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PubMed1998

Effects of trimetazidine on lipid peroxidation and phosphorus metabolites during cold storage and reperfusion of isolated perfused rat kidneys.

This study was undertaken to evaluate the effect of trimetazidine (TMZ) during cold storage (CS) and the consequence during normothermic reperfusion in an isolated perfused rat kidney model (IPK). IPK was used to assess the rate of perfusion flow, the ratio of ATP to inorganic phosphate (ATP/Pi) as a reflection of the energetic status during reperfusion, intracellular pH (pHi), tissue water content and malondialdehyde (MDA) tissue levels in four different preservation solutions after 48-hr preservation at 4 degreesC and 2-hr reperfusion at 37.5 degreesC: EuroCollins (EC), University of Wisconsin (UW), EC plus TMZ (10(-)6 M) (EC + TMZ) and UW plus TMZ (10(-)6 M) (UW + TMZ). When TMZ was added to the preservation solutions, perfusion flow rate (PFR) was significantly improved during reperfusion. Tissue water content, which reflected tissue edema, was significantly lower in TMZ groups than in groups without TMZ during both CS and reperfusion conditions. In TMZ groups, ATP/Pi ratio was also significantly improved during CS and reperfusion. In addition, TMZ lowered the pHi both during preservation and after reperfusion. MDA renal tissue level significantly decreased with TMZ both during the preservation period and after reperfusion. These overall results strongly suggested that TMZ contributes to renal protection from cold ischemia-reperfusion injury in this IPK model, especially when TMZ was added to UW solution and during prolonged hypothermic ischemia.

Adenosine Triphosphate↗
PubMed1999

Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies.

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

Administration, Oral↗
PubMed2004

Cooperative function of Chk1 and p38 pathways in activating G2 arrest following exposure to temozolomide.

OBJECT: The Chk1 and p38 mitogen-activated protein kinase (MAPK) pathways play key roles in the G2 arrest caused by exposing glioma cells to temozolomide (TMZ). Although inhibition of either pathway sensitizes glioma cells to TMZ-induced cytotoxicity, the relative contributions of these pathways to TMZ-induced G2 arrest and to TMZ resistance conferred by G2 arrest have not been defined. METHODS: The authors pharmacologically inhibited the Chk1 and/or p38 pathways in U87MG human glioma cells prior to and/or after exposure to TMZ; thereafter, effects on the TMZ-induced G2 arrest pathway and toxicity were monitored. The p38 inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ-mediated inactivation of cdc25C and cdc2, suggesting that p38 and Chk1 pathways work cooperatively and are both necessary to inactivate cdc25C and cdc2. Consistent with this idea, the inhibition of both Chk1 and p38 pathways did not lead to greater bypass of TMZ-induced G2 arrest or greater cytotoxicity than inhibition of either pathway alone. Inhibition of p38 did not alter TMZ-induced Chk1 activation/phosphorylation and vice versa, suggesting that p38 and Chk1 do not cooperatively bring about G2 arrest by reciprocal activation/phosphorylation. The two pathways, however, are not functionally identical; the Chk1 pathway was required for both the initiation and maintenance of TMZ-induced G2 arrest, whereas the p38 pathway played a role only in the initiation. CONCLUSIONS: The Chk1 and p38 pathways cooperate to bring about TMZ-induced G2 arrest, and the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity.

Antineoplastic Agents, Alkylating↗
PubMed1999

A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies.

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.

Adult↗
PubMed2000

Pharmacological limitation of damage to renal medulla after cold storage and transplantation by trimetazidine.

