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PubMed2005

Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC.

PURPOSE: To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children. METHODS: LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145-200 mg/m(2) per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations. RESULTS: The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively. CONCLUSIONS: Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.

Antineoplastic Agents, Alkylating↗

PubMed1999

Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide.

PURPOSE: Temozolomide is an imidazotetrazine alkylating agent which undergoes chemical conversion at physiological pH to the active species 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC) but is stable at acid pH. This study evaluated the effect of an increase in gastric pH, through the use of ranitidine, on the oral bioavailability and plasma pharmacokinetics of temozolomide and MTIC. METHODS: Fifteen patients with advanced cancer were enrolled of which 12 were evaluable, all of whom had pharmacokinetic blood sampling. Each patient received temozolomide 150 mg m(-2) day(-1) for 5 days in cycle 1 and also received ranitidine 150 mg every 12 h either on days 1 and 2 or days 4 and 5. Gastric pH was monitored by the use of the Heidelberg capsule system. RESULTS: Following the administration of ranitidine there was a rise in gastric pH by 1-2 pH units over the duration of the study period (pH range 2.2-5.2 without ranitidine and 3.5-6.0 with ranitidine). There was no difference in the pharmacokinetic parameters of temozolomide or MTIC with or without the concomitant administration of ranitidine. There was however, a lower C(max) for temozolomide and MTIC for patients receiving ranitidine on day 1 and 2 versus day 4 and 5. Temozolomide was rapidly absorbed [time to maximum plasma concentration (t(max)) 1.8 h] and eliminated [elimination half-life (t(1/2)) 1.8 h] and MTIC followed a similar pattern with a t(max) of 1.9 h and a t(1/2) of 1.9 h. Overall, the AUC of the MTIC represented about 2-4% of the AUC for temozolomide.

Administration, Oral↗

PubMed2001

Temozolomide in combination with other cytotoxic agents.

Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) has several characteristics that make it appealing for combination therapies: broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. Preclinical and phase I trials have shown the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. Toxicity is lower and the maximum tolerated dose is higher when carmustine is given before temozolomide. Studies also have examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 was more effective than either agent alone. A major issue facing investigators now is determining which of the several schedules of temozolomide and CPT-11 are optimal. Completed and ongoing studies of temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

High-performance liquid chromatographic analysis and stability of anti-tumor agent temozolomide in human plasma.

Temozolomide (SCH 52365; TEMODAL) is an antineoplastic agent with activity against a broad spectrum of murine tumors. This compound is currently marketed in the European Union for the treatment of patients with glioblastoma multiforme and anaplastic astrocytoma, which are serious and aggressive types of brain cancers. It has been postulated that temozolomide exerts its in vivo activity via the decomposition product MTIC, which is believed to alkylate nucleophiles, and in the process is converted to AIC. A high-performance liquid chromatographic (HPLC) method was developed and validated for the analysis of temozolomide in human plasma. The determination of temozolomide involved extraction with ethyl acetate followed by separation on a reversed phase C-18 column and quantification by UV absorbance at 316 nm. The calibration curve was linear over a concentration range of 0.1-20 microg/ml. The limit of quantitation was 0.1 microg/ml, where the coefficient of variation (CV) was 0% and the bias was 10.0%. The method was precise with a coefficient of variation ranging from 2.5 to 6.9% and accurate with a bias ranging from 5.0 to 10.0%. Temozolomide was unstable at 37 degrees C in human plasma with a degradation t1/2 of 15 min; however, it was stable at 4 degrees C for at least 30 min. Temozolomide was stable in acidified human plasma (pH < 4) for at least 24 h at 25 degrees C, and for at least 30 days at -20 degrees C. Moreover, temozolomide was stable in acidified human plasma after being subjected to three freeze thaw cycles. The assay was shown to be specific, accurate, precise, and reliable for use in pharmacokinetic studies.

Antineoplastic Agents↗

PubMed2000

Population pharmacokinetics of temozolomide in cancer patients.

PURPOSE: To evaluate covariate effects on the pharmacokinetics of temozolomide in cancer patients, and to explore the dose-pharmacokinetics-toxicity relationship of temozolomide. METHODS: Non-linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical trials. All patients in the phase I trials had advanced cancer. Patients in the phase II trials had anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectively developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease, smoking status, and selected concomitant medications. Descriptive statistics were used to summarize the toxicity and temozolomide dose and exposure relationship. RESULTS: The pharmacokinetics of temozolomide follows a one-compartment model with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GBM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m2, and 8.8 L/hr for female with BSA equal to 1.7 m2. The mean clearance for MM patients was slightly higher. The inter-subject variability in clearance was 15%, and the residual variability was 26%. Other factors investigated in this analysis had little effect on clearance. The overall incidence of neutropenia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predict nadir neutrophil and platelet counts due to large variability in counts. CONCLUSIONS: The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.

