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PubMed2026

Extracellular Vesicles From Glioblastoma Cells Reflect 2D vs. 3D Culture Adaptation and Resistance to Temozolomide.

Glioblastoma (GBM) is an aggressive brain tumor marked by extensive heterogeneity, resistance to therapy, and dismal prognosis. Extracellular vesicles (EVs) have emerged as key players in GBM biology, mediating intercellular communication and therapy adaptation. However, the exact functions and molecular impact of EVs in GBM remain incompletely understood. In this study, we performed a comparative proteomic analysis of U87MG GBM cells grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroids following temozolomide (TMZ) treatment, alongside characterization of EVs derived from both culture systems. 3D-spheroids secreted more EVs of smaller size and exhibited a more TMZ-resistant, stem-like proteome under TMZ-induced genotoxic stress. In contrast, 2D cell cultures demonstrated greater proteome remodeling, with EVs enriched in protein families involved in DNA repair, oxidative stress adaptation, and methylation processes. Notably, several methyltransferases were decreased intracellularly but selectively retained in EVs, suggesting active sorting to influence the tumor microenvironment or modulate epigenetic states in recipient cells. EVs also carried adhesion molecules and signaling proteins linked to migration, invasion, and Wnt pathway activation, as well as metabolic enzymes connecting serine metabolism and redox control to TMZ resistance. Mapping EV and cellular proteomes onto The Cancer Genome Atlas (TCGA) dataset identified prognostic protein families associated with either poor or favorable patient outcomes. Our data demonstrate that EV cargo composition mirrors TMZ-induced phenotypic adaptation and reveals molecular mechanisms underlying therapeutic resistance. These EV-associated signatures may serve as clinically actionable biomarkers for patient stratification and offer potential targets to overcome chemoresistance in GBM.

Humans↗
PubMed2000

Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between low- and zero-flow ischaemia.

OBJECTIVE: The aim of this study was to investigate whether trimetazidine (TMZ; 10(-6)M), which has been shown to inhibit fatty acid oxidation, reduces the ionic imbalance induced by ischaemia and reperfusion, especially through an attenuation in intracellular changes in H(+) and Na(+). METHODS: Isovolumic rat hearts receiving 5.5 mM glucose and 1.2 mM palmitate as metabolic substrates were exposed to zero-flow ischaemia (TI) or low-flow ischaemia (LFI - coronary flow decreased by an average of 90%) (30 min at 37 degrees C) and then reperfused. 23Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor intracellular Na(+) (Na(+)(i)) and 31P NMR spectroscopy was used to monitor intracellular pH (pH(i)). RESULTS: During LFI the major effect of TMZ was a significant reduction in intracellular acidosis, whereas during TI the main effect of TMZ was a significant reduction in Na(+)(i) gain. In addition, the further gain in Na(+)(i) that occurred during the first minutes of reperfusion following TI, and to a far lesser extent following LFI, was suppressed in TMZ-treated hearts and also suppressed when hearts were perfused without fatty acid. In both LFI and TI, TMZ-induced attenuation of ionic imbalance was associated with a significantly improved recovery of ventricular function on reperfusion, as assessed by a lower increase in diastolic pressure and an increased recovery of developed pressure. CONCLUSION: Our data provide evidence that specific myocardial metabolic modulation plays a significant role in reducing ionic imbalance during ischaemia and reperfusion.

Analysis of Variance↗
PubMed2001

The effects of trimetazidine on heart rate variability and signal-averaged electrocardiography in early period of acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is accompanied by electrophysiological changes in cardiovascular system as well as those in autonomic cardiac control. Heart rate variability (HRV) is depressed due to increased sympathetic activity and/or decreased parasympathetic activity following AMI. Moreover, the frequency of ventricular late potentials (VLP) is increased due to the electrophysiological changes. Based on the hypothesis that the treatments increasing HRV and decreasing the frequency of VLP can improve the prognosis of AMI, we investigated the short-term effects of trimetazidine (TMZ) on HRV and VLP in patients with AMI. METHODS: The study group consisted of 64 patients (men 49, mean age 55+/-12 years, range 26-70) suffering from first Q-wave AMI. Thirty-one of them were treated with conventional therapy (thrombolytic therapy, aspirin, beta-blocker, heparin and intravenous nitroglycerin) plus TMZ 20 mg tid. The remaining 33 patients served as controls. Holter monitorization between 24 and 48 h, echocardiography at average day 6 (range 4-7 days) and SAECG and sub-maximal exercise at average day 7 (range 6-9 days) were performed to all patients. RESULTS: While HRV parameters reflecting parasympathetic activity (SDSD: 43+/-16 ms-35+/-13 ms, RMSSD: 34+/-14 ms-27+/-8 ms, HF: 7.8+/-5 ms(2) -4.3+/-4 ms(2), P<0.05) were of significantly higher levels in TMZ group, the low frequency component mainly reflecting sympathetic activity (LF: 10+/-6 ms(2)-10+/-5 ms(2), P>0.05) was similar in both groups. In addition, LF/HF ratio showing sympatho-vagal balance was significantly decreased in TMZ group (1.5-3.0, P=0.005). About VLP, the mean FQRS (105+/-8 ms-107+/-10 ms), LAS (28+/-10 ms-30+/-11 ms) and RMS-40 (34+/-15 microV-41+/-12 microV) were not different in both two groups (P>0.05). CONCLUSION: Our results suggest that TMZ treatment causes changes in sympatho-vagal balance in favor of vagal activity by increasing parasympathetic activity in AMI at early period; however, no effect on VLP was observed.

