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PubMed2006

Early change in glucose metabolic rate measured using FDG-PET in patients with high-grade glioma predicts response to temozolomide but not temozolomide plus radiotherapy.

PURPOSE: To compare the ability of positron emission tomography (PET) to predict response to temozolomide vs. temozolomide plus radiotherapy. METHODS AND MATERIALS: Nineteen patients with high-grade glioma (HGG) were studied. Patients with recurrent glioma received temozolomide 75 mg/m2 daily for 7 weeks (n=8). Newly diagnosed patients received temozolomide 75 mg/m2 daily plus radiotherapy 60 Gy/30 fractions over 6 weeks, followed by six cycles of adjuvant temozolomide 200 mg/m2/day (Days 1-5 q28) starting 1 month after radiotherapy (n=11). [18F]Fluorodeoxyglucose ([18F]FDG) PET scan and magnetic resonance imaging (MRI) were performed at baseline, and 7 and 19 weeks after initiation of temozolomide administration. Changes in glucose metabolic rate (MRGlu) and MRI response were correlated with patient survival. RESULTS: In the temozolomide-alone group, patients who survived>26 vs. or=25%, survived longer than nonresponders with mean survival times of 75 weeks (95% CI, 34-115 vs. 20 weeks (95% CI, 14-26) (p=0.0067). In the small group of patients studied, there was no relationship between MRI response and survival (p=0.52). For patients receiving temozolomide plus radiotherapy, there was no difference in survival between PET responders and nonresponders (p=0.32). CONCLUSIONS: Early changes in MRGlu predict response to temozolomide, but not temozolomide plus radiotherapy.

Adolescent↗
PubMed2006

Radiotherapy and sequential temozolomide compared with radiotherapy with concomitant and sequential temozolomide in the treatment of newly diagnosed glioblastoma multiforme.

Our objective was to determine and compare effects of sequential temozolomide vs. concomitant plus sequential temozolomide with conventional radiotherapy, in patients with newly diagnosed glioblastoma multiforme, comparing two independent trials. Sixty-four patients were treated on two consecutive separate phase II studies that used identical eligibility criteria and the same radiotherapy (60 Gy, 2 Gy/day, after surgery) and adjuvant temozolomide (200 mg/m/day for 5 days/28 days until progression), but differed in the absence or presence of a concomitant treatment with temozolomide (75 mg/m/day) during radiotherapy. In the first protocol (1999-2002), 21 patients (median age of 64 years) received radiotherapy alone and sequential temozolomide; in the succeeding protocol (2002-2004), 43 patients (median age of 61 years) with similar characteristics received radiotherapy with concomitant and sequential temozolomide. Median number of adjuvant cycles was five in both trials. Median survival was similar in both studies (18 vs. 17.4 months); overall survival rates at 6, 12, 18 and 24 months of all the population were 89, 69, 45 and 24%. No statistically significant differences were found among prognostic factors considered. Hematologic toxicities were mild and similar, with grade 3-4 neutropenia in 5-7% and grade 3-4 thrombocytopenia in 7-10% of patients in the sequential phases, and grade 3-4 thrombocytopenia in 7% in the concomitant phase of temozolomide. We confirmed that temozolomide combined with radiotherapy is well tolerated and provides a survival advantage compared with historical data using radiotherapy alone. Nevertheless, a concomitant use of temozolomide during radiotherapy does not seem to improve survival, although it does not increase toxicity.

Aged↗
PubMed2002

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Adult↗
PubMed2005

Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiforme orthotopic xenografts.

OBJECT: Malignant gliomas consist of both heterogeneous proliferating and migrating cell subpopulations, with migrating glioma cells exhibiting less sensitivity to antiproliferative or proapoptotic drugs than proliferative cells. Therefore, the authors combined cimetidine, an antiinflammatory agent already proven to act against migrating epithelial cancer cells, with temozolomide to determine whether the combination induces antitumor activities in experimental orthotopic human gliomas compared with the effects of temozolomide alone. METHODS: Cimetidine added to temozolomide compared with temozolomide alone induced survival benefits in nude mice with U373 human glioblastoma multiforme (GBM) cells orthotopically xenografted in the brain. Computer-assisted phase-contrast microscopy analyses of 9L rat and U373 human GBM cells showed that cimetidine significantly decreased the migration levels of these tumor cells in vitro at concentrations at which tumor growth levels were not modified (as revealed on monotetrazolium colorimetric assay). Computer-assisted microscope analyses of neoglycoconjugate-based glycohistochemical staining profiles of 9L gliosarcomas grown in vivo revealed that cimetidine significantly decreased expression levels of endogenous receptors for fucose and, to a lesser extent, for N-acetyl-lactosamine moieties. Endogenous receptors of this specificity are known to play important roles in adhesion and migration processes of brain tumor cells. CONCLUSIONS: Cimetidine, acting as an antiadhesive and therefore an antimigratory agent for glioma cells, could be added in complement to the cytotoxic temozolomide compound to combat both migrating and proliferating cells in GBM.

