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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7646-7653
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.02.0024
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Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Katherine E. Warren, Alberta A. Aikin, Madeleine Libucha, Brigitte C. Widemann, Elizabeth Fox, Roger J. Packer, Frank M. Balis

From the National Cancer Institute, Bethesda, MD.

Address reprint requests to Katherine E. Warren, MD, National Cancer Institute Neuro-Oncology Branch, Building 82, Room 219, 9030 Old Georgetown Rd, Bethesda, MD 20892-8200; e-mail: warrenk{at}mail.nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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 ≤ 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.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Temozolomide (TMZ; Temodar; Schering-Plough, Kenilworth, NJ) is an alkylating agent that has a broad range of antitumor activity in preclinical studies.1-3 Clinical antitumor activity has been observed in adults with gliomas4-7 with objective response rates of up to 61% in patients with progressive low-grade gliomas,8 and 35% in patients with high-grade gliomas (anaplastic astrocytomas and anaplastic oligoastrocytomas).6,9 TMZ is an oral prodrug that is rapidly absorbed and spontaneously converted to monomethyl 5-triazeno imidazole carboxamide (MTIC) at physiologic pH.1-3,10 MTIC forms a reactive intermediate1,10 that reacts with DNA, producing methyl adducts primarily at N7-guanine, N3-adenine, and O6-guanine.9 Although the O6-methylguanine (O6-MG) lesion accounts for a minority of DNA adducts formed, this lesion is particularly cytotoxic, and the cytotoxicity of TMZ is correlated with its formation.11-13 If left unrepaired, the O6-MG lesion results in DNA chain termination or strand-breaks.14,15

Two pediatric phase I trials of TMZ administered orally on a daily schedule for 5 days have been conducted.16,17 The maximum-tolerated dose (MTD) was 200 to 215 mg/m2/d for 5 days in children who had not previously received craniospinal radiation,16,17 and 180 mg/m2/d orally for 5 days in patients who had received craniospinal radiation.17 Myelosuppression was the dose-limiting toxicity (DLT) and nonhematologic toxicity was infrequent. Pharmacokinetic analyses demonstrated greater drug exposure in children compared to adults.16 However, even though TMZ has demonstrated antitumor activity in adults with brain tumors, pediatric trials have not demonstrated significant activity of TMZ in childhood brain tumors, with the possible exception of progressive low grade gliomas.18 The reasons are likely multifactorial, but may be due, in part, to the ability of some tumors to repair the DNA damage produced by TMZ.

O6-alkylguanine-DNA alkyltransferase (AGT) is a single-turnover DNA repair protein that is highly conserved across species19 and is expressed in all tissues.20 It specifically recognizes and binds to O6-MG adducts, undergoes a conformational change, and restores guanine by transferring the methyl moiety from the O6-position to an internal cysteine.21,22 The receptor site on AGT becomes irreversibly alkylated and the AGT is permanently inactivated and rapidly degraded.23 Therefore, the ability of AGT to repair O6-MG is related to the number of AGT molecules and the rate of its synthesis.24,25 High levels of AGT have been reported in brain tumors and other solid tumors.26,27 In retrospective and prospective studies of adults with brain tumors treated with BCNU, tumor AGT levels correlated inversely with overall survival.28 TMZ is known to deplete AGT, and its cytotoxic activity in tumor cells in vitro is inversely proportional to AGT activity.12,20,29

O6-benzylguanine (O6BG) is a potent inactivator of AGT.30 It acts as an alternate and highly specific AGT binding substrate that irreversibly inactivates AGT.31 At micromolar concentrations, O6BG depletes ≥ 99% of AGT activity within minutes in tumor cell lines in vitro and in human tumor xenografts in vivo,30 and AGT remains depleted for 8 hours to more than 24 hours after a single dose of O6BG. Pretreatment with O6BG has been shown to increase the cytotoxicity of TMZ in malignant glioma xenograft models,3,32 and in a variety of human tumor xenografts grown in nude mice.33-35 In adults with brain tumors, the dose of O6BG required to deplete AGT in tumor tissue that had been resected 6 hours to 25 hours after a single intravenous dose of O6BG, was determined to be 100 to 120 mg/m2.36,37 In subsequent studies, an O6BG dose of 120 mg/m2 was determined to be the optimal modulatory dose and recommended phase II dose.38-40