Delayed graft function remains an important complication after renal transplantation. In this study, we investigated the influence of trimetazidine (TMZ), a cytoprotective agent, on renal medullary damage after prolonged preservation and autotransplantation. Pig kidneys were cold-flushed and preserved (48 h at 4 degrees C) with two standard renal preservation solutions Euro-Collins and University of Wisconsin supplemented or not with TMZ (10(-6) M). Analysis of plasma and urine from 48-h-cold-stored and autotransplanted kidneys was performed with biochemical methods and proton NMR spectroscopy. Histological study by light and electron microscopy was performed after reperfusion (30-40 min) and on day 14. The results showed that the preservation in either Euro-Collins or University of Wisconsin solution containing TMZ improved significantly glomerular filtration rate compared with kidneys preserved without TMZ. TMZ significantly reduced renal medullary damage, evidenced by decreased excretion of trimethylamine-N-oxide, dimethylamine, dimethylglycine, and acetate in urine. Proximal tubular injury in TMZ-free groups was assessed by significantly greater Na(+) excretion, amino aciduria, and lactic aciduria than in TMZ-supplemented groups. Urinary concentrating ability was significantly improved in TMZ-preserved groups compared with TMZ-free groups. In TMZ-supplemented groups, there was also a greater excretion of citrate, which is a citric acid cycle metabolite. An extensive reduction in apical brush border of tubular cells, notably those of the proximal tubules, was noted in TMZ-free groups. This study clearly shows that TMZ has a beneficial action on in vivo renal preservation and its major impact is the vulnerable renal medulla.

Animals↗
PubMed1994

Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation.

This study was undertaken to evaluate the direct cardioprotective effect of trimetazidine (TMZ), an anti-anginal drug devoid of haemodynamic action, on isolated myocytes. Cultured rat ventricular myocytes were treated with the drug 16 h and 1 h before the experiments. The drug-treated cells and control cells were placed in a substrate free medium and submitted in a specially designed device to either normoxia (N4), or hypoxia (150 min, H2.5, or 240 min, H4), or 150 min hypoxia followed by 90 min reoxygenation (HR). The treatment of the cells with TMZ (5 x 10(-4) M) resulted in a significant decrease of lactate dehydrogenase (LDH) leakage (-58% in H2.5, -36% in H4 and -37% in HR). The LDH release provoked by oxidizing agents. H2O2 and 13-s-HpOTrE (13(S)-hydroperoxyoctadecatrienoic acid) during post-hypoxic reoxygenation was also lowered by TMZ. However, this effect reflected the beneficial action of TMZ during hypoxia since the drug was not efficient in altering the LDH leakage induced by the oxidizing agents in normal conditions. Moreover, the hypoxia-induced decrease of ATP content was not affected by TMZ, and resynthesis of ATP during substrate-free reoxygenation was similar in TMZ-treated and control cells. The respiration parameters have been studied in rat heart mitochondria isolated from control and TMZ-treated rats, in the presence or absence of TMZ in the respiration medium (10(-4) M). The main result was a rapid and potent inhibition of palmitoylcarnitine oxidation, when TMZ was added to the respiration medium. The chronic treatment only resulted in a slight alteration of pyruvate oxidation. In conclusion, a pre-treatment of ventricular myocytes with TMZ resulted in an increased cell resistance to hypoxic stress, as evidenced by LDH leakage. This cytoprotective effect of TMZ should not be mediated through an antioxidant activity, but could be related to a modification of lipid metabolism.

Adenine Nucleotides↗
PubMed2003

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors.

PURPOSE: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors. METHODS: We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling. RESULTS: The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies. CONCLUSIONS: This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.

Adolescent↗
PubMed2001

Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells.

We have previously shown that human cancer cells deficient in DNA mismatch repair (MMR) are resistant to the chemotherapeutic methylating agent temozolomide (TMZ) and can be sensitized by the base excision repair (BER) blocking agent methoxyamine (MX) [21]. To further characterize BER-mediated repair responses to methylating agent-induced DNA damage, we have now evaluated the effect of MX on TMZ-induced DNA single strand breaks (SSB) by alkaline elution and DNA double strand breaks (DSB) by pulsed field gel electrophoresis in SW480 (O6-alkylguanine-DNA-alkyltransferase [AGT]+, MMR wild type) and HCT116 (AGT+, MMR deficient) colon cancer cells. SSB were evident in both cell lines after a 2-h exposure to equitoxic doses of temozolomide. MX significantly increased the number of TMZ-induced DNA-SSB in both cell lines. In contrast to SSB, TMZ-induced DNA-DSB were dependent on MMR status and were time-dependent. Levels of 50 kb double stranded DNA fragments in MMR proficient cells were increased after TMZ alone or in combination with O6-benzylguanine or MX, whereas, in MMR deficient HCT116 cells, only TMZ plus MX produced significant levels of DNA-DSB. Levels of AP endonuclease, XRCC1 and polymerase beta were present in both cell lines and were not significantly altered after MX and TMZ. However, cleavage of a 30-mer double strand substrate by SW480 and HCT116 crude cell extracts was inhibited by MX plus TMZ. Thus, MX potentiation of TMZ cytotoxicity may be explained by the persistence of apurinic/apyrimidinic (AP) sites not further processed due to the presence of MX. Furthermore, in MMR-deficient, TMZ-resistant HCT116 colon cancer cells, MX potentiates TMZ cytotoxicity through formation of large DS-DNA fragmentation and subsequent apoptotic signalling.

