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PubMed2000

Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is important in cellular resistance to certain alkylating antitumor agents such as the methylating drug temozolomide (TMZ). To provide a more rational basis for clinical combinations with another commonly used drug, cisplatin, we assessed the modulation of MGMT protein and mRNA levels in the human leukemic cell line Jurkat after treatment with these agents. Cisplatin decreased MGMT activity in a time- and dose-dependent manner, with maximal suppression (50%) observed 24 h after treatment with 25 microM cisplatin. This was probably the result of decreased transcription of the MGMT gene, because there was an earlier nadir of MGMT mRNA levels after cisplatin treatment and neither cisplatin nor DNA reacted with cisplatin in vitro was able to inhibit MGMT activity in an in vitro assay. TMZ alone depleted MGMT activity in a time- and dose-dependent manner with almost complete loss of activity occurring immediately after treatment with 500 microM TMZ. Combinations of cisplatin (12.5 microM) and TMZ (250 microM) caused substantial and prolonged MGMT depletion with recovery to only 30% of pretreatment levels by 48 h. These results suggest that the clinical efficacy of TMZ and cisplatin may be improved by appropriate schedules of combinations of these agents.

Antineoplastic Agents↗
PubMed2001

Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470.

The angiogenic phenotype is associated with increased tumor neovascularization and a state of vascular hyperpermeability to macromolecules. Angiogenesis inhibitors could reverse these processes, resulting in tumor capillaries that have normal membrane permeability. It was proposed that the switch from a hyperpermeable to a normal permeable state could have the untoward effect of decreasing tumor concentrations of anticancer drugs coadministered with angiogenesis inhibitors. The current investigation evaluated a potential drug interaction between the angiogenesis inhibitor O-(N-chloroacetyl-carbamoyl)-fumagillol (TNP-470) and the alkylating agent temozolomide (TMZ), in xenograft models that differentially expressed vascular endothelial growth factor (VEGF), a driving force for angiogenesis. Nude rats bearing either s.c. low VEGF (V-) or high VEGF (V+) or intracerebral V+ gliomas were administered either a multiple-dose regimen of TNP-470 or vehicle control. One day after the last dose of vehicle or TNP-470, a steady-state dosing regimen of TMZ was administered with subsequent collection and high-performance liquid chromatography analysis of plasma and either tumor homogenate or tumor microdialysis steady-state TMZ concentrations, and in some cases [5-(3-methyltriazen-1-yl)imidazole-4-carboximide] MTIC, its active metabolite. Microvessel density (MVD) was quantitated by image analysis using an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end points in the control and TNP-470 treatment groups were completed by nonparametric tests. In both the s.c. and intracerebral V+ models, TNP-470 treatment produced significant reductions in TMZ tumor concentrations and tumor:plasma concentration ratios compared with control, being reduced an average of 25% and 50% in the s.c. and intracerebral tumors, respectively. MTIC concentrations in V+ s.c. tumors also were reduced by 50% in the presence of TNP-470. Consistent with the lower extent of neovascularization in the V- tumors, TMZ and MTIC tumor concentrations were not different in TNP-470 and control treatment groups in s.c. tumors. MVD was reduced by TNP-470 compared with vehicle control in the V+ tumors, but was unaltered in V- tumors, attesting to the use of MVD as a pharmacodynamic end point and the effectiveness of TNP-470 as an angiogenesis inhibitor. Angiogenesis inhibitor's pharmacodynamic actions on tumor angiogenesis can produce a reduction in tumor concentrations of coadministered anticancer agents. It is increasingly important to understand the pharmacokinetic and pharmacodynamic behavior of each class of drug so that optimal dosing regimens can be designed.

Angiogenesis Inhibitors↗
PubMed2003

Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.

Animals↗
PubMed2004

Combined treatment of glioblastoma patients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and temozolomide.