Adult↗

PubMed1999

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies.

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m(-2) day(-1). Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for phase II studies.

Administration, Oral↗

PubMed2001

An Australian experience with temozolomide for the treatment of recurrent high grade gliomas.

Temozolomide has an evolving role in the treatment of high grade gliomas. Recent studies suggest that temozolomide is well tolerated and efficacious. This study retrospectively analysed the activity and toxicity associated with temozolomide at two Australian centres over a 24 month period. Fifty-six patients with recurrent high grade gliomas were treated with temozolomide. Patients received temozolomide orally at 150-200mg/m(2)daily, days 1-5, every 4 weeks. The median number of treatment cycles was 4 (1-12). Of the 56 patients, 15 (27%) achieved complete or partial response and 18 (32%) achieved minor response or stable disease. There were no episodes of febrile neutropenia and temozolomide was generally well tolerated. In conclusion, temozolomide is an active therapy in patients with recurrent high grade glioma and our results concord with published studies.

Adult↗

PubMed2003

Health-related quality of life in patients with advanced metastatic melanoma: results of a randomized phase III study comparing temozolomide with dacarbazine.

Health-related quality of life (HRQL) is a crucial endpoint in the evaluation of treatments that have limited survival benefits. The HRQL evaluations help ensure that patients are not sacrificing life quality for quantity. Current treatments for metastatic melanoma are primarily palliative, because cure is unattainable. The purpose of this article is to report detailed HRQL results of a phase III clinical trial comparing temozolomide to dacarbazine (DTIC) in patients with metastatic melanoma. Patients were randomized to receive either oral temozolomide for 5 days every 4 weeks or intravenous DTIC for 5 days every 3 weeks. The HRQL was evaluated on day 1 cycle 1 and after each subsequent treatment cycle using the EORTC QLQ-C-30. The HRQL was compared between groups at weeks 12 and 24. Patients treated with temozolomide reported significantly better physical functioning and less fatigue and sleep disturbances than patients treated with DTIC at week 12. For all but two function and symptom subscales, EORTC QLQ-C30 subscale scores were numerically better for patients treated with temozolomide at week 12. All subscales except diarrhea were better for temozolomide at week 24. Analyses of change scores revealed that patients treated with temozolomide reported statistically significant improvements in emotional well-being and sleep disturbance. Patients also reported near significant change in cognitive functioning (3.9, p = 0.06). Patients treated with DTIC deteriorated on most function subscales and many symptom subscales at week 12. Deterioration in physical functioning approached significance (-6.8, p = 0.06). At week 24, patients treated with DTIC improved on the emotional functioning subscale and deteriorated on the physical, role, and global HRQL subscales, although many of the symptom scores improved. The results of this study suggest that treatment with temozolomide leads to important functional improvements and decreased symptoms compared to treatment with DTIC in patients being treated for metastatic melanoma.

Administration, Oral↗

PubMed2004

Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors.

BACKGROUND: Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150-200 mg/m(2)/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. PATIENTS AND METHODS: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting daily dose was 200 mg/m(2) in a group of at least six patients, with subsequent increments of 50 mg/m(2) in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonald's criteria were used to evaluate antitumor activity. RESULTS: Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 1-3). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m(2)/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m(2), respectively. Grade 3-4 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m(2)/day, respectively. Grade 3-4 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m(2)/day temozolomide, respectively. At a dose of 350 mg/m(2), sustained grade 2-3 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m(2)/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients. CONCLUSIONS: Temozolomide can be given safely using a dose-dense regimen of 300 mg/m(2)/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.

Adolescent↗

PubMed1997

In vitro evaluation of temozolomide combined with X-irradiation.

The in vitro cytotoxicity of 8-carbamoyl-3-methylimidazo [5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) with concurrent X-irradiation was examined in a human glioblastoma cell line (U373MG) as a potential radio-chemotherapeutic treatment for malignant glioma. The combination was also examined in a human colorectal adenocarcinoma (Mawi) which had 100-fold greater O6-alkylguanine-DNA alkyltransferase (AGT) activity, a DNA-repair protein which confers resistance to temozolomide. A comparison of IC50 values indicated U373MG to be over 32-fold more sensitive to temozolomide than Mawi, but slightly more resistant to X-irradiation (p < 0.035; unpaired two-tailed t-test). Temozolomide and X-irradiation proved largely additive in U373MG by isobologram analysis (50% iso-effect) and the addition of 10 microM temozolomide to 1-2 Gy of X-irradiation increased cell kill by 2.5- to 3.0-fold. However, the combination was antagonistic in Mawi: an effect attributed to AGT induction by X-irradiation as the antagonism was removed by co-incubation with the AGT inhibitor O6-benzylguanine (O6-BG 1 microM; 24 h). O6-BG did not affect the radiation dose-response curve, but significantly increased temozolomide cytotoxicity (p < 0.015). In conclusion, the combination of temozolomide with radiation is at best additive, but could nonetheless by of considerable therapeutic benefit in glioma, particularly if administered for prolonged periods. If AGT induction compromises the efficacy of this therapy, it may be circumvented with an appropriate inhibitor such as O6-BG.