Adult↗
PubMed2003

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN alpha in patients with metastatic melanoma.

The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.

Adult↗
PubMed2003

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972.

BACKGROUND: Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. PATIENTS AND METHODS: In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. RESULTS: Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. CONCLUSIONS: TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.

Adult↗
PubMed2006

Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma. PATIENTS AND METHODS: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression. RESULTS: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases. CONCLUSION: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.

Antineoplastic Agents, Alkylating↗
PubMed2004

Evidence for protective roles of polyethylene glycol plus high sodium solution and trimetazidine against consequences of renal medulla ischaemia during cold preservation and reperfusion in a pig kidney model.

BACKGROUND: The renal medulla is particularly sensitive to oxidant stress and to ischaemia-reperfusion injury (IRI). In organ transplantation, delayed graft function is an important problem and cold ischaemia is thought to be the most important factor in short- and long-term complications. Our aim was to study cold-induced damage in proximal tubular segments and renal medulla osmolite excretion during use of various preservation solutions, and to clarify the role of trimetazidine (TMZ) in limiting renal dysfunction. METHODS: Using an autotransplanted pig kidney model, we assessed renal tubule function, medullary osmolite excretion and renal damage between day 1 and week 2 after 24 or 48 h cold storage in University of Wisconsin solution (UW), Celsior and ECPEG (two new high Na(+) preservation solutions) or the Hopital Edouard Herriot solution (HEH; a high Na(+) version of UW). In additional groups, TMZ was added to these preservation solutions for 24 and 48 h cold storage. RESULTS: Renal function was reduced under these preservation conditions. Tubular injury was associated with aminoaciduria and with a limited Na(+) reabsorbtion. Medullary damage led to the early appearance of trimethylamine-N-oxide and dimethylamine in urine. However, renal damage was modulated by preservation conditions. In addition, TMZ added to each of the solutions efficiently protected against IRI even after prolonged preservation. CONCLUSION: TMZ efficiently protected kidneys against damage when added to the HEH and particularly ECPEG solutions, even after 24 h cold storage. These findings point to a role for drugs that target mitochondria, and demonstrate that TMZ may provide a valuable therapeutic tool against IRI and could be included in therapeutic protocols.

Animals↗
PubMed1992

Myocardial protection during percutaneous transluminal coronary angioplasty: effects of trimetazidine.

Trimetazidine (TMZ) has recently been shown to improve anginal symptoms without altering haemodynamic variables. A randomized, double-blind, placebo-controlled study was conducted in 20 patients to study the effects of TMZ on the severity of myocardial ischaemia during PTCA of the left anterior descending coronary artery. Five minutes after a first successful dilatation (D0), a control balloon inflation (D1) was performed until onset of ischaemic signs on both the intracoronary (i.c.) and precordial ECG. Two minutes later, patients received either TMZ 6 mg or placebo i.c. Another inflation (D2) was performed 5 min after D1. No differences were found between the two groups regarding responses in heart rate, systemic and i.c. pressures during the study. TMZ decreased the maximum ST-segment shift at D2 compared with D1 (0.8 +/- 0.1 vs 1.4 +/- 0.3 mV, P = 0.023) and delayed its onset (46 +/- 4 vs 36 +/- 5 s, P = 0.024). TMZ also decreased maximum T-wave changes (1.06 +/- 0.24 vs 2.19 +/- 0.3 mV, P = 0.001), and significantly reduced the area under the curve (mv s-1) of the i.c. ST-segment and T-wave changes during balloon inflation (P = 0.042 and P = 0.009 respectively). The placebo had no effect on these parameters. These results support the hypothesis that trimetazidine has a direct anti-ischaemic effect on human myocardial cells.

