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PubMed2002

Trimetazidine as a potential neuroprotectant in transient global ischemia in gerbils: a behavioral and histological study.

The effect of Trimetazidine (TMZ) as a potential neuroprotectant against stroke was studied in the gerbil model of transient forebrain global ischemia. Animals were subjected to a 5-min period of ischemia and assessed 4 and 21 days later. Gerbils were divided into two groups: in group one, gerbils were treated with TMZ at a dose of 25 mg/kg given by intraperitoneal injection prior to ischemia. In group two, gerbils were treated with TMZ at a dose of 25 mg/kg given intraperitoneally after ischemia. Saline-injected gerbils served as controls. Histological evaluation of neuronal damage was carried out using the silver staining technique in gerbils 4 and 21 days after the start of the experimental protocol. Behavioral functions were assessed in gerbils from the 14th to the 21st day after the start of the experimental protocol using the Morris water maze test. Results obtained from this study showed no significant difference between saline treated TMZ-treated gerbils when TMZ was administered after ischemia. When TMZ was administered prior to ischemia, there was a reduction in neuronal damage although it did not reach statistical significance and a statistically significant improvement in behavior. We conclude that TMZ shows signs of promise as a neuroprotective agent, and further studies should look at pre-treatment with different doses and different times.

Animals↗
PubMed2001

The effect of trimetazidine on intrahepatic cholestasis caused by carmustine in rats.

This study investigated the effect of trimetazidine (TMZ), known as an anti-oxidant agent, on intrahepatic cholestasis caused by Carmustine (BCNU) in rats. Rats were assigned into four groups. The first group (Saline) consisted of 12 rats, which were injected with 2 ml/kg of saline intraperitoneally (IP) 48 h before the study. The second group (corn oil group, n=15), which were injected with 2 ml/kg of corn oil IP 48 h before the study. The third group (BCNU group, n=16), which were injected with 2 ml/kg of corn oil+25 mg/kg BCNU IP 48 h before the study. The fourth group (TMZ group, n=12), which were injected with 2.5 mg/kg per day of TMZ IP, administered at the same hour of the day as a single-dose. Twelve hour after the first dose of TMZ, corn oil 2 ml/kg+BCNU 25 mg/kg IP were injected, and the rats were included in the study 48 h after the administration of corn oil+BCNU. Following a pentobarbital anaesthesia, abdomen was opened with incision, a cannula was placed into the channel of choledocus, and the amount of bile was measured per hour. Then intracardiac blood sample was taken, and consequently centrifuged to obtain the plasma. Finally, the rats were killed with cervical dislocation, and their livers were removed and weighted. In addition to histopathological examination of liver, the levels of malon dialdehyde (MDA), oxidised glutation (GSSG), and reduced glutation (GSH) were detected. Also the osmolality of bile and plasma was estimated in mOsm/kg. As a result, the biliary flow was seen to decrease in BCNU group (P<0.005), but to be normal in TMZ group. The serum level of conjugated biluribin was higher in BCNU group compared to other groups (P<0.05 for each). Although the level of total glutation was lower (P<0.005) in TMZ group, GSH/GSSG ratio was normal. These findings suggest that TMZ has a protective effect on intrahepatic cholestasis caused by BCNU.

Journal Article↗
PubMed1999

Effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: short-term and long-term results.

Reperfusion may prevent or reduce the development and extent of necrosis, but may also lead to an increase in reperfusion damage. Experimental studies performed in various animal models of myocardial ischemia have demonstrated the anti-ischemic properties of trimetazidine (TMZ) and have suggested that TMZ has antioxidant properties, without any direct hemodynamic effects. Our study was aimed at investigating the effects of TMZ before thrombolysis in acute anterior myocardial infarction and included 81 patients, hospitalized within 4 hours of the onset of symptoms. Patients were randomly (double-blind) subdivided in two groups The first group (40 patients, Group A, TMZ-pretreatment), received 40 mg TMZ orally about 15 minute before thrombolysis and, subsequently, 20 mg every 8 hours. The second group (41 patients, Group B) received placebo before thrombolysis. Ventricular arrhythmias (VA) due to reperfusion were evaluated in the first 2 hours. VA occurred in 15 of patients in group A, versus 29 in group B, p<0.05. Creatine kinase (CK) normalization time was achieved after 55.7+/-12.5 hours in group A, versus 61.2+/-12.1 hour in group B, p = 0.048. CK peak was 1772+/-890 in group A vs. 2285+/-910 Ul/l in group B, (p = 0.012). In the follow-up (range 6-22 months), there were 4 deaths, two patients in each group. After 180 days from treatment, the TMZ group showed a smaller end systolic volume than the placebo group (echocardiographic data), 46.2+/-12 and 52.8+/-13 ml/m2, respectively, p = 0.037. Our data suggest that TMZ probably reduces reperfusion damage and/or infarct size in patients with anterior AMI subjected to thrombolysis and affects the post-AMI remodeling. Our data must be interpreted with caution because of the selection of patients. These findings require further extensive trials.

