transition, leading to mitotic catastrophe, aberrant mitotic exit, and/or cell death. It is realized through alteration of the cytokinetic cleavage furrow by interference of proteins possessing large dipole moments, like septin heterotrimer complex and α/β-tubulin, and that results in disordered membrane contraction and failed cytokinesis. Aberrant mitotic exit also elicits immunogenic cell death, which may potentiate an immune response against treated tumors. Notably, in patients with recurrent glioblastoma multiforme (GBM) a prospective clinical trial demonstrated comparable overall survival and progression-free survival after TTFields therapy and best physician's choice chemotherapy. Moreover, it was shown that in patients with newly diagnosed GBM initially treated with standard chemoradiotherapy with daily temozolomide (TMZ), adjuvant TTFields combined with TMZ offered better survival than adjuvant TMZ alone. Therefore, TTFields therapy can be appreciated as a standard treatment option in cases of intracranial malignant gliomas, whereas future studies should establish its optimal combination with other existing anticancer modalities, which may offer additional survival benefits for patients.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Electric Stimulation Therapy; Electromagnetic Fields; Glioma; Humans; Mitosis; Neoplasm Recurrence, Local; Temozolomide
PubMed: 29990984
DOI: 10.1159/000469690 -
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 -
Medicine Oct 2018Retrospective studies have suggested that capecitabine combined with temozolomide (CAPTEM) is effective for treating patients with advanced neuroendocrine neoplasms... (Meta-Analysis)
Meta-Analysis Review
Retrospective studies have suggested that capecitabine combined with temozolomide (CAPTEM) is effective for treating patients with advanced neuroendocrine neoplasms (NENs); however, the efficacy and safety of this regimen needs to be verified by high-quality evidence or results of randomized controlled trials.We carried out a meta-analysis to evaluate the safety and effectiveness of a CAPTEM protocol for patients with advanced NENs. Systematic electronic literature searches were conducted using PubMed, EMBASE, and the Cochrane Library, and among meeting abstracts of the American Society of Clinical Oncology, European Society for Medical Oncology, European Neuroendocrine Tumor Society, and North American Neuroendocrine Tumor Society, up to June 30, 2017. We selected studies describing CAPTEM regimens for treating advanced NENs and reported on tumor response and/or toxicities according to clear World Health Organization (WHO) grading of patients. Three reviewers independently and repeatedly identified studies, extracted data, and assessed the quality of the literature. A single-proportion meta-analysis was applied to included articles.Fifteen studies with a total of 384 individuals were included. Medium overall survival in most studies was more than 12 months, whereas medium progression-free survival was similar or slightly higher than that in studies using other treatment regimes. Disease control rate of CAPTEM administration for patients with NENs was 72.89% (95% confidence interval, 64.04-81.73%; I = 82.4%; P < .01). WHO grade 3 to 4 toxicities, such as thrombocytopenia (3.36%), neutropenia (0.69%), lymphopenia (0.65%), anemia (0.59%), mucositis (0.57%), fatigue (0.54%), diarrhea (0.49%), nausea (0.39%), and transaminase elevation (0.13%) were reported in the trials included.CAPTEM is effective and relatively safe for treating patients with advanced NENs.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Dacarbazine; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Observational Studies as Topic; Survival Analysis; Temozolomide
PubMed: 30313101
DOI: 10.1097/MD.0000000000012784 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2016This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy... (Review)
Review
AIM
This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy (PRRT)-chemotherapy of GEPNETs, analyses the risk of both short- and long-term hematotoxicity.
BACKGROUND
Myelodysplastic syndrome (MDS) and acute leukemia (AL) have been associated with PRRT in heavily pretreated patients with a history of exposure to alkylating agents. Commenced 15 years ago, PRRT is now becoming established as first- and second-line therapy for gastroentero pancreatic neuroendocrine tumors (GEPNETs), and early treatment minimizes myelotoxicity, which is the most significant potential adverse event following PRRT.
RESULTS
Sixteen key articles involving primary research were identified. A total of 2225 patients were treated (2104 treated with PRRT monotherapy and 121 with PRRT combined with chemotherapy). The average age of patients in these studies ranged from 53 to 64 years with median duration of follow-up ranging from 6 to 62 months. Short-term myelotoxicity was observed in 221 patients (10%), occurring in 213 of 2104 patients treated with PRRT monotherapy and 8 of 121 patients treated with PRRT combined with chemotherapy. Acute toxicity manifested as modest self-limited grade 3/4 toxicity (CTCAE or WHO), most often affecting platelets during the first cycle of treatment. Toxicity manifesting early was easily managed with dose modification or therapy cessation and was ameliorated by appropriate patient selection. MDS/AL was a rare stochastic event occurring in 32 (1.4%) patients. Where bone marrow biopsy was performed, cases of MDS displayed cytogenetic abnormalities, consistent with secondary MDS. Factors associated with myelotoxicity included age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior chemotherapy (alkylating agents), and prior radiotherapy.
CONCLUSION
Early therapy with PRRT-containing regimens improves outcomes, minimizes myelotoxicity, and renders the risk of MDS and AL negligible.
Topics: Capecitabine; Dacarbazine; Female; Humans; Lutetium; Male; Middle Aged; Myelodysplastic Syndromes; Neuroendocrine Tumors; Octreotide; Radiation Injuries; Radioisotopes; Radiopharmaceuticals; Temozolomide
PubMed: 27419665
DOI: 10.1089/cbr.2016.2035 -
Hormones (Athens, Greece) Apr 2017Pituitary tumors represent 10-15% of all intracranial tumors; of these, prolactinomas account for 40-50% of cases. Prolactinomas usually respond well to dopamine... (Review)
Review
Pituitary tumors represent 10-15% of all intracranial tumors; of these, prolactinomas account for 40-50% of cases. Prolactinomas usually respond well to dopamine agonists (DA) as first-line therapy. However, treatment resistance remains a concern. Temozolomide (TMZ) is an oral alkylating agent that has shown promise in treating aggressive pituitary adenomas and carcinomas that are resistant to other therapies. To date, no control trials have been undertaken and only single case reports of pituitary tumors treated with TMZ have been published. A systematic literature search was conducted for studies reporting the use of TMZ for the treatment of prolactinomas that were resistant to standard therapy. In total, 42 reported cases were identified and included in our analysis: 23 cases of prolactin-secreting adenomas and 19 of prolactin-secreting carcinomas. Prior to TMZ administration, patients had exhibited tumor progression and had previously undergone various treatments including surgery, radiotherapy, and drug therapy. Tumor shrinkage was reported in 76% of patients. Reduced prolactin levels were observed in 75% of patients, while normalization of prolactin was reported in 8%. TMZ failure occurred in 20.6% of cases. Most patients exhibited no serious adverse effects. In conclusion, TMZ has potential for the treatment of highly aggressive and resistant prolactin-secreting adenomas and carcinomas, as demonstrated by tumor shrinkage or complete response and normalization of hormone hypersecretion, and exhibits good tolerability and few side effects.
Topics: Antineoplastic Agents, Alkylating; Carcinoma; Dacarbazine; Humans; Pituitary Neoplasms; Prolactinoma; Temozolomide
PubMed: 28742502
DOI: 10.14310/horm.2002.1729