We performed a phase I dose escalation study of O6BG in combination with TMZ on a daily schedule for 5 consecutive days every 28 days in pediatric patients with refractory solid tumors, including brain tumors, to determine the maximum dose of TMZ that could be safely administered with a biologically active dose of O6BG. O6BG had not previously been administered to patients on this daily schedule for 5 days; therefore, we started at a dose of 60 mg/m2/d and escalated the dose in subsequent cohorts to 90 and 120 mg/m2/d to ensure that five daily doses of O6BG were tolerable, before escalating the dose of TMZ.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Eligibility
Pediatric patients ≤ 21 years old with a histologically confirmed solid tumor refractory to standard treatment were eligible for this study. Histologic confirmation was not required for brainstem or optic pathway gliomas. Patients must have recovered from the toxic effects of prior therapy, have an Eastern Cooperative Oncology Group performance score of ≤ 2 and a life expectancy of at least 8 weeks.8 Patients had to be able to swallow capsules. Patients must have had their last fraction of limited-field radiation therapy at least 4 weeks before study entry and their last fraction of extensive radiation (eg, craniospinal radiation) at least 4 months before study entry. Patients must have received their last dose of chemotherapy at least 3 weeks before study entry (4 weeks for nitrosoureas), their last investigational therapy at least 4 weeks before study entry, and be off colony-stimulating factors for at least 1 week before study entry. Prior TMZ use was allowed if it was more than 3 months since the last dose and prior use was not associated with significant toxicity. Patients with brain tumors receiving corticosteroids for the control of tumor-associated edema had to be on a stable or decreasing dose for at least 1 week before study enrollment. Patients were required to have adequate bone marrow function (absolute neutrophil count of > 1,500/µL, hemoglobin > 8 gm/dL, and platelet count > 100,000/µL), adequate liver function, (bilirubin within normal limits and ALT < 2x the upper limit of normal), and an age-adjusted normal serum creatinine or a creatinine clearance ≥ 60 mL/min/1.73 m2.

Patients currently receiving other investigational chemotherapeutic agents were excluded, as were patients with a history of myeloablative therapy requiring bone marrow or stem cell transplantation within the previous 4 months, pregnant or breast-feeding females and patients with clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate this therapy or interfere with the study procedures or results. This trial was approved by the National Cancer Institute's (NCI) institutional review board. All patients or their legal guardians signed a document of informed consent indicating their understanding of the investigational nature and the risks of this study.

Unlike the prior pediatric phase I trials of TMZ, patients were not stratified based on whether they had received prior craniospinal radiation, because the MTDs in the two strata were similar on the previous trials.17,41

Treatment Regimen and Dose Escalation
O6BG was supplied by the Pharmaceutical Management Branch of the NCI's Cancer Therapy Evaluation Program (CTEP). TMZ was purchased through commercial sources in 5 mg, 20 mg, and 100 mg capsules. O6BG was administered as a 60-minute intravenous infusion daily for 5 consecutive days, every 28 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion daily for 5 consecutive days, every 28 days. Premedication with standard antiemetics was prescribed on the protocol. The dose escalation scheme is shown in Table 1. O6BG dose was initially escalated from 60 mg/m2/d to the biologically active dose of 120 mg/m2/d, while the TMZ dose was held fixed at 28 mg/m2/d. Once this biologically active dose of O6BG was achieved, the TMZ dose was escalated in subsequent patient cohorts. Intrapatient TMZ dose escalations up to 100 mg/m2/d were allowed if no grade ≥ 3 hematologic and no grade ≥ 2 nonhematologic toxicities were observed on previous cycles. Treatment cycles were repeated every 28 days if the patient had recovered from the O6BG/TMZ-related toxicity from the previous cycle.