Aged↗
PubMed1999

Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours.

BACKGROUND: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. PATIENTS AND METHODS: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. RESULTS: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. CONCLUSIONS: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

Adult↗
PubMed2004

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.

Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

Adenine↗
PubMed2003

Trimetazidine effect on phospholipid synthesis in ventricular myocytes: consequences in alpha-adrenergic signaling.

The anti-anginal drug trimetazidine (TMZ) has been shown to increase the synthesis of phospholipids in ventricular myocytes, including phosphatidyl-inositol (PI). This study focused on the consequences of increasing PI metabolism on alpha-adrenergic signaling pathway in cultured rat cardiomyocytes. In the cells treated with TMZ, the synthesis of PI from inositol was largely increased as compared with the control (+55% in 60 min). The stimulation of alpha-adrenergic receptors by phenylephrine (PE) induced a dose-dependent production of inositide phosphates (IPs) by phospholipase C (PLC) activation. However, the amount of available IPs was significantly lower in TMZ-treated cells, in a dose-dependent manner. This effect was observed in the presence and absence of the IP1-phosphatase inhibitor LiCl. The in vitro determination of PLC activity revealed that this effect could not be attributed to the direct inhibition of the enzyme by TMZ. The TMZ-induced reduction of IPs in the PE-stimulated cardiomyocytes should be attributed to the increase of inositol recycling and incorporation in membrane structures, elicited by increased phospholipid synthesis. The consequences of this reduction in IPs availability were investigated on the cardiomyocyte hypertrophy induced by alpha-adrenergic chronic stimulation. Acute stimulation with PE increased protein synthesis (+50%), but this increase was largely prevented by TMZ. In conclusion, TMZ reduces cell available IPs, by accelerating their recycling in membranes as PI. This effect results in a cytoprotection in the pathological process of hypertrophy elicited by chronic alpha-adrenergic stimulation.

Animals↗
PubMed2000

Effects of trimetazidine on oxidant/antioxidant status in trinitrobenzenesulfonic acid-induced chronic colitis.

Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (i.r.) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (i.p.) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSG values. In conclusion, our results demonstrated that (a) i.r. administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) i.p. TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the i.p. compared to i.r. route, and (e) TMZ seems to show its antioxidant effect via preserving the tissue's GSH/GSSG ratios.

Administration, Rectal↗
PubMed2003

Effects of trimetazidine on acetic acid-induced colitis in female Swiss rats.

Induction of colitis by acetic acid (AA) in the rat is widely used experimental model of inflammatory bowel disease (IBD) and ulcerations. AA as an irritant induces colitis involving infiltration of colonic mucosa with neutrophils and increased production of inflammatory mediators, such as hydrogen peroxide (H2O2), nitric oxide (NO), myeloperoxidase activity (MPO), and tumor necrosis factor (TNF-alpha). Trimetazidine (TMZ), an antianginal compound, was administered to investigate if its cytoprotective features in cardiac tissue are also effective in AA colitis where ischemic injury contributes to colitis. Administration of TMZ intraperitoneally improved the macroscopic and microscopic score alterations produced by AA. AA administration significantly elevated colonic MPO activity; however, treatment with TMZ significantly lowered this enzyme activity compared to AA. AA administration significantly enhanced superoxide dismutase (SOD) activities, except for AA + TMZ given rectally. TMZ treatment significantly lowered nitrate levels, but AA increased these levels. AA administration markedly lowered TNF-alpha levels, but TMZ treatment elevated these levels to control. These findings indicate that overproduction of NO may be involved in the immunosuppression observed during acute AA-induced rat colitis. In conclusion, TMZ treatment was more effective via the intraperitoneal than rectal route, and may be beneficial in therapy of colitis.

Acetic Acid↗
PubMed2003

Inhibition of angiogenesis by non-toxic doses of temozolomide.