Angioplasty, Balloon, Coronary↗
PubMed2006

Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma.

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the antitumor activity of the topoisomerase I inhibitor irinotecan (CPT-11), which is used to treat advanced colorectal carcinoma. Since PARP inhibitors sensitize tumor cells also to the methylating agent temozolomide (TMZ) and clinical trials are evaluating CPT-11 in combination with TMZ, we tested whether the PARP inhibitor GPI 15427 (10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one) increases the efficacy of CPT-11 + TMZ against colon cancer. Moreover, due to the ability of PARP inhibitors to avoid cell death consequent to PARP-1 overactivation, we evaluated whether oral administration of GPI 15427 provides protection from the dose-limiting intestinal toxicity of CPT-11. The results of colony formation assay indicated that GPI 15427 increased the antiproliferative effects (combination index <1) of TMZ + SN-38 (the active metabolite of CPT-11) against colon cancer cells. Accordingly, GPI 15427 (40 mg/kg/dayx5 days per os) in combination with TMZ (10 mg/kg/dayx5 days) + CPT-11 (4 mg/kg/dayx5 days) significantly reduced the growth of tumor xenografts. Oral administration of GPI 15427 (40 mg/kg/q2x3 days) prevented intestinal injury and diarrhea induced by CPT-11 (30 mg/kg/day x 3 days) reducing inflammation and PARP-1 overactivation, as evidenced by immunohistochemical staining of intestinal tissue with antipoly(ADP-ribose) antibody (Ab). In conclusion, the PARP inhibitor represents a novel strategy to enhance the antitumor efficacy and reduce toxicity of chemotherapy in colon cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)--phase I/II trial: study protocol.

BACKGROUND: The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory. The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising. METHODS/DESIGN: GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial. Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrollment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient. DISCUSSION: The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM.

Adolescent↗
PubMed2004

First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia.

PURPOSE: Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. PATIENTS AND METHODS: Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. RESULTS: A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). CONCLUSION: The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

Adult↗
PubMed2005

Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme.

PURPOSE: Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM. PATIENTS AND METHODS: One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m(2)/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m(2) on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53). RESULTS: Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild. CONCLUSION: TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.

Adult↗
PubMed2006

Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial.

PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.

Adult↗
PubMed2006

The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas.

Temozolomide (TMZ) administered daily with radiation therapy (RT) for six weeks, followed by adjuvant TMZ for six months, has become standard therapy for patients with glioblastoma multiforme (GBM). After several newly diagnosed patients at our institution developed severe (grade 3-4), prolonged thrombocytopenia, we conducted a retrospective review to define the incidence, depth, and duration of thrombocytopenia associated with this therapy. We reviewed the medical records and laboratory data of all adult patients with newly diagnosed high-grade gliomas who started treatment with this regimen between June 2004, when the regimen was first used at our institution, and August 2005. Of the 52 patients who met the criteria for this review, grade 3-4 thrombocytopenia occurred in 10 (19%; 95% CI, 10%-33%). In eight patients, the thrombocytopenia was attributable to concurrent daily TMZ and RT. The median duration of grade 3-4 thrombocytopenia was 32 days (range, 1-389 days). Five patients (10%) required platelet transfusions, two (4%) have required continued biweekly platelet transfusions for over six months, and nine (17%) discontinued therapy because of thrombocytopenia. Grade 3-4 thrombocytopenia occurred in 25% of women and 14% of men. Grade 3-4 neutropenia and anemia were noted in 10% and 8% of patients, respectively, and were not clinically significant. Between 15% and 20% of our newly diagnosed patients receiving TMZ and RT developed severe (grade 3-4) and potentially irreversible thrombocytopenia. The factors that predispose patients to this toxicity have yet to be determined. This toxicity should be considered when (1) prescribing this regimen to patient populations where a clinical benefit has yet to be shown, (2) contemplating empirical escalations of the dose or duration of TMZ, or (3) combining it with other potentially myelosuppressive therapies.

Adult↗
PubMed1988

Inhibitory effects of trimetazidine dihydrochloride on aggregation, serotonin release and malondialdehyde production in rabbit platelets.