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  		Table 1. Dose Escalation Schema for O6BG and TMZ

 
This trial used an accelerated single-patient design for the O6BG dose escalation component of the trial. Escalation proceeded to the next dose level if the patient on the prior dose level did not experience grade ≥ 2 toxicity (excluding nausea and vomiting) during the first 28-day treatment cycle. If grade ≥ 2 toxicity was observed in the first patient at any dose level, that dose level and all subsequent dose levels enrolled three to six patients.

Definition of MTD and DLT
The MTD was defined as that dose level immediately below the dose level at which two or more patients in a cohort of three to six patients experienced a DLT. Toxicity data from the first treatment cycle was used to determine the MTD. Toxicities were graded according to the NCI/CTEP common toxicity criteria version 2 (http://ctep.info.nih.gov). Nonhematologic DLT was defined as any grade ≥ 3 toxicity (with the exception of grade 3 vomiting and grade 3 elevations of serum transaminases), or failure to recover to grade ≤ 1 toxicity level by day 42 of a treatment cycle. Hematologic DLT was defined as grade 4 neutropenia (< 500/µL) for ≥ 5 days, a platelet count less than 10,000/µL on two separate days of a treatment cycle, or failure to recover to an absolute neutrophil count (ANC) of 1,500/µL and platelet count of 100,000/µL by day 42 of a treatment cycle. For brain tumor patients transfused for platelet counts less than 50,000/µL, DLT was defined as the requirement for more than two platelet transfusions in a treatment cycle.

Dose Modification for Toxicity
Patients on the O6BG dose escalation portion of the trial who experienced DLT had the dose of TMZ decreased by 25%. Patients entered onto the TMZ dose escalation portion of the trial who experienced DLT had their dose of TMZ decreased to the next lowest level or to a 40% lower dose if entered at the starting dose. Patients who developed DLT following two dose reductions were removed from the study.

Definition of Response
Although this was a phase I study and measurable disease was not a criteria for patient eligibility, if a patient had a measurable tumor, efforts were made to observe changes in the tumor size during therapy. Magnetic resonance imaging or computed tomography scan (consistent with pretreatment evaluation studies) of all sites of active disease was performed before cycles 1, 2, 4, 6, 8, 10, and 12. Complete response (CR) was defined as complete resolution of all measurable tumors and no appearance of new lesions. Partial response (PR) was defined as a ≥ 50% reduction in the sum of the products of the two longest perpendicular diameters of all measurable tumors and no appearance of new tumors. Minor response (MR) was defined as a ≥ 25% but less than 50% reduction in the sum of the product of the two longest perpendicular diameters of all measurable tumors and no appearance of new tumors. Progressive disease was defined as the appearance of new tumors or an increase in any previously measurable lesion by ≥ 25% in the product of the two longest perpendicular diameters. Stable disease (SD), which was defined as a change in tumor size that was insufficient to meet the criteria for a CR, PR, MR, or progressive disease, was considered clinically significant if the duration was at least 4 cycles (16 weeks).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
Forty-one children with recurrent or refractory solid tumors were enrolled between April 2000 and August 2004. The characteristics of the patients are shown in Table 2. The nine patients who were not assessable included one patient who required surgical intervention for shunt malfunction after her first dose; one patient who withdrew after the first dose because of grade 3 nausea and vomiting; one patient who withdrew for personal reasons; and six patients who had rapidly progressive disease and were unable to complete a full 28 day cycle. One patient initially assigned to dose level six required emergency radiation therapy for cord compression and did not initially receive therapy at her assigned dose level; she later progressed and was reassigned and treated at dose level seven. None of the patients who were not assessable experienced DLT. Twenty-five of the 32 assessable patients had primary brain tumors and seven patients had sarcomas. The number of patients entered at each dose level is shown in Table 1.