AIM: In a previous phase I-II study, the safety profile and anti-tumor efficacy of pre-targeting locoregional radioimmunotherapy (LR-RIT), based on the ''3 step'' method, was assessed in 24 high-grade glioma patients. The encouraging results in terms of low toxicity and objective response rate (25%) prompted us to continue our study. METHODS: An analysis of 73 patients with hystologically confirmed glioblastoma multiforme (GBM), treated with the ''3 step'' (90)Y-biotin based LR-RIT, is herein reported. All patients had a catheter implanted at 2(nd) surgery and underwent at least 2 cycles of LR-RIT (range 2-7) with 2 months interval. Thirty-five out of 73 patients were also treated with Temozolomide (TMZ). Two cycles of TMZ (200 mg/m(2)/day, for 5/28 days) were administered in between each course of LR-RIT. Overall survival (OS) and progression free survival (PFS) were retrospectively calculated. RESULTS: Stabilization of disease was achieved in 75% of patients, while 25% progressed. In the 38 patients treated with LR-RIT alone, median OS and PFS were respectively 17.5 months (95%CI=[17-20]) and 5 months (95%CI=[4-8]), while in the 35 treated with the combined treatment (LR-RIT+TMZ) respective values were 25 months (95%CI=[23-30]) and 10 months (95%CI=[9-18] (p<0.01). The addition of TMZ to LR-RIT did not increase neurological toxicity, and no major hematological toxicity was observed. CONCLUSION: These results confirm the safety and the efficacy of (90)Y LR-RIT in recurrent GBM patients; the addition of TMZ significantly improved the overall outcomes; a further controlled prospective, randomized study is fully justified.

Antineoplastic Agents, Alkylating↗
PubMedDate not supplied

[Usefulness of trimetazidine in ischemia-reperfusion lesion. Experimental study in myocardial stunning model].

OBJECTIVE: The aim of this study is to evaluate the effect of trimetazidine (TMZ) on myocardial systolic dysfunction resulting from an isolated episode of induced coronary ischemia. METHODS: In a double-blinded randomized design we studied 13 mongrel anesthetized dogs of either sex (6 of them treated with oral TMZ previously). The anterior descending coronary artery was totally occluded during 15 minutes followed by 60 minutes of reperfusion. Global and regional cardiac variables were recorded in control and ischemic areas. RESULTS: There were no significant differences between TMZ and placebo series with respect to global cardiac function variables. Both series showed no significant variations in global variables during the ischemia-reperfusion process. The shortening fraction in the ischemic area fell significantly during the ischemic period in both TMZ and placebo series reaching dyskinetic values. Myocardial contractility dysfunction persisted after 60 minutes of reperfusion in both series with no significant differences (41% vs 50% placebo). CONCLUSIONS: Contrary to shorter and repeated occlusion periods, myocardial contractility recovery after a complete episode of ischemia did not show significant differences between TMZ-treated and placebo series.

Animals↗
PubMed2006

[Temozolomide in the treatment of recurrent malignant glioma].

Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent malignant gliomas in carious prospective phase II studies. No information is, however, available on TMZ treatment for recurrent malignant glioma in Japanese patients. We report Hokkaido University Hospital experience on 35 adult patients with a recurrent malignant glioma, including 13 glioblastomas, 9 anaplastic astrocytomas, and 13 anaplastic oligondendroglial tumors. The median age was 52 years. The starting dose of TMZ was 150 mg/m2/day for 5 days. When no remarkable toxicity was observed, the dose was increased to 200 mg/m2 for subsequent cycles, every 4 week. In the 35 patients, the overall objective response rate (partial response) was 12% and 74% of the patients achieved disease stabilization. The median progression-free survival was 28 weeks and the median overall survival was 43 weeks. Although hematological toxicity was the most frequent adverse event (CTC grade 3 or 4 in 6 patients), overall toxicity was generally mild. Four patients required hospitalization due to the toxicity, but 28 patients had been treated with TMZ at our outpatient clinic. These results suggested that the reported efficacy and toxicity profile of TMZ for the treatment of Japanese patients with recurrent malignant glioma is reproducible from the setting of clinical trials in the western countries.