Adjuvants, Immunologic↗
PubMed2005

Salvage temozolomide for prior temozolomide responders.

BACKGROUND: Temozolomide (TMZ) often is used as adjuvant or first-line therapy for patients with glioma. Because of potential hematologic complications, it usually is discontinued after 12-18 cycles, even in responders. Subsequent salvage therapies are reported to have limited efficacy at the time of disease recurrence. In the current study, the authors assessed the outcome and complications of reusing TMZ at the time of disease recurrence in patients who previously responded to treatment. METHODS: A retrospective review of patients with recurrent/progressive glioma who had a history of response to TMZ and were treated with the same agent at the time of disease recurrence was conducted. RESULTS: Fourteen patients were identified (8 men and 6 women). The median age of the patients was 56 years (range, 25-67 yrs) at the time of diagnosis; 9 patients had glioblastoma, 3 had anaplastic astrocytoma, and 2 patients had low-grade oligodendroglioma. No patient developed disease progression while receiving the initial TMZ treatment. At the time of the initial disease recurrence, 13 patients were readministered TMZ. One patient received TMZ at the time of second disease recurrence. All patients were assessed for radiographic response. Objective response or stable disease was achieved in 6 patients (43%; 95% confidence interval [95% CI], 21-67%) and the 6-month progression-free survival was 36% (95% CI, 16-61%). CONCLUSIONS: TMZ was found to be well tolerated and effective in this setting, suggesting that repeat use of TMZ in previous responders warrants further investigation.

Adult↗
PubMed2005

Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (CDDP) is able to down-regulate the AGAT activity, suggesting that CDDP could enhance the antitumor activity of TMZ. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination versus single-agent TMZ in patients with advanced melanoma. PATIENTS AND METHODS: From January 2000 to April 2002, 132 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the two arms. Patients with cerebral metastases were included. Patients received TMZ 200 mg/m(2)/day orally for five consecutive days every 4 weeks or TMZ + CDDP 200 mg/m(2) daily on days 1-5 and 75 mg/m(2) of CDDP on day 1. RESULTS: Tumor responses (complete and partial responses) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.8 months in arm A and 5.8 months in arm B. The median overall survival (OS) was 11.5 months in arm A and 12 months in arm B. The difference between treatment arms regarding objective response rates, TTP and OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralgias/myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. CONCLUSIONS: No clear benefit in terms of response rates, median TTP or OS was shown with the combination of TMZ + CDDP. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis.

Adult↗
PubMed2003

Inhibition of telomerase increases resistance of melanoma cells to temozolomide, but not to temozolomide combined with poly (adp-ribose) polymerase inhibitor.

In the present study, we have investigated the influence of telomerase inhibition in chemosensitivity of melanoma cells to temozolomide (TMZ), a methylating agent with promising antitumor activity against metastatic melanoma. In fact, telomerase, a ribonucleoprotein enzyme expressed in the majority of tumors, is presently considered an attractive target for anticancer therapy, with the double aim of reducing tumor growth and increasing chemosensitivity of cancer cells. Susceptibility to TMZ and to other antitumor agents used for treatment of metastatic melanoma was initially assessed in melanoma lines with different basal levels of telomerase activity. Thereafter, chemosensitivity was investigated after inhibition of telomerase by means of stable transfection of a catalytically inactive, dominant-negative mutant of hTERT (DN-hTERT). This study shows for the first time that: a) susceptibility to TMZ of melanoma lines derived from the same patient did not depend on basal telomerase activity; b) inhibition of telomerase by DN-hTERT resulted in reduced growth rate and increased resistance to TMZ and to the chloroethylating agent carmustine, increased sensitivity to cisplatin, and no change in response to tamoxifen or to a selective N3-adenine methylating agent; c) inhibition of poly(ADP-ribose) polymerase (PARP), an enzyme involved in the repair of N-methylpurines, restored sensitivity of DN-hTERT clones to TMZ. These results indicate that a careful selection of the antitumor agent has to be made when antitelomerase therapy is combined with chemotherapy. Moreover, the data presented here suggest that TMZ + PARP inhibitor combination is active against telomerase-suppressed and slowly growing tumors.