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  		Table 2. Patient Characteristics

 
Intrapatient Dose Escalation
Nineteen patients received more than one cycle of O6BG/TMZ. Two patients who entered at a TMZ dose level of 28 mg/m2/d were escalated to 40 mg/m2/d on subsequent cycles and tolerated this TMZ dose. One patient who entered at 40 mg/m2/d was escalated to 55 mg/m2/d, which he continued to receive for 17 cycles. Three patients who entered at a TMZ dose of 55 mg/m2/d were escalated to 75 mg/m2/d; one of these patients was subsequently escalated to 100 mg/m2/d on cycle 3, but had to deescalate to 75 mg/m2/d on cycle 7 and 55 mg/m2/d on cycle 11 because of dose-limiting myelosuppression. One patient who entered at a TMZ dose of 75 mg/m2/d was escalated to 100 mg/m2/d, which she continued to receive for four cycles.

Toxicity
The toxicity spectrum of the combination of TMZ and O6BG was similar to that of TMZ alone, but O6BG clearly enhanced the toxic effects of TMZ, such that the tolerable dose of TMZ is much lower when administered with O6BG. The toxicities are listed in Table 3. The most common was myelosuppression. Neutropenia occurred sporadically at all levels, but was more severe and frequent at higher dose levels of TMZ (Table 4). At the second dose level (28 mg/m2/d TMZ and 90 mg/m2/d O6BG) the first patient, who was heavily pretreated, experienced DLT consisting of neutropenia and fever requiring hospital admission. Therefore, the second dose level was expanded to six patients (without other DLTs) and all subsequent dose levels enrolled at least three patients.


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  		Table 3. Toxicities (by Grade) That Were at Least Possibly Attributed to O6BG/TMZ During the First Cycle

 

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  		Table 4. Severity (Grade) of Neutropenia and Thrombocytopenia According to TMZ Dose During Cycle 1

 
Grade 4 neutropenia (ANC < 500/µL) occurred in 10 patients at TMZ doses ranging from 28 to 100 mg/m2/d and was dose-limiting (≥ 5 days duration) in five patients, including two patients treated at the 100 mg/m2/d dose level on cycle 1. Neutrophil nadirs in patients with grade 4 neutropenia occurred on days 16 to 23 of the cycle, and six patients required more than 28 days to recover to their neutrophil count to ≥ 1,500/µL. Seven of the 32 assessable patients had previously received craniospinal radiation, and four of these patients (TMZ doses of 28 to 100 mg/m2/d) experienced dose-limiting myelosuppression during cycle 1. Three of these four patients recovered their ANC to ≥ 1,500/µL by day 42 of the cycle.

Five out of six patients enrolled at the 100 mg/m2/d dose level experienced grade 4 neutropenia and two patients had DLT. Only one out of seven patients enrolled at the 75 mg/m2/d dose level experienced DLT, and therefore, 75 mg/m2/d of TMZ in combination with 120 mg/m2/d of O6BG represent the MTD and recommended phase II dose. Two patients enrolled at 75 mg/m2/d or lower were escalated on subsequent treatment cycles to the 100 mg/m2/d dose of TMZ and were able to tolerate this higher dose level for four additional cycles. One patient enrolled at 100 mg/m2/d dose of TMZ was able to tolerate four cycles without significant myelosuppression.

Gastrointestinal toxicity was generally mild and did not appear to be dose related. All patients were premedicated with ondansetron. One patient withdrew because of grade 3 emesis after the first day of O6BG/TMZ. Two additional patients had emesis (grade 1 and grade 3, respectively), although the patient with grade 3 emesis had concurrent shunt malfunction, which was the likely etiology. There were no toxicities directly attributable to O6BG.