Administration, Oral↗
PubMed1987

Anti-ischemic effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart.

The effects of trimetazidine (TMZ) on ischemia-induced metabolic damage were evaluated by 31P-NMR spectroscopy in the isolated rat heart. Isolated rat hearts underwent retrograde perfusion (37 degrees C, 9.81 kPa, pH 7.4, bicarbonate buffer) and were subjected to either partial global ischemia (24 min, 0.2 ml.min-1 residual coronary flow) or total global ischemia (12 min, no flow). 31P-NMR spectra (132 accumulations, 45 degrees, 101.3 MHz) were recorded every 3 min. Changes in cardiac ATP, PC and Pi were followed, and intracellular pH was estimated from the chemical shift of Pi. Trimetazidine (TMZ) was added to the perfusion fluid at the beginning of the perfusion. The drug was used at 2 concentrations: 6.10(-7) M, with no effect upon cardiac contractility under normoxic conditions, and 6.10(-4) M, which significantly depresses cardiac work. When TMZ was used at a concentration of 6.10(-7) M, intracellular acidosis at the end of the 24 min low-flow ischemia protocol was lower than in control hearts (6.6 vs 6.0). During reperfusion, restoration of phosphorylation (as expressed by ATP/Pi ratios) was accelerated by the drug. Similar but more pronounced effects were seen following 12 min total ischemia when TMZ was used at a concentration (6.10(-4) M) which brings about a reduction in cardiac work. In this case, myocardial ATP content was also protected during ischemia. It is concluded that restoration of phosphorylation processes upon reperfusion is more rapid under the effects of trimetazidine than in control hearts. Protection of the mechanisms or structures involved in energy transfer could be due to a reduction in ischemia-induced intracellular acidosis under the effect of TMZ.

Adenosine Triphosphate↗
PubMed1997

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.

Administration, Oral↗
PubMed2006

Progressive low-grade oligodendrogliomas: response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression.

BACKGROUND: Loss of heterozygosity (LOH) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with oligodendrogliomas. The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) may induce resistance to DNA-alkylating agents. Recent studies demonstrated that temozolomide (TMZ), an oral alkylating agent, has efficacy in the treatment of patients with progressive, low-grade oligodendroglioma (LGO). However, to the authors' knowledge, limited data are available regarding the 1p/19q profile and its correlation with MGMT protein expression and response to treatment with DNA-alkylating drugs. METHODS: Adult patients with magnetic resonance imaging (MRI) findings and/or clinical deterioration compatible with progressive LGO were eligible for the study if they were radiotherapy-naive. TMZ cycles were repeated every 28 days at a dose of 200 mg/m2 daily for 5 consecutive days. Clinical and MRI data were used to evaluate outcomes, and Kaplan-Meier estimates were used to assess the median time to tumor progression (TTP). The 1p/19q status was analyzed from paired tumor-blood DNA samples using polymerase chain reaction-based microsatellite analysis. MGMT protein expression was estimated semiquantitatively by immunohistochemistry using paraffin embedded tumor sections. RESULTS: There were 28 patients who received treatment, and the median time from diagnosis to tumor progression was 33.5 months. The median number of TMZ cycles per patient was 12.5. Marked clinical improvements were recorded in 15 patients (54%), and objective responses were recorded in 17 patients (61%). The median TTP was 31 months, and the progression-free survival rate was 70% at 24 months. Loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). CONCLUSIONS: TMZ was active in patients with progressive LGO, and their response to treatment was associated with 1p deletion and low MGMT protein expression. The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting tumor chemosensitivity.

Adolescent↗
PubMed1997

Effects of trimetazidine on the calcium transport and oxidative phosphorylation of isolated rat heart mitochondria.