Antineoplastic Agents, Alkylating↗
PubMed2005

Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group.

PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week). RESULTS: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001). CONCLUSION: In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

Adult↗
PubMed2006

A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma.

Frequent regular administration of chemotherapeutic agents at low doses, known as 'metronomic chemotherapy', can increase the anti-angiogenic activity of the drugs, as has been confirmed by several other experimental tumor models. The aim of this pilot study was to evaluate the efficacy and safety of metronomic temozolomide (TMZ) treatment in twelve consecutive patients with recurrent TMZ-refractory glioblastoma. The patients were administered by metronomic treatment schedule (continuous low-dose chemotherapy) with TMZ at a daily dose of 40 mg/m(2). The median overall survival (OS) and progression-free survival (PFS) from the start of metronomic treatment were 11.0 months (95% CI, 5.2-10.5 months) and 6.0 months (95% CI, 0-12.3 months), respectively. During the follow-up period, complete response (CR) was not achieved in any patient, partial response (PR) in 2, and stable disease (SD) in 5 patients. Estimated PFS (CR+PR+SD) was 58.3% at 3 months. Grade III/IV toxicity according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was not found. These results suggest that the change of chemotherapeutic schedule from conventional to metronomic treatment overcomes the chemo-resistance in patients with recurrent TMZ-refractory glio-blastoma without any major toxicity.

Adult↗
PubMed2003

Metabolic activation of temozolomide measured in vivo using positron emission tomography.

The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed with both forms of [(11)C]temozolomide in 6 patients with gliomas. Another PET scan with (11)C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [(11)C]temozolomide and [(11)C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [(11)C]CO(2). The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor. There was rapid systemic clearance of both radiolabelled forms of [(11)C]temozolomide over 90 min (0.2 liter/min/m(2)), with [(11)C]CO(2) being the primary elimination product. Plasma [(11)C]CO(2) was present in all of the studies with [4-(11)C-carbonyl]temozolomide and in half the studies with [3-N-(11)C-methyl]temozolomide. The mean contributions to total plasma activity by [(11)C]CO(2) at 10 and 90 min were 12% and 28% with [4-(11)C-carbonyl]temozolomide, and 1% and 4% with [3-N-(11)C-methyl]temozolomide, respectively. There was a 5-fold increase in exhaled [(11)C]CO(2) sampled with [4-(11)C-carbonyl]temozolomide compared with [3-N-(11)C-methyl]temozolomide (P < 0.05). A decrease in tissue exposure [area under the curve between 0 and 90 min (AUC(0-90 min))] to [(11)C]temozolomide was also observed with [4-(11)C-carbonyl] temozolomide compared with [3-N-(11)C-methyl]temozolomide. Of potential therapeutic advantage was the higher [(11)C]radiotracer and [(11)C]temozolomide exposure (AUC(0-90 min)) in tumors compared with normal tissue. [(11)C]temozolomide ring opening over 90 min was less in plasma (20.9%; P < 0.05) compared with tumor (26.8%), gray matter (29.7%), and white matter (30.1%), with no differences (P > 0.05) between tumor and normal tissues. The significantly higher amounts of [(11)C]CO(2) sampled in plasma and exhaled air, in addition to the lower normal tissue and tumor [(11)C]temozolomide AUC(0-90 min) observed with [4-(11)C-carbonyl]temozolomide, confirmed the postulated mechanism of metabolic activation of temozolomide. A higher tumor [(11)C]temozolomide AUC(0-90 min) in tumors compared with normal tissue and the tissue-directed metabolic activation of temozolomide may confer potential therapeutic advantage in the activity of this agent. This is the first report of a clinical PET study used to quantify and confirm the in vivo mechanism of metabolic activation of a drug.

Adult↗
PubMed2003

Temozolomide: realizing the promise and potential.

PURPOSE OF REVIEW: The discovery of temozolomide in the 1980s was expected to be an important advance in improving survival for patients with malignant brain tumors. Numerous clinical studies have demonstrated the activity of temozolomide against recurrent or refractory gliomas and noncentral nervous system malignancies. In the last 2 years, studies have focused on exploring strategies to optimize the efficacy of temozolomide, including evaluating different temozolomide dosing schedules and combining temozolomide with other antineoplastic agents, radiation therapy, or drug resistance-modifying agents. RECENT FINDINGS: A critical review of these studies suggests that temozolomide, as currently used, has limited efficacy in treating refractory malignant infiltrative brain tumors, and survival benefit is, at best, a few weeks longer than that with procarbazine. There is enthusiasm about the activity of temozolomide in the treatment of recurrent low-grade gliomas and advanced malignant melanomas. Temozolomide has activity and a favorable safety profile in all dosing schedules tested. Nevertheless, the trials evaluating the efficacy of temozolomide suffer from being uncontrolled, with short follow-up periods. SUMMARY: Despite the advantages of a favorable safety profile and oral administration, temozolomide has yet to realize its initial promise and full potential. Studies of temozolomide combined with novel drug resistance-modifying agents will likely improve disease control while minimizing toxicities, leading to improved survival benefit. Larger, randomized trials comparing temozolomide with standard therapy are needed to confirm the suggested benefit from temozolomide in malignant brain tumors. Temozolomide will continue to be attractive as an agent in the treatment of brain tumors because of its desirable features and safety.