Responses
Thirty-two patients were assessable for response, and antitumor activity was observed in nine patients (Table 5). A complete response on contrast-enhancing T1 magnetic resonance imaging was observed in a patient with an exophytic pilocytic astrocytoma of the brainstem; three patients (one high-grade thalamic glioma, one medulloblastoma, and one brainstem glioma) had partial responses; and five patients had prolonged SD (more than four cycles). The four objective responses were observed in patients receiving an O6BG dose of 120 mg/m2/d and a TMZ dose of ≥ 55 mg/m2/d (Fig 1).


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  		Table 5. Responses to the Combination of O6BG and TMZ

 


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  		Fig 1. T1 magnetic resonance sequences post gadolinium demonstrating responses observed in (A) patient with biopsy-proven pilocytic astrocytoma of brainstem, (B) patient with multiply-recurrent medulloblastoma, and (C) patient with high-grade thalamic glioma.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
The combination of O6BG and TMZ is safe and well-tolerated when administered on a 5-day schedule at doses of 120 mg/m2/d and 75 mg/m2/d, respectively, in this heavily pretreated patient population. Enhanced toxicity at lower doses of the cytotoxic agent was also observed in a separate study when O6BG was combined with carmustine.42 The toxicity profile of the combination in our study is similar to that observed with temozolomide alone at higher doses.

Neutropenia, which was the primary DLT, occurred at all dose levels, but was more frequent and severe at the higher dose levels. Several patients tolerated higher dose levels of TMZ with little or no evidence of myelosuppression, while others appeared to be very sensitive to the myelosuppressive effects, even at TMZ doses as low as 28 mg/m2/d. The timing of the neutrophil nadir also varied considerably among patients. It is not clear whether this variability in toxic effects is related to variability in drug disposition. Hematologic toxicity was not related to TMZ area under the concentration time curve (AUC) in a prior study in children,43 but AUC was related to dose-limiting hematologic toxicity in adult patients.44

TMZ alone has demonstrated significant activity against a variety of murine tumor models, CNS tumor xenografts, and adult gliomas. However, clinical trials of TMZ in children to date have failed to demonstrate significant antitumor activity in childhood tumors, with the possible exception of low-grade gliomas. Kuo et al18 performed a retrospective review of 13 pediatric patients with progressive low grade gliomas treated with TMZ on two different schedules. Three patients had a PR and one patient had an MR. The response rate to TMZ alone in pediatric high-grade gliomas and brainstem gliomas is 11% and 4%, respectively,16,17,41 which is significantly lower than the response rates of up to 35% in adults with anaplastic astrocytomas and anaplastic oligoastrocytomas.6,9 Several mechanisms of tumor resistance to TMZ have been proposed, including AGT45 and DNA mismatch repair proteins.46 However, the role of DNA mismatch repair proteins is still being investigated. A study using xenograft tumors from children demonstrated a relationship between defects in the DNA mismatch repair protein, MLH1, and TMZ resistance,45 but a second study correlating the presence of MLH1 or MSH2 in more than 60% of tumor cells (detected by immunohistochemistry) with response in adults with newly diagnosed high-grade gliomas was unable to demonstrate a significant relationship.47

Encouraging antitumor activity was observed on this phase I trial, even though the tolerable dose of TMZ was less than half of the conventional dose when the drug is administered as a single agent. The objective response rate (CR + PR) was 12% and five additional patients have had prolonged SD for four to 17 cycles. One patient with high-grade glioma remains on study, currently on cycle 18, with SD. No responses were observed in patients with sarcomas; however, the majority of these patients were treated early in the study at low doses of TMZ. Only one assessable patient with sarcoma was treated at TMZ doses of more than 55 mg/m2/d.