Adenocarcinoma↗

PubMed2003

Temozolomide is active in childhood, progressive, unresectable, low-grade gliomas.

PURPOSE: To assess the activity and tolerability of temozolomide in children with progressive low-grade gliomas (LGGs). PATIENTS AND METHODS: The authors reviewed the records of 13 children (6 months to 19 years old) with progressive LGGs and magnetic resonance imaging evidence of unresectable tumors who were treated with temozolomide at the authors' institution since 1999. RESULTS: Four patients received a 5-day regimen of temozolomide (150 mg/m2 per day) repeated every 28 days, and nine patients received a 42-day regimen (75 mg/m2 per day) repeated every 56 days. Three patients demonstrated partial responses to temozolomide, with a median time to maximal response of 5 months (range 4-12 months), and one had a minor response at 9 months. Four patients developed progression while on temozolomide, with a median time to progression of 7 months (range 1-12 months). Five patients had disease stabilization. Among the five patients with prior chemotherapy and/or radiation therapy, temozolomide was associated with disease stabilization in three and tumor response in one. In the three patients with neurofibromatosis type 1, two patients experienced tumor responses and one disease stabilization. Thrombocytopenia, nausea, emesis, and fatigue were the most common toxicities. Four patients discontinued therapy because of the side effects. CONCLUSIONS: Temozolomide is active in children with LGGs. It is effective in previously treated patients and in patients with neurofibromatosis type 1. The 42-day regimen appears less toxic than the 5-day regimen. Any impact on survival for these patients remains to be demonstrated.

Adolescent↗

PubMed2004

The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma.

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.

Adult↗

PubMed2003

Pharmacodynamic-mediated effects of the angiogenesis inhibitor SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral glioma xenograft models.

The objective of this study was to determine the tumor distribution of temozolomide, an alkylating agent, in the absence and presence of the angiogenesis inhibitor 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]indolin-2-one (SU5416), a specific vascular endothelial cell growth factor receptor 2 inhibitor. The study was conducted in nude rats bearing either subcutaneous or intracerebral tumors that overexpressed vascular endothelial cell growth factor. For both tumor locations, animals were assigned to either of two treatment groups, SU5416 (25 mg/kg, dissolved in dimethyl sulfoxide) or vehicle control, dimethyl sulfoxide (710 microl/kg) administered i.p. every day for a total of nine doses. Twenty-four hours after the last dose of SU5416 or dimethyl sulfoxide, temozolomide was administrated as a steady-state infusion regimen designed to achieve target plasma concentrations (Cp) of 20 microg/ml. In addition to the measurement of temozolomide Cp, tumor interstitial fluid unbound concentrations of temozolomide were evaluated by microdialysis. In subcutaneous tumors, SU5416 treatment produced a 24% reduction in steady-state temozolomide Ct values (p < 0.05) as well as 21% reductions in tumor/plasma concentration ratios (Ct/Cp; p = 0.11) compared with controls. In intracerebral tumors, steady-state temozolomide Ct and Ct/Cp ratios were significantly increased by 2-fold in the SU5416 treatment group compared with control. The apparent paradoxical effect of SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral tumors is discussed in the context of physiological changes (for example, interstitial fluid pressure and microvessel density) and the sampling region in the tumor. It is proposed that the net balance of antiangiogenic drug-mediated pharmacodynamic actions will determine how drug disposition in tumors may be affected.

Angiogenesis Inhibitors↗

PubMed2005

Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence.

Pharmacologic inhibition of the DNA signal transducers Chk1 and p38 blocks G2 arrest and sensitizes glioblastoma cells to chemotherapeutic methylating agent-induced cytotoxicity. Because Akt pathway activation has been suggested to also block G2 arrest induced by DNA-damaging agents and because glioma cells frequently have high levels of Akt activation, we examined the contribution of the Akt pathway to methylating agent-induced G2 arrest and toxicity. U87MG human glioma cells containing an inducible Akt expression construct were incubated with inducing agent or vehicle, after which the cells were exposed to temozolomide and assayed for activation of the components of the G2 arrest pathway and survival. Temozolomide-treated control cells activated the DNA damage signal transducers Chk1, Chk2, and p38, leading to Cdc25C and Cdc2 inactivation, prolonged G2 arrest, and loss of clonagenicity by a combination of senescence and mitotic catastrophe. Temozolomide-treated cells induced to overexpress Akt, however, exhibited significantly less drug-induced Cdc25C/Cdc2 inactivation and less G2 arrest. Akt-mediated suppression of G2 arrest was associated not with alterations in Chk1 or p38 activation but rather with suppression of Chk2 activation and reduced recruitment of Chk2 to sites of damage in chromatin. Unlike bypass of the G2 checkpoint induced by pharmacologic inhibitors of Chk1 or p38, however, Akt-induced bypass of G2 arrest suppressed, rather than enhanced, temozolomide-induced senescence and mitotic catastrophe. These results show that whereas Akt activation suppresses temozolomide-induced Chk2 activation and G2 arrest, the overriding effect is protection from temozolomide-induced cytotoxicity. The Akt pathway therefore represents a new target for the sensitization of gliomas to chemotherapeutic methylating agents such as temozolomide.