Antineoplastic Agents, Alkylating↗
PubMed2006

Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms.

PURPOSE: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells. EXPERIMENTAL DESIGN: Using a panel of four primary human glioblastoma cell lines with heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. RESULTS: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O(6)-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O(6)-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. CONCLUSIONS: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O(6)-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.

Animals↗
PubMed2005

The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death.

DNA-alkylating agents have a central role in the curative therapy of many human tumors; yet, resistance to these agents limits their effectiveness. The efficacy of the alkylating agent temozolomide has been attributed to the induction of O6-MeG, a DNA lesion repaired by the protein O6-methylguanine-DNA methyltransferase (MGMT). Resistance to temozolomide has been ascribed to elevated levels of MGMT and/or reduced mismatch repair. However, >80% of the DNA lesions induced by temozolomide are N-methylated bases that are recognized by DNA glycosylases and not by MGMT, and so resistance to temozolomide may also be due, in part, to robust base excision repair (BER). We used isogenic cells deficient in the BER enzymes DNA polymerase-beta (pol-beta) and alkyladenine DNA glycosylase (Aag) to determine the role of BER in the cytotoxic effect of temozolomide. Pol-beta-deficient cells were significantly more susceptible to killing by temozolomide than wild-type or Aag-deficient cells, a hypersensitivity likely caused by accumulation of BER intermediates. RNA interference-mediated pol-beta suppression was sufficient to increase temozolomide efficacy, whereas a deficiency in pol-iota or pol-lambda did not increase temozolomide-mediated cytotoxicity. Overexpression of Aag (the initiating BER enzyme) triggered a further increase in temozolomide-induced cytotoxicity. Enhanced Aag expression, coupled with pol-beta knockdown, increased temozolomide efficacy up to 4-fold. Furthermore, loss of pol-beta coupled with temozolomide treatment triggered the phosphorylation of H2AX, indicating the activation of the DNA damage response pathway as a result of unrepaired lesions. Thus, the BER pathway is a major contributor to cellular resistance to temozolomide and its efficacy depends on specific BER gene expression and activity.

Animals↗
PubMed2006

The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity.

The chemotherapeutic agent temozolomide produces O(6)-methylguanine (O6MG) in DNA, which triggers futile DNA mismatch repair, DNA double-strand breaks (DSB), G(2) arrest, and ultimately cell death. Because the protein complex consisting of Mre11/Rad50/Nbs1 (MRN complex) plays a key role in DNA damage detection and signaling, we asked if this complex also played a role in the cellular response to temozolomide. Temozolomide exposure triggered the assembly of MRN complex into chromatin-associated nuclear foci. MRN foci formed significantly earlier than gamma-H2AX and 53BP1 foci that assembled in response to temozolomide-induced DNA DSBs. MRN foci formation was suppressed in cells that incurred lower levels of temozolomide-induced O6MG lesions and/or had decreased mismatch repair capabilities, suggesting that the MRN foci formed not in response to temozolomide-induced DSB but rather in response to mismatch repair processing of mispaired temozolomide-induced O6MG lesions. Consistent with this idea, the MRN foci colocalized with those of proliferating cell nuclear antigen (a component of the mismatch repair complex), and the MRN complex component Nbs1 coimmunoprecipitated with the mismatch repair protein Mlh1 specifically in response to temozolomide treatment. Furthermore, small inhibitory RNA-mediated suppression of Mre11 levels decreased temozolomide-induced G(2) arrest and cytotoxicity in a manner comparable to that achieved by suppression of mismatch repair. These data show that temozolomide-induced O6MG lesions, acted upon by the mismatch repair system, drive formation of the MRN complex foci and the interaction of this complex with the mismatch repair machinery. The MRN complex in turn contributes to the control of temozolomide-induced G(2) arrest and cytotoxicity, and as such is an additional determining factor in glioma sensitivity to DNA methylating chemotherapeutic drugs such as temozolomide.