A daily schedule for 5 days was chosen because of the previously demonstrated schedule-dependent activity of TMZ,1,3,48 and the prolonged pharmacodynamic effect of O6BG, which may be related to the favorable half-life of its active metabolite. A greater therapeutic effect was observed when temozolomide was administered daily for 5 days compared with single-dose administration in preclinical murine tumor models,1 and in adults on the initial phase I trial of TMZ.49 The pharmacokinetic profile of 8-oxo-O6BG, the primary active metabolite of O6BG, allows a similar dosing schedule. The half-life of O6BG in a nonhuman primate model receiving a dose of 200 mg/m2 was 1.6 hours while the half-life of the metabolite was 14 hours.50

Measurement of AGT levels within tumor tissue after treatment with O6BG to ensure complete AGT inhibition would not have been feasible or ethical on this pediatric phase I trial. In the absence of DLT attributable to O6BG on the daily for 5 days schedule, we elected not to escalate beyond the O6BG dose that was demonstrated on several single-dose studies37-40 to completely inhibit tumor AGT levels in the vast majority of patients.

Although the MTD and recommended dose of temozolomide when given with a biologically active dose of O6BG is 75 mg/m2/d for 5 days, consideration should be given to dose escalation of the TMZ dose to 100 mg/m2/d in subsequent cycles for those patients who tolerate 75 mg/m2/d. Responses on this study appear to be dose-related, with the objective responses observed in patients receiving an O6BG dose of 120 mg/m2/d and a TMZ dose of ≥ 55 mg/m2/d. An analogous dosing schema is used in patients treated with TMZ alone. Patients begin treatment at 150 mg/m2/d and dose escalate to 200 mg/m2/d if the initial dose is tolerated.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Presented in part at the 8th Annual Meeting of the Society of Neuro-Oncology, Keystone, CO, November 13-16, 2003.

This manuscript represents original work performed at the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
1. Stevens M, Hickman J, Langdon S, et al: Antitumor activity and pharmacokinetics in mice of 8-carbonyl-3-methylimidazo[5, 1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M&B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47:5846-5852, 1987[Abstract/Free Full Text]

2. Horspool KR, Stevens MF, Newton CG, et al: Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents. J Med Chem 33:1393-1399, 1990[CrossRef][Medline]

3. Friedman H, Dolan M, Pegg A, et al: Activity of temozolomide in the treatment of central nervous system xenografts. Cancer Res 55:2853-2857, 1995[Abstract/Free Full Text]

4. Stupp R, Dietrich P-Y, Kraljevic S, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375-1382, 2002[Abstract/Free Full Text]

5. Brada M, Hoang-Xuan K, Rampling R, et al: Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 12:259-266, 2001[Abstract/Free Full Text]

6. Yung W, Prados M, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762-2771, 1999[Abstract/Free Full Text]

7. Yung W, Albright R, Olson J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-593, 2000[CrossRef][Medline]

8. Quinn J, Reardon D, Friedman A, et al: Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol 21:646-651, 2003[Abstract/Free Full Text]

9. Newlands E, Stevens M, Wedge S, et al: Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35-61, 1997[CrossRef][Medline]

10. Denny B, Wheelhouse R, Stevens M, et al: NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 33:9045-9051, 1994[CrossRef][Medline]

11. Tisdale M: Antitumor imidazoterazinones-XV. Role of guanine O6 alkylation in the mechanism of cytotoxicity of imidazotetrazinones. Biochem Pharmacol 36:457-462, 1987[CrossRef][Medline]

12. Baer J, Freeman A, Newlands E, et al: Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer 67:1299-1302, 1993[Medline]

13. Mitra G, Pauly G, Kumar R, et al: Molecular analysis of O6-substituted guanine-induced mutagenesis of ras oncogenes. Proc Natl Acad Sci U S A 86:8650-8654, 1989[Abstract/Free Full Text]

14. Griffin S, Branch P, Xu Y, et al: DNA mismatch binding and incision at modified guanine bases by extracts of mammalian cells: Implications for tolerance to DNA methylation damage. Biochemistry 33:4787-4793, 1994[CrossRef][Medline]