Apoptosis↗
PubMed1997

Trimetazidine increases phospholipid turnover in ventricular myocyte.

Trimetazidine (TMZ) is an anti-ischemic compound devoid of hemodynamic effects. It was recently suggested to induce cardiomyocyte protection by a mechanism involving lipid metabolism. The effects of TMZ were evaluated in rats on cardiac lipid composition, and in cultured rat cardiomyocytes on phospholipid metabolism. Rats were treated with TMZ for 4 weeks, and the fatty acid compositions were determined. Treatment with TMZ induced a significant decrease in phospholipid linoleic acid, balanced by a small increase in oleic and stearic acids. These changes were not correlated to alterations in plasma fatty acid composition. Cultured ventricular myocytes were treated with TMZ, 16 and 1 before experimentation. The time-dependent incorporation of radio labelled precursors of membrane phospholipids (3-inositol, 14C-ethanolamine, 14C-choline, 14C-arachidonic acid, 10 mumol/L) was investigated. The cells were harvested 30, 60, 105 or 150 min after precursor addition. In TMZ-cells, arachidonic acid (AA) incorporation was increased in the phospholipids, but not in other lipid fractions. This increase elicited a net increase in the total AA uptake. The incorporation of 3-inositol in the phospholipids was strongly stimulated by TMZ, although the uptake of inositol was not altered. The difference was significant within 30 min, and after 150 min the phospholipid labelling in TMZ cells was higher by 70%. A similar result was obtained with ethanolamine as precursor, which turnover increased by 50% in TMZ-treated cells. Conversely, the incorporation of choline was not significantly affected by the presence of TMZ. In conclusion TMZ appears to interfere with the metabolism of phospholipids in cardiac myocytes in a manner which could indicate an increase of membrane phospholipid turnover.

Animals↗
PubMed2003

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide.

Temozolomide (TMZ, 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d]-as-tetrazine-8-carboxamide) is a new alkylating agent with promising antitumour efficacy for malignant gliomas. The resistance of tumour cells to TMZ is primarily associated with levels of the alkylguanine alkyltransferase (AGT). O(6)-benzylguanine (O(6)-BG), an inhibitor for AGT, reduced resistance to TMZ. Recently, it has been demonstrated that chemosensitivity of tumour cells is related to a decline in telomerase activity. However, it is unknown if TMZ sensitivity of malignant glioma cells correlates with telomerase. In this study, using malignant glioma cells with low levels of AGT (U373-MG and U87-MG) and high levels of AGT (T98G), we investigated the association among AGT, telomerase, and TMZ sensitivity. U373-MG and U87-MG cells were sensitive to TMZ (IC(50) for a 2-day treatment=100 microM), while T98G cells were resistant to TMZ (IC(50) for a 2-day treatment >500 microM). Treatment with TMZ (100 microM) suppressed telomerase activity in U373-MG and U87-MG cells in a time-dependent manner, but not in T98G cells. The downregulation of telomerase activity in U373-MG and U87-MG cells was due to inhibition of the human telomerase reverse-transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was induced by interfering with transcription factor Sp1 binding sites of the hTERT core promoter. Interestingly, O(6)-BG not only sensitised T98G cells to TMZ, but also suppressed telomerase activity. These findings suggest that response of malignant glioma cells to TMZ can be monitored by reduction in telomerase activity. Therefore, quantification of telomerase activity during or after treatment with TMZ may be a useful marker to detect treatment efficacy.