It is well established that certain chemotherapeutic agents have potent antiangiogenic properties which may be part of their antitumor activity. Temozolomide (TMZ) is a lipophilic methylating agent used in the therapy of malignant melanoma and other tumors. We sought to determine whether TMZ is capable of inhibiting angiogenesis or influencing endothelial function. We used the in vivo chorioallantoic membrane (CAM) assay, and HUVEC-based in vitro Matrigel, adhesion and proliferation assays to determine the antiangiogenic effects of different doses of TMZ. In the CAM assay, angiogenesis was significantly inhibited by 5 microM TMZ, a concentration also found to be effective in interfering with in vitro angiogenesis as measured by the Matrigel assay. For the inhibition of basic fibroblast growth factor (bFGF)-, vascular endothelial growth factor (VEGF)- or beta-phorbol 12-myristate-13-acetate (PMA)-induced endothelial cell proliferation or endothelial cell adhesion to fibronectin, TMZ concentrations of at least 25 microM were necessary, indicating that bFGF-, VEGF- or protein kinase C-mediated pathways may not primarily be involved in the observed antiangiogenic effect. Thus, we could demonstrate that TMZ inhibits angiogenesis at low, non-toxic doses that correspond to the plasma concentrations achieved by an oral application of 20 mg/m2 every 8 h. This 'metronomic' scheduling has already been used in phase I studies and has produced antitumor effects. Therefore, the antitumor activity of TMZ may, at least in part, be due to its antiangiogenic properties. The precise mechanism of its antiangiogenic action remains to be elucidated.

Angiogenesis Inhibitors↗
PubMed1994

Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts.

Trimetazidine (1-[2,3,4-trimethoxibenzyl)]-piperazine, TMZ) is a drug with a proposed metabolically based antiischemic action. Because ischemic contracture is a serious complication of ischemia and is considered metabolic in origin, we studied the effect of trimetazidine (TMZ) on development of ischemic contracture in experimental low-flow ischemia. TMZ was either added to the perfusion fluid or given as pretreatment to the donor rats. Langendorff-perfused isolated rat hearts were submitted to 30-min subtotal global ischemia (residual flow = 0.2 ml/min, n = 6 per group) (normal flow = 12.4 +/- 0.8 ml/min, heart fresh weight = 0.9 +/- 0.3 g). Ischemic contracture was measured by a water-filled intraventricular balloon. Thereafter, the hearts were reperfused for 20 min and recovery of intraventricular pressure was monitored. Furthermore, because the mechanisms of action of TMZ may involve cellular energy metabolism, we assessed throughout glycolytic flux by collecting the coronary effluent every 5 min during control perfusion, ischemia, and reperfusion periods. Animals from the pretreated groups received TMZ [3 mg/kg orally (p.o.) twice daily] for 5 days. Animals from the control group received placebo for the same time period. Concentrations of 10(-6) and 10(-4) M were used when the drug was added to the perfusate. In our experimental conditions, TMZ pretreatment alone had no measurable cardioprotective effect, but addition to the perfusate of TMZ 10(-6) M, approximately a therapeutic concentration in humans, reduced ischemic contracture in both pretreated and control groups and improved postischemic recovery of developed pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Renoprotective effects of trimetazidine against ischemia-reperfusion injury and cold storage preservation: a preliminary study.

BACKGROUND: Initial ischemia-reperfusion injury is associated with organ retrieval, storage, and transplantation adversely affects early graft function and influences the development of chronic graft dysfunction. We have recently shown that the protective agent trimetazidine (TMZ) added to preservation solutions: Euro-collins (EC) and University of Wisconsin (UW) was efficient to protect kidneys from ischemia-reperfusion injury in an isolated perfused kidney model. We extended these observations to investigate the role of this drug in the development and progression of organ dysfunction in the autotransplant pig kidney model. METHODS: Five experimental groups were studied. After 48-hr cold preservation, autotransplantation and immediate controlateral nephrectomy was then performed in group EC (EC+placebo (n=8), EC+TMZ (n=8), UW+placebo (n=7), and (UW+TMZ) (n=7) and compared with control group (uninephrectomized, n=4) during 14 days. Blood and urine samples were collected for the measurement of creatinine and blood urea nitrogen on postoperative days 1, 3, 5, 7, 11, and 14. Histological analysis was performed after reperfusion and at day 14. RESULTS: Survivals were 100% in group B and D versus 42% in group A and 57% in group C. Urine production occurred earlier after autotransplantation from TMZ preserved kidneys than in placebo preserved groups. Peak creat and blood urea nitrogen was significantly greater in groups B and D than in groups A and C. TMZ was also efficient both to reduce ischemia-reperfusion injury and to decrease cellular infiltration. CONCLUSION: These results support the beneficial effect of TMZ against ischemia-reperfusion injury and its early effects on grafts in the form of delayed graft function and decreased graft survival. In addition, TMZ reduces inflammatory cellular infiltration in the renal parenchyma.