Acid Anhydride Hydrolases↗
PubMed1998

Phase I trial of temozolomide using an extended continuous oral schedule.

Temozolomide, a methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanoma, and mycosis fungoides and is presently administered as a 5-day oral schedule every 4 weeks. This Phase I study aimed to determine the maximum tolerated dose of temozolomide administered as a single oral daily dose for a continuous 6- or 7-week period, evaluate the plasma pharmacokinetics on this schedule, and compare total plasma exposure over 7 weeks with the conventional 5-day regimen. Twenty-four patients with varying tumor types (17 of 24 gliomas) received temozolomide. All had clinically evaluable, refractory disease; normal renal, hepatic, and bone marrow function; and WHO performance status < or = 2. Temozolomide was administered at 50 mg/m2/day, increasing by 25 mg/m2/day/cohort until at 100 mg/m2/day grade 4 myelotoxicity forced dose reductions to 85 mg/m2/day, then 75 mg/m2/day. At 75 mg/m2/day the regimen was extended to 7 weeks, allowing the future potential combination with irradiation for primary gliomas. Patient responses (standard Union International Contre Cancer criteria; for gliomas objective response) and toxicity were assessed. Temozolomide plasma pharmacokinetics were determined on day 1 and at the beginning of the final week of administration (n = 5). The most frequent toxicities were myelosuppression and grades 1 and 2 nausea and vomiting. Grade 4 leucopenia and thrombocytopenia occurred in one of four patients receiving 100 mg/m2/day temozolomide and in one of seven patients receiving 85 mg/m2/day. These hematological toxicities did not exceed grade 2 in 10 patients receiving 75 mg/m2/day temozolomide. One of 4 malignant melanoma patients and 7 of 17 glioma patients (41%) demonstrated tumor responses. The overall response rate for this prolonged schedule was 33% (objective response, 7 of 24 patients; partial response, 1 of 24 patients); also, 6 of 17 glioma patients maintained SD. Peak plasma temozolomide concentrations were obtained 30-90 min after oral administration. Elimination in plasma was best described by a monoexponential equation with an elimination half-life of 96 +/- 16 min. No plasma accumulation of temozolomide occurred. Toxicity was greatest in higher dose cohorts, with a resultant maximum tolerated dose of 85 mg/m2/day, whereas lower dose cohorts tolerated the schedule well. The area under the temozolomide plasma versus time curve was noncumulative between the first and last week of the schedule. Temozolomide administration of 75 mg/m2/day over a 7-week period permits a 2.1-fold greater drug exposure/4 weeks in comparison with the 5-day schedule of 200 mg/m2/day repeated every 28 days. The overall response rate was 33% (glioma patients, 41% and a further 25% SD). Temozolomide (75 mg/m2/day) for 7 weeks is the recommended starting dose for further assessment of this schedule.

Administration, Oral↗
PubMed2003

Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates.

Temozolomide is a prodrug that undergoes spontaneous chemical degradation at physiologic pH to form the highly reactive alkylating agent, methyl-triazenyl imidazole carboxamide (MTIC). In clinical trials, temozolomide has activity in gliomas and is approved for recurrent anaplastic astrocytoma. We, therefore, studied the penetration of temozolomide into the cerebrospinal fluid (CSF) as a surrogate for blood-brain barrier penetration in a non-human primate model. Three Rhesus monkeys with indwelling Ommaya reservoirs received 7.5 mg/kg (150 mg/m2) of temozolomide as a 1 h intravenous infusion. Frequent blood and CSF samples were obtained over 24 h, plasma was immediately separated by centrifugation at 4 degrees C, and plasma and CSF samples were acidified with HCl. Temozolomide concentration in plasma and CSF was measured by reverse-phase high-pressure liquid chromatography. Plasma temozolomide concentration peaked 0.5 h after the end of the infusion and was 104 +/- 3 microM. The mean peak CSF temozolomide concentration was 26 +/- 4 microM at 2.5 h. The mean areas under the temozolomide concentration-time curves in plasma and CSF were 392 +/- 18 and 126 +/- 18 microM h, respectively, and the CSF: plasma ratio was 0.33 +/- 0.06. Clearance of temozolomide was 0.116 +/- 0.004 l/kg/h, and the volume of distribution at steady state was 0.254 +/- 0.033 l/kg. In this non-human primate model, temozolomide penetrated readily across the blood-brain barrier. These findings are consistent with the activity of temozolomide in brain tumors.

Animals↗
PubMed2005

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.

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