Antineoplastic Agents, Alkylating↗
PubMed1993

Clinical features of an anti-anginal drug in angina pectoris.

Trimetazidine (TMZ) exerts anti-ischaemic effects without any associated central haemodynamic change, both at rest and with exercise. These findings suggest that TMZ has a direct cytoprotective effect, the efficacy of which has been confirmed by clinical studies in effort angina. TMZ as monotherapy when compared with placebo, in acute (60 mg) as well as in chronic (20 mg t.i.d.) administration, significantly improves exercise tolerance: total work, duration of exercise and time to 1 mm ST segment depression, without changing the rate-pressure product. Moreover, during chronic treatment TMZ decreases the rate of anginal attacks. In patients with coronary heart disease insufficiently controlled with nifedipine or a beta-blocker as monotherapy, the addition of TMZ (20 mg t.i.d.) significantly reduces the number of anginal attacks and improves exercise capacity. TMZ antianginal activity in monotherapy has also been compared in double-blind controlled studies with that of a calcium channel antagonist and a beta-blocker as reference drugs. TMZ is as efficient as nifedipine or propranolol on clinical variables as well as on ergometric criteria, but unlike these two reference drugs, which act through a haemodynamic mechanism, TMZ does not decrease rate-pressure product. Furthermore, in the study comparing TMZ with propranolol, TMZ was shown to decrease ischaemic episodes recorded by ECG ambulatory monitoring. These data show that TMZ belongs to the major antianginal agents available today. However, the absence of central haemodynamic effects suggests that the drug has a novel anti-ischaemic mechanism involving direct myocardial cytoprotection.

Adrenergic beta-Antagonists↗
PubMed2006

O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells.

Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L). We found that the levels of MGMT expression were a major predictor of TMZ sensitivity in human glioma cells. MGMT activity and clonogenic survival after TMZ exposure are highly correlated (p < 0.0001, r2 = 0.92). In contrast, clonogenic survival after TMZ exposure does not correlate with the expression levels of the mismatch repair proteins mutS homologue 2, mutS homologue 6 or post-meiotic segregation increased 2. The MGMT inhibitor O6-benzylguanine sensitizes MGMT-positive glioma cells to TMZ whereas MGMT gene transfer into MGMT-negative cells confers protection. The antiapoptotic BCL-X(L) protein attenuates TMZ cytotoxicity in MGMT-negative LNT-229 but not in MGMT-positive LN-18 cells. Neither ionizing radiation (4 Gy) nor clinically relevant concentrations of dexamethasone modulate MGMT activity or TMZ sensitivity. Abrogation of p53 wild-type function strongly attenuates TMZ cytotoxicity. Conversely, p53 mimetic agents designed to stabilize the wild-type conformation of p53 sensitize glioma cells for TMZ cytotoxicity. Collectively, these results suggest that the determination of MGMT expression and p53 status will help to identify glioma patients who will or will not respond to TMZ.

Antineoplastic Agents, Alkylating↗
PubMed1996

Effects of trimetazidine on pHi regulation in the rat isolated ventricular myocyte.