Adenosine↗
PubMed1997

Comparison of the effects of cyclosporine A and trimetazidine on Ca(2+)-dependent mitochondrial swelling.

Cyclosporine A (CsA) is a known potent inhibitor of pro-oxidant-induced mitochondrial swelling. In the present study we show that CsA's effect is only transient when the liver mitochondrial swelling in induced by Ca2+ plus tert-butylhydroperoxide (t-BH). After an initial inhibition, swelling is worsened by CsA as evidenced by an extent of mitochondrial swelling that exceeds that of the control. Unlike CsA, trimetazidine (TMZ), an anti-ischemic drug decreases both the extent and the rate of the swelling with an IC50 value of 214 +/- 24 microM. Its inhibition effect on the initial swelling rate mimicks that of CsA but the mechanism may be independent. During long-term swelling. TMZ counteracts the worsening effect of CsA. The inhibition of swelling induced by TMZ is assessed by the fact that TMZ significantly increases the EC50 of Ca(2+)-induced mitochondrial swelling (46.6 +/- 6.0 to 85 +/- 10 microM, P < 0.01), without affecting its cooperativity. Apparently, TMZ seems to behave like trifluoperazine (TFP), a phospholipase A2 inhibitor that, under our experimental conditions, inhibits the mitochondrial swelling induced by Ca2+ and t-BH with an IC50 value of 25 +/- 10 microM. Both drugs are able to protect mitochondria from both phases (early and late) of the swelling, especially the late, which is enhanced in the presence of CsA. TFP and other phospholipase A2 inhibitors were able to displace [3H]TMZ from its mitochondrial binding sites whereas CsA was ineffective. We suggest that TMZ, like TFP, inhibits the CsA insensitive mechanism involved in the swelling process which is responsible for the worsening effect observed in the presence of CsA when the swelling is generated by Ca2+ and t-BH.

Animals↗
PubMed2004

Agonist-induced internalization of leukotriene B(4) receptor 1 requires G-protein-coupled receptor kinase 2 but not arrestins.

The leukotriene B(4) (LTB(4)) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB(4) stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB(4), BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail-truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB(4), suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type-specific signaling in response to LTB(4), depending on GRK expression levels.

Animals↗
PubMedDate not supplied

Effects of trimetazidine on lipid peroxidation, antioxidant enzyme activities and plasma brain natriuretic peptide levels in patients with chronic cor pulmonale.

An oxidant/antioxidant imbalance in favour of oxidants appears to occur in chronic cor pulmonale (CCP). Oxidative stress could also be a critical event in the pathogenesis of this condition. Trimetazidine (TMZ) has antioxidant properties and may affect the utilization of oxygen radicals. We investigated the effect of TMZ (20 mg three times daily, orally) on activities of erythrocyte malondialdehyde (MDA) and catalase (eCAT), erythrocyte and plasma glutathione peroxidase (GSH-Px) and plasma superoxide dismutase (pSOD) in CCP patients. We also assessed changes in plasma levels of brain natriuretic peptide (BNP) with TMZ therapy. Sixty CCP patients with significantly higher MDA and markedly lower pSOD, eCAT and GSH-Px (erythrocyte) activities than 24 healthy controls were randomly allocated to receive routine treatment or routine treatment plus TMZ. After 3 months' therapy, greater pSOD, eCAT and GSH-Px (erythrocyte and plasma) activities and lower MDA activity were found with TMZ treatment compared with routine treatment. Plasma BNP levels were significantly lower in TMZ-treated patients and higher in the routine treatment group than in the control group. TMZ improved antioxidant levels, decreased oxidative stress and decreased plasma BNP levels in CCP patients.

Aged↗
PubMed2003

DNA repair enzymes and cytotoxic effects of temozolomide: comparative studies between tumor cells and normal cells of the immune system.