Trimetazidine (TMZ) added in vitro to isolated cardiac mitochondria at concentrations 10-100 microM in the presence of 25-100 nM extramitochondrial Ca2+ increased Ca2+ uptake and matrix Ca2+ concentration. This effect was less evident in the presence of physiologically Na+ and Mg2+ extramitochondrial concentrations since only 100 microM TMZ was able to increase mitochondrial Ca2+ entry in the presence of 100 nM Ca2+. The drug stimulated a Ca(2+)-cooperative effect on mitochondrial Ca2+ transport, but did not modify the rate of Ca2+ egress stimulated by 10 mM NaCl. An increase in mitochondrial Ca2+ level produced by TMZ enhanced oxoglutarate dehydrogenase activity and then ATP synthesis, particularly when 50 nM extramitochondrial Ca2+ was used. These data suggest that a possible cardiac mechanism of action of TMZ at mitochondrial level could support ATP synthesis by elevating the mitochondrial Ca2+ level.

Adenosine Triphosphate↗
PubMedDate not supplied

Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers.

The pharmacokinetics of immediate (IR) and modified release (MR) trimetazidine (TMZ) in dogs and pigs, have been compared under single dose conditions, then predicted at steady-state under conditions mimicking an actual human pharmacokinetic study. In both animal species, the MR tablet has demonstrated sustained release properties, as assessed by delayed time to peak and increased mean absorption times. Multiple dose simulations in dogs revealed a delayed time to peak (3.0 vs. 1.0 h), a decrease in peak plasma concentration (544 vs. 659 microg/L), an increase in trough concentrations (115 vs. 63 microg/L), a decrease in peak-trough fluctuation (141 vs. 193%), and an increase in plateau time (5.5 vs. 4.9 h). Qualitatively similar changes were simulated in pigs. These properties have then been verified in humans where a TMZ MR 35 mg b.i.d regimen did provide similar total exposure, increased plateau time (11 vs. 4 h), decreased peak-trough fluctuation (86 vs. 121%), a 31% increase in trough concentrations, and no increase in inter-individual variability as compared to a TMZ IR 20 mg t.i.d. regimen. Furthermore, the TMZ MR 35 mg b.i.d. regimen is likely to result in improved patient compliance and better patient anti-ischemic protection in the early morning.

Administration, Oral↗
PubMed2005

Inactivation of p53 sensitizes astrocytic glioma cells to BCNU and temozolomide, but not cisplatin.

p53 inactivation sensitizes U87MG astrocytic glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ), drugs used clinically to treat high-grade astrocytomas. In this report, we examined the effect of p53 inactivation on the chemosensitivity of two additional human astrocytic glioma cell lines, D54 and A172, in order to assess whether sensitization is a general property of astrocytic tumor cells. Compared to control cells with intact p53 function, derived lines in which p53 was inactivated displayed significantly reduced clonogenic survival after exposure to BCNU and TMZ. Sensitization to both BCNU and TMZ was associated with failure of p21(WAF1) induction, lack of a sustained G2 cell cycle arrest and significant tumor cell death. These findings suggest that enhanced sensitivity to BCNU and TMZ is a general property of human astrocytic glioma cells in which p53 was disrupted. In contrast, p53 inactivation rendered D54 and U87MG cells significantly more resistant to cis-dichlorodiamminoplatinum (CDDP), another chemotherapeutic to which high-grade astrocytomas sometimes respond. These results indicate that p53 status influences the chemosensitivity of astrocytic glioma cells in a drug-type specific manner, a finding that may have implications for the selection of drug treatments for patients with astrocytic gliomas.

Antineoplastic Agents↗
PubMed2006

Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial.