1. We have examined the effects of trimetazidine (TMZ) on intracellular pH (pHi) regulation in rat isolated ventricular myocytes. pHi was recorded ratiometrically by use of the pH-sensitive fluoroprobe, carboxy-SNARF-1 (carboxy-seminaphtorhodafluor). 2. Following an intracellular acid load (induced by 10 mM NH4Cl removal), pHi recovery in HEPES-buffered Tyrode solution was significantly slowed down upon application of 0.3 mM TMZ only when myocytes were pretreated for 5 h 30 min (slowing by approximately 50%; P < 0.01). This effect of TMZ on pHi recovery was shown to be not only time- but also dose-dependent with a large, quickly reversible, effect obtained with 1 mM TMZ applied for 2-3 h (slowing by approximately 64%; P < 0.001). This slowing of pHi recovery was also associated with a decrease of the NH4+ removal-induced acidification. 3. Relationship between intracellular intrinsic buffering power (beta i) and pHi was assessed in absence or presence of TMZ (0.3 mM or 1 mM). As expected, beta i increased roughly linearly with a decrease in pHi in all cases. However, both concentrations of TMZ significantly increased beta i (by approximately 55 and 65% at pHi 7.1, respectively). 4. When Na+/H+ exchange was inhibited by dimethyl amiloride (DMA; 40 microM), trimetazidine (1 mM) did not change the H+ flux estimated at pHi 7.1 (0.31 +/- 0.03 mequiv l-1 min-1, n = 5, control, versus 0.30 +/- 0.025 mequiv l-1 min-1, n = 5, TMZ), ruling out any effect of TMZ on background acid loading. 5. Acid efflux carried by Na+/H+ exchange was significantly decreased only when myocytes were pretreated with 1 mM TMZ, for 2-3 h (JeH = 2.86 +/- 0.38 mequiv l-1 min-1, n = 26, control, versus 1.66 +/- 0.26 mequiv l-1 min-1, n = 10, TMZ, estimated at pHi 7.1; P < 0.05). 6. In conclusion, the present work demonstrates that, following an intracellular acid load in HEPES-buffered medium, trimetazidine slows down pHi recovery in rat isolated ventricular myocytes, primarily through an increase of beta i. An effect on Na+/H+ exchange is also detected but only after long-term incubation of the myocytes with TMZ.

Animals↗
PubMed2004

Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications.

PURPOSE: Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients. MATERIALS AND METHODS: TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa. RESULTS: Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients. CONCLUSION: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Adult↗
PubMed2005

Phase I study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors.

PURPOSE: This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. PATIENTS AND METHODS: Patients < or = 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. RESULTS: Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. CONCLUSION: The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Adolescent↗
PubMed2003

Delayed repletion of O6-methylguanine-DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity.

OBJECT: Temozolomide (TMZ)-induced O6-methylguanine (MG) DNA lesions, if not removed by MG-DNA methyltransferase (MGMT), mispair with thymine, trigger rounds of futile mismatch repair (MMR), and in glioma cells lead to prolonged G2-M arrest and ultimately cell death. Depletion of MGMT by O6-benzylguanine (BG) sensitizes tumor cells to TMZ, and this combination is currently used in clinical trials. The use of the TMZ+BG combination in gliomas, however, is complicated by the prolonged TMZ-induced G2-M arrest, which may delay activation of poorly defined cell death pathways and allow for MGMT repletion and reversal of toxicity. METHODS: To address these issues, the actions of TMZ were monitored in DNA MMR-proficient SF767 glioma cells depleted of MGMT by BG, and in cells in which BG was removed at various times after TMZ exposure. In MGMT-depleted cells, TMZ exposure led to DNA single-strand breaks and phosphorylation of cdc2, followed by G2-M arrest, induction of p53/p21, and DNA double-strand breaks. Although DNA single-strand breaks, phosphorylation of cdc2, and G2-M arrest could be reversed by repletion of MGMT up to 5 days after TMZ exposure, TMZ-induced cytotoxicity could only be prevented if MGMT was replenished within 24 hours of the onset of G2-M arrest, and before the creation of DNA double-strand breaks. CONCLUSIONS: These results indicate that although SF767 glioma cells undergo a prolonged G2-M arrest in response to TMZ, their ability to escape TMZ-induced cytotoxicity by MGMT repletion is limited to an approximately 24-hour period after the onset of G2-M arrest.

Antineoplastic Agents↗
PubMed1999

Pharmacologic disruption of base excision repair sensitizes mismatch repair-deficient and -proficient colon cancer cells to methylating agents.