O6-alkylguanine-DNA alkyltransferase (OGAT) and the mismatch repair system (MRS) play a crucial role in the susceptibility of tumor cells to the cytotoxic effects of agents that generate O6-methylguanine in DNA, including the triazene compound temozolomide (TMZ). Studies performed with peripheral blood mononuclear cells (MNC) showed that TMZ was scarcely active on lymphocyte functions not dependent on cell proliferation (e.g. NK activity and cytokine-mediated induction of CD1b molecule in adherent MNC). In contrast, TMZ depressed proliferation and lymphokine activated killer (LAK) cell generation in response to IL-2. In this case, a reasonably good inverse relationship was found between OGAT levels of MNC and their susceptibility to TMZ. This study also analyzed the ratio of the toxic effect of TMZ on MNC and on tumor cells (i.e. "Tumor-Immune Function Toxicity Index", TIFTI). A particularly favorable TIFTI can be obtained when OGAT levels are extremely high in MNC and markedly low in tumor cells. This holds true for MRS-proficient neoplastic cells, but not for MRS-deficient tumors. In conclusion, strategies aimed at modulating OGAT and MRS may improve the clinical response to TMZ. However, the use of OGAT inhibitors to potentiate the antitumor activity of TMZ might result in a concomitant increase of the immunosuppressive effects of the drug, thus reducing the relative TIFTI.

Antineoplastic Agents, Alkylating↗
PubMed2025

NR2F6 regulates Temozolomide resistance in glioma via the E2F2-PARP1 pathway.

BACKGROUND: Glioma is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Elucidating the mechanisms of temozolomide (TMZ) resistance in glioma is of critical clinical importance for improving patient prognosis and developing novel therapeutic strategies. METHODS: We obtained RNA sequencing (RNA-seq) data of 648 glioma samples from The Cancer Genome Atlas (TCGA) and 325 samples from the Chinese Glioma Genome Atlas (CGGA) as study cohorts. Additionally, we validated the expression characteristics of the NR2F6 gene in our in-house cohort of glioma patients. Furthermore, we investigated the potential mechanism of NR2F6 in TMZ resistance in glioma by constructing TMZ-resistant cell lines in vitro. Statistical analyses and graphical work were primarily performed using R language and GraphPad Prism software. RESULTS: We observed a significant upregulation of NR2F6 expression in high-grade gliomas, which is associated with an unfavorable prognosis in patients. Concurrently, our findings revealed a significant upregulation of NR2F6 in drug-resistant cells, which induced TMZ resistance in glioma cells via the E2F2-PARP1 axis. CONCLUSION: In brief, NR2F6, as a nuclear transcription factor, enhances the transcription of E2F2.The increased expression of E2F2 enhances PARP1 expression, which in turn facilitates TMZ-mediated DNA damage repair, thereby diminishing glioma sensitivity to TMZ.

Journal Article↗
PubMed2000

Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme.

PURPOSE: To determine whether chemotherapy with temozolomide (TMZ) versus procarbazine (PCB) for recurrent glioblastoma multiforme (GBM) was associated with improvement in health-related quality of life (HRQOL). PATIENTS AND METHODS: HRQOL was assessed at baseline and during treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a Brain Cancer Module (BCM20) in two clinical trials that enrolled a total of 366 patients. Two hundred eighty-eight patients provided HRQOL data that could be used for analysis; 109 patients received TMZ in a phase II study, whereas 89 patients received TMZ and 90 received PCB in a randomized phase III study. Changes from baseline in the scores of seven preselected HRQOL domains (role and social functioning, global quality of life [QOL], visual disorders, motor dysfunction, communication deficit, and drowsiness) were calculated for all groups. Statistical significance, effect sizes, and proportions of patients with improved HRQOL scores (changes of > or = 10 points) were calculated. RESULTS: Before disease progression, patients treated with TMZ were found to have an improvement in most of the preselected HRQOL domain scores compared with their baseline (pretreatment) scores. Those who were progression-free on TMZ at 6 months had improvement in all the preselected HRQOL domains. Conversely, patients treated with PCB reported deterioration in HRQOL that was independent of whether or not the disease had progressed by 6 months. Patients with disease progression, regardless of treatment, experienced a sharp decline in all domains at the time of progression. CONCLUSION: Treatment with TMZ was associated with improvement in HRQOL scores compared with treatment with PCB. The deterioration reported by PCB-treated patients was likely because of toxicity. Delaying disease progression by treatment with TMZ is beneficial to the HRQOL status of patients with recurrent GBM.

Adult↗
PubMed2003

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.

PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

Adult↗