Temozolomide (TMZ) has shown modest efficacy in the treatment of recurrent brain metastasis (BM). We designed a new regimen utilizing dose-intensified, protracted course of TMZ in combination with vinorelbine, a lipophilic large-spectrum agent, in an attempt to improve the efficacy of TMZ. This phase I study was conducted to establish the maximum tolerated dose (MTD) of vinorelbine for this combination. Patients with recurrent or progressive BM were eligible. Chemotherapy consisted of 28-day cycles with TMZ (150 mg/m2, days 1-7 and 15-21) and vinorelbine (days one and eight at escalating doses). The starting dose was 15 mg/m2, with increments of 5 mg/m2 for each cohort of 3-6 patients, until MTD was reached (30 mg/m2). A total of 21 patients were enrolled; the median age was 59 (41-77). The primary tumor was lung cancer in 13 patients (NSCLC in 10, SCLC in 3), breast in 6, renal in 1 and endometrial in 1. Vinorelbine dose was 15 mg/m2 in seven patients, 20 mg/m2 in five, 25 mg/m2 in four and 30 mg/m2 in six. Grades 3 and 4 neutropenia developed in six patients, lymphopenia in nine, and thrombocytopenia in six; other toxicities were rare. No dose-limiting toxicity was seen. Out of 18 evaluable patients 2 had a radiographic response (one partial and one minor). Disease was stable in 6 of 18 patients and the median survival was 27 weeks. This regimen was well tolerated and a phase II trial using a dose of 30 mg/m2 of vinorelbine is warranted.

Adult↗
PubMed2006

Complications of a temozolomide overdose: a case report.

PURPOSE AND BACKGROUND: This is a report of a 53 year-old man with a glioblastoma multiforme (GBM) treated with an excessive dose of temozolomide (TMZ). METHODS: This is a single case review of all clinically relevant records. O6-methylguanine-DNA methyltransferase activity was determined by a biochemical assay. RESULTS: Following conventional radiotherapy (RT) without concurrent chemotherapy, the patient received 5,500 mg of TMZ over 2 days. At the standard dose of 200 mg/m2/day his total 5-day dose should have been 1,940 mg. Acutely he had nausea, vomiting and diarrhea for 2 days which cleared. The dominant severe toxicity was pancytopenia between one and four weeks after TMZ which was complicated by secondary infections that were successfully managed. Transient transaminitis occurred but there were no significant pulmonary, renal or other systemic toxicities. His progression free survival was 22 months and overall survival 24 months. CONCLUSION: His outcome suggests that TMZ may prove to be a good agent for dose-escalation trials with hematopoietic stem cell rescue.

Antineoplastic Agents, Alkylating↗
PubMed2004

Influence of colloid, preservation medium and trimetazidine on renal medulla injury.

In organ transplantation, preservation injury is an important factor which could influence short-term and long-term graft outcome. The renal medulla is particularly sensitive to oxidant stress and ischemia-reperfusion injury (IRI). Using an autotransplant pig kidney model, we investigated renal function and medullary damage determined between day 1 and week 2 after 24- or 48-h cold storage in different preservation solutions: University of Wisconsin solution (UW), Hopital Edouard Herriot solution (a high Na+ version of UW), ECPEG (high Na+ preservation solution with PEG) and ICPEG (a high K+ version of ECPEG) with or without trimetazidine (TMZ). TMZ improved renal preservation and increased renal function when added in each preservation solution (particularly HEH and ECPEG). Medullary damage led to the early appearance of trimethylamine-N-oxide (TMAO) followed by 1H-NMR in urine and plasma. TMZ and ECPEG is the most efficient association to reduce medullary damage. This study clarifies the role of colloid and polarity solution and the role of mitochondrial protection by TMZ.

Colloids↗
PubMed2003

Evidence for a protective role of trimetazidine during cold ischemia: targeting inflammation and nephron mass.