Previously we showed that a mismatch repair (MMR)-deficient cell line, HCT116 (hMLH1 mut), unlike a MMR wild-type cell line, SW480, was more resistant to the therapeutic methylating agent, temozolomide (TMZ), because the MMR complex fails to recognize TMZ-induced O6-methylguanine DNA adduct mispairings with thymine that arise after replication. TMZ also produces N7-methylguanine and N3-methyladenine adducts that are processed efficiently by the base excision repair (BER) system. After removal of the methylated base by methylpurine glycosylase, which creates the abasic or apurinic-apyrimidinic (AP) site, the phosphodiester bond is hydrolyzed immediately by AP endonuclease, initiating the repair of the AP site. Methoxyamine (MX) reacts with the abasic site and prevents AP endonuclease cleavage, disrupting DNA repair. MX potentiated the cytotoxic effect of TMZ with a dose modification factor (DMF) of 2.3+/-0.12 in SW480 and 3.1+/-0.16 in HCT116. When combined with O6-benzylguanine (BG), MX and TMZ dramatically increased TMZ cytotoxicity (65.8-fold) in SW480, whereas no additive effect was seen in HCT116. This suggests that N7-methylguanine and N3-methyladenine adducts are cytotoxic lesions in MMR-deficient and wild-type cells when BER is interrupted. Because poly(ADP-ribose) polymerase (PARP) aids in processing of DNA strand breaks induced during MMR and BER, we asked whether PARP inhibitors would also affect BER-mediated cell killing. We found that PARP inhibitors PD128763, 3-aminobenzimide, and 6-aminonicotinamide increased the sensitivity to TMZ in both HCT116 MMR-deficient cells and SW480 MMR wild-type cells. In HCT116 cells, PD128763 remarkably decreased resistance to TMZ, with a DMF of 4.7+/-0.2. However, the combination of PD128763, BG, and TMZ had no greater effect, indicating that persistent O6-methylguanine had no effect on cytotoxicity. In SW480, the DMF for TMZ cytotoxicity was 3.1+/-0.12 with addition of PD128763 and 36 with addition of PD128763 and BG. Synergy analysis by median effect plots indicated a high degree of synergy between TMZ and MX or PD128763. In contrast, 1,3-bis(2-chloroethyl)-1-nitrosourea combined with either MX or PD128763 showed little if any potentiation observed in the absence of BG in either cell line, suggesting that BER pathway has little impact on cytotoxic processing of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced adducts. These studies indicate that targeting BER with MX or PARP inhibitors enhances the cytotoxicity of methylating agents, even in MMR-deficient cells.

Antineoplastic Agents, Alkylating↗
PubMed1995

Trimetazidine: in vitro influence on heart mitochondrial function.

The mechanism of action of the antianginal trimetazidine (TMZ) remains largely unknown. In cultured rat ventricular myocytes in physiologic conditions, TMZ (5 x 10(-4) M) reduced the plateau potential level, the upstroke velocity, and the spontaneous action potential rate. When the cardiomyocytes were submitted to hypoxia (150 or 240 minutes) in a glucose-free medium, treatment with TMZ largely prevented the hypoxia-induced electromechanical alterations, i.e., the decrease in plateau amplitude, in resting membrane potential, in action potential duration, in rate, and in contractility. No hypoxia-induced arrhythmia was observed in the TMZ-treated cells. Moreover, the lactate dehydrogenase leakage was significantly reduced in the TMZ-treated cardiomyocytes (-58% and -36%, after 150 and 240 minutes of hypoxia, respectively). The drug was not efficient in reducing the hypoxia-induced decrease in adenosine triphosphate (ATP) content. The cellular ATP content was slightly lower in the TMZ-treated cells in normoxic conditions and in hypoxic conditions, but only in the glucose-free medium. To investigate further the relation between TMZ and energy metabolism, the respiration parameters were measured in heart mitochondria isolated from control and TMZ-treated rats (6 mg/kg/day, 7 days) with different substrates. This treatment resulted in a slight alteration of pyruvate oxidation, which was observed in the absence and in the presence of TMZ (10(-4) M) in the respiration medium. Conversely, a potent inhibition of palmitoylcarnitine oxidation was measured when TMZ was added to the respiration medium. Neither pretreatment of the rats, nor addition of TMZ to the medium affected the oxidation of glutamate or citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