Aggregation, serotonin release and malondialdehyde (MDA) production via cyclooxygenase and thromboxane A2 synthetase were investigated in rabbit platelets. Trimetazidine dihydrochloride (TMZ) attenuated the collagen-induced aggregation more strongly than the arachidonic acid (AA)-, thromboxane A2 agonist (U-46619)-, Ca2+-ionophore (A-23187)- and ADP-induced aggregation: IC50 values were 1.0 +/- 0.1, 4.4 +/- 0.3, 4.3 +/- 0.4, 4.1 +/- 0.7 and 3.3 +/- 0.2 mM, respectively. TMZ decreased dose-dependently the serotonin release induced by collagen and A-23187, but did not decrease that induced by AA. TMZ also decreased the MDA production induced by collagen and A-23187 (IC50: 0.3 +/- 0.03 and 1.0 +/- 0.1 mM, respectively), but did not decrease the production induced by AA. Furthermore, TMZ decreased dose-dependently the MDA production induced by exogenous phospholipase A2. On the other hand, indomethacin (10 microM) attenuated the aggregation induced by collagen and AA, but not by the other agents, and decreased the serotonin release and the MDA production induced by collagen, A-23187 and AA. The present results suggest that TMZ may inhibit the process preceding the cyclooxygenase pathway in the AA cascade, and subsequently may attenuate the aggregation and the serotonin release via thromboxane A2 production from endogenous AA.

Animals↗
PubMed2005

Temozolomide: a milestone in the pharmacotherapy of brain tumors.

Temozolomide (TMZ) is an alkylating agent earlier approved for recurrent anaplastic astrocytoma and approved for the treatment of newly diagnosed glioblastoma in the USA and Europe in 2005. TMZ shows good blood-brain barrier penetration and exhibits a favorable side effect profile. Its key mode of action appears to be methylation at N(7) and O(6)-positions of guanine. The level of expression and activity of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase is thought to be a major predictor of response to TMZ. The demonstration of prolonged survival when TMZ was added to radiotherapy in the European Organisation for Research and Treatment of Cancer 26981/22981/NCIC CE.3 trial has been a breakthrough in the treatment of newly diagnosed glioblastoma. The early preliminary evidence for activity in recurrent malignant gliomas further resulted in a broad evaluation of TMZ for other tumors in neuro-oncology, mainly low-grade gliomas, brain metastases and primary cerebral lymphomas.

Antineoplastic Agents, Alkylating↗
PubMed1992

Diazepam metabolism by rat and human liver in vitro: inhibition by mephenytoin.

1. Diazepam metabolism and its association with mephenytoin hydroxylase were studied in vitro using human and rat livers. 2. Enzyme kinetic parameters were obtained for the formation of p-hydroxydiazepam (p-hydroxy-DZP), N-desmethyldiazepam (NDZ), and temazepam (TMZ) from diazepam (DZP) in rat liver fractions. The Km values for formation in rat of p-hydroxy-DZP, NDZ and TMZ were 14 +/- 3 (SEM) microM, 44 +/- 4 and 63 +/- 8, respectively; clearance values calculated from Vmax/Km were 5.7, 3.2 and 4.9 ml/g per min, respectively. 3. Mephenytoin (MP) competitively inhibited, in rat liver, the formation of NDZ, but not the formation of p-hydroxy-DZP or TMZ; in human liver neither NDZ nor TMZ formation was inhibited by MP. 4. In seven different human livers the formation of p-hydroxy-DZP represented a minor pathway compared to the formation of NDZ and TMZ.

Animals↗
PubMed2000

Lipid peroxidation and glutathione levels after cortical injection of ferric chloride in rats: effect of trimetazidine and deferoxamine.

Intracortical injection of iron salts causes seizures. Oxidation of lipids in neural membranes by reactive oxygen species is involved in the mechanism responsible for iron-induced seizures as a model of posttraumatic epilepsy. In this study, we examined the effect of trimetazidine (TMZ) and deferoxamine (DFO) on lipid peroxidation after cortical injection of 5 microliters of an aqueous solution containing 100 mM of ferric chloride (FeCl3) in rats. Animals were divided into four groups (n = 7 each) and treated as follows: group 1, saline injection into the cortex (control group); group 2, iron injection into the cortex (injury group); group 3, iron injection into the cortex plus TMZ; group 4, iron injection into the cortex plus DFO. The animals were killed 3 h after injections, and the levels of malondialdehyde (MDA), a lipid peroxidation product, and reduced glutathione (GSH) were measured. A significant elevation of MDA was observed in group 2 (P < 0.05). MDA levels were found to be lower in both the TMZ-treated (P < 0.05) and DFO-treated (P < 0.05) groups than in the injury group. Tissue GSH levels were significantly decreased in group 2 (P < 0.05). GSH levels were increased in the TMZ-treated (P < 0.05) and DFO-treated (P < 0.05) groups compared to the injury group. The results of our study suggest that lipid peroxidation is a critical event in iron-induced epilepsy and that treatment with TMZ and DFO is effective in preventing the formation of free radicals and reducing lipoperoxides in brain tissue.

Analysis of Variance↗