Antineoplastic Agents, Alkylating↗

PubMed2006

Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors.

PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer. EXPERIMENTAL DESIGN: Lomeguatrib was administered at dose levels of 10 to 40 mg/m2 days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m2 on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination. RESULTS: Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m2 days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months. CONCLUSION: This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.

Adenosine Triphosphatases↗

PubMed2006

Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line.

Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.

Antineoplastic Agents, Alkylating↗

PubMed2002

Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors.

Temozolomide, an oral alkylating agent has a significant activity in preclinical testing and in clinical trials in adults and children as well. Penetration across the blood brain barrier has been documented. In adult and pediatric phase I and II trials a five-day every 28 days schedule was first approved for clinical use. With respect to temozolomide proximal mechanism of resistance, and further to increase dose intensity, new schedules are proposed to use more prolonged drug exposure. Higher doses of metronomic temozolomide were piloted. Eight children with poor prognosis brain tumors were eligible. Treatment consisted from concomitant radiotherapy given 1x170 cGy, 5d/wk, for total dose 55/56 Gy, together with temozolomide 90 mg/m2/day for 42 days. No further dose escalation has been planned for this group of patients. Myelosuppression was the primary toxicity, occurring around day 21. Nonhematologic toxicities were infrequent and in no case dose limiting toxicity (DLT) occurred. The most common nonhematologic toxicity was vomiting, effectively managed with antiemetics. Six responses were documented. The best responses (CR) were seen in 2 patients with high-risk medulloblastomas, who have progressed early after neurosurgery. Furthermore, one more patient had CR and 3 patients PR at the end of temozolomide treatment. We have piloted novel dose schedule of temozolomide and evaluated clinical toxicities in a cohort of 8 children. This is the first study to report feasibility and tolerability of 90 mg/m2/day of temozolomide treatment in metronomic fashion. In addition, we have documented encouraging responses in children with medulloblastomas, progressing early after their initial surgery.

Adolescent↗

PubMed1997

Activity of temozolomide against human tumor colony-forming units.

8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one (temozolomide) is a new imidazole tetrazinone compound with promising preclinical and clinical activity in nitrosourea-sensitive and -resistant models and manageable toxicity in Phase I and II clinical trials. In this study, we investigated the antiproliferative activity of temozolomide against a large variety of human tumors taken directly from patients in an in vitro soft agar tumor cloning system. Temozolomide was studied using a continuous exposure at final concentrations from 0.1 to 10.0 microM against a total of 222 tumor specimens, of which 101 (45%) were evaluable. A decrease in tumor colony formation was considered significant if survival of colonies treated with temozolomide was </=50% of that in controls. In vitro responses were seen in 9 of 101 [9%; 95% confidence interval (CI), 3-14], 16 of 100 (16%; 95% CI, 8. 5-23), and 35 of 101 (35%; 95% CI, 26-45) tumor specimens at concentrations of 0.1, 1.0, and 10.0 microM, respectively (P < 0. 001). The level of O6-guanine-alkyl-transferase was evaluable in 19 specimens before treatment but did not correlate with a response to temozolomide. At a concentration of 10 microM, a good cytotoxic activity was seen in breast (42%; 95% CI, 15-72), ovarian (36%; 95% CI, 11-69), and non-small cell lung cancers (27%; 95% CI, 6-61). Interestingly, activity was also seen in renal cell carcinomas (50%; 95% CI, 19-81), colon cancers (42%; 95% CI, 15-72), melanomas (33%; 95% CI, 13-59), and some other tumors, including sarcomas and both prostatic and pancreatic carcinomas that are usually considered very resistant to several conventional chemotherapy agents. Moreover, we observed that a subset of tumors that were not sensitive to dacarbazine, carmustine, cisplatin, doxorubicin, 5-fluorouracil, etoposide, and vinblastine were sensitive to temozolomide. These data indicate both that temozolomide is an active drug in vitro against a large variety of human tumors, including some tumors usually resistant to conventional chemotherapy, and that further clinical evaluation is warranted.

Adrenal Gland Neoplasms↗