Ischemia-reperfusion injury (IRI) is associated with an increased risk of acute rejection, delayed graft function, or chronic graft dysfunction. Mitochondria plays a central role in this process. Using an autotransplant pig kidney model, changes in renal function and morphology were determined after different periods of cold ischemia in kidneys preserved in the University of Wisconsin solution (UW), high-Na(+) version of UW (HEH) or Celsior (CEL) a newly developed high-Na(+) solution, with or without trimetazidine (TMZ). Kidney function was better preserved in HEH after 24 hr and particularly 48- and 72-hr cold storage than in CEL and UW. TMZ improved the preservation quality when added to the different solutions tested, particularly after 48- and 72-hr cold storage. Interstitial fibrosis and tubular atrophy were reduced in HEH with TMZ. CD4(+) T-cell infiltration was also modulated by the preservation conditions. Peripheral-type benzodiazepine receptor (PBR) positive cells infiltration was also modulated by preservation conditions. TMZ was efficient to reduce IRI when added in the various preservation solutions. These results suggest that protection of the mitochondrial function should be a major target to limit IRI. In addition, this study outlines the role of CD4(+) T cells and PBR expression in inflammatory responses after IRI.

Animals↗
PubMed2006

1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment.

BACKGROUND: Combined loss of 1p/19q predicts an almost 100% response rate to first line procarbazine, CCNU and vincristine chemotherapy (PCV) chemotherapy in oligodendroglial tumours. We assessed the impact of 1p and 19q loss on the outcome to first line temozolomide (TMZ) chemotherapy and to second line PCV or TMZ in progressive oligodendroglial tumours. MATERIALS AND METHODS: Tumour samples from patients included in two prospective EORTC studies on first line and second line TMZ chemotherapy in recurrent oligodendroglioma were used for this study. Most patients in the first line TMZ trial received PCV at further progression. Loss of 1p and 19q was assessed on paraffin embedded tumour samples by fluorescent in situ hybridisation with locus specific probes for 1p36 and 19q13. RESULTS: Losses of 1p and 19q were mainly observed in morphologically classical oligodendrogliomas (OD). Thirteen out of 18 patients with 1p loss (72%) responded to first line temozolomide (p<0.01). Both response to second line salvage PCV or to second line temozolomide was limited, even in patients with combined 1p/19q loss. Patients with tumours with 1p loss treated with salvage PCV had improved PFS (p<0.05). More patients with 1p loss were alive at 60 and 120 months after initial surgery (p<0.001). CONCLUSION: Combined 1p/19q loss is mainly observed in classical OD. Responses to first line temozolomide are strongly correlated to loss of 1p. Response to second line alkylating treatment is modest even in tumours with 1p/19q loss. For further improvement of outcome in OD novel treatments are needed.

Antineoplastic Agents, Alkylating↗
PubMed2004

Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors.

PURPOSE: To determine the safety and toxicity of carmustine (BCNU) and temozolomide (TMZ) with radiotherapy (RT) in newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Patients >18 years old with anaplastic astrocytoma, a Karnofsky performance status score of > or =60, and adequate pulmonary function were eligible. All patients provided informed consent. Standard RT started within 5 weeks of diagnosis. In both arms, 150 mg/m(2) of TMZ was given on Days 1-5 of RT. In Arm 1, 200 mg/m(2) of carmustine was given on Day 1 of RT. In Arm 2, 150 mg/m(2) of carmustine was given on Day 5 of RT. After RT, TMZ and carmustine were repeated for a total of six cycles. RESULTS: A total of 15 and 14 patients were enrolled in the two pilot arms. Because of hematologic and pulmonary toxicities, dose reductions by the second cycle of therapy occurred in >70% of the patients in Arm 1 and >50% in Arm 2 despite a reduction in the carmustine dose. CONCLUSION: The results of these pilot studies have implications for the design of studies testing the initial treatment of brain tumors. Because of the poor tolerance of the combination, the multicooperative group Phase III study consists of two randomized arms of single-agent carmustine vs. single-agent TMZ.

Antineoplastic Combined Chemotherapy Protocols↗