15. Voigt JM, Topal MD: O6-methylguanine-induced replication blocks. Carcinogenesis 16:1775-1782, 1995[Abstract/Free Full Text]

16. Estlin E, Lashford L, Ablett S, et al: Phase I study of temozolomide in paediatric patients with advanced cancer. Br J Cancer 78:652-661, 1998[Medline]

17. Nicholson HS, Krailo M, Ames MM, et al: Phase I study of temozolomide in children and adolescents with recurrent solid tumors: A report from the Children's Cancer Group. J Clin Oncol 16:3037-3043, 1998[Abstract/Free Full Text]

18. Kuo D, Weiner H, Wisoff J, et al: Temozolomide is active in childhood, progressive, unresectable, low-grade gliomas. J Pediatr Hematol Oncol 25:372-378, 2003[CrossRef][Medline]

19. Pegg A, Dolan M, Moschel R: Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol 51:167-223, 1995[Medline]

20. D'Incalci M, Taverna P, Erba E, et al: O6-methylguanine and temozolomide can reverse the resistance to chloroethyl-nitrosoureas of a mouse L1210 leukemia. Anticancer Res 11:115-122, 1991[Medline]

21. Kanugula S, Goodtzova K, Edara S, et al: Alteration of arginine-128 to alanine abolishes the ability of human o6-alkylguanine-DNA alkyltransferase to repair methylated DNA but has no effect on its reaction with O6-benzylguanine. Biochemistry 34:7113-7119, 1995[CrossRef][Medline]

22. Pauly G, Hughes S, Moschel R: Response of repair-competent and repair-deficient Escherichia coli to three O6-substituted guanines and involvement of methyl-directed mismatch repair in the processing of O6-methylguanine residues. Biochemistry 33:9169-9177, 1994[CrossRef][Medline]

23. Tano K, Shiota S, Collier J, et al: Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for o6-alkylguanine. Proc Natl Acad Sci U S A 87:686-690, 1990[Abstract/Free Full Text]

24. Gerson S, Liu L, Phillips W, et al: Drug resistance mediated by DNA repair: The paradigm of O6-alkylguanine DNA alkyltransferase. Proc Am Assoc Cancer Res 35:699-700, 1994

25. D'Incalci M, Citti L, Taverna P, et al: Importance of the DNA repair enzyme O6-alkylguanine alkyltransferase (AT) in cancer chemotherapy. Cancer Treat Rev 15:279-292, 1988[CrossRef][Medline]

26. Myrnes B, Norstrand K, Giercksky KE, et al: A simplified assay for O6-methylguanine-DNA methyltransferase activity and its application to human neoplastic and nonneoplastic tissues. Carcinogenesis 5:1061-1064, 1984[Abstract/Free Full Text]

27. Wiestler O, Kleihues P, Pegg A: O6-alkylguanine-DNA alkyltransferase activity in human brain and brain tumors. Carcinogenesis 5:121-124, 1984[Abstract/Free Full Text]

28. Jaekle K, Eyre H, Townsend J, et al: Correlation of tumor O6-methylguanine DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bischloroethylnitrosourea: A Southwest Oncology Group Study. J Clin Oncol 16:3310-3315, 1998[Abstract]

29. Lacal P, D'Atri S, Orlando L, et al: In vitro inactivation of human O6-alkylguanine DNA alkyltransferase by antitumor triazeno compounds. J Pharmacol Exp Ther 279:416-422, 1996[Abstract/Free Full Text]

30. Dolan M, Mitchell R, Mummert C, et al: Effect of O6-benzylguanine analogs on sensitivity of tumor cells to the cytotoxic effects of alkylating agents. Cancer Res 51:3367-3372, 1991[Abstract/Free Full Text]

31. Pegg A, Boosalis M, Sampson L, et al: Mechanism of inactivation of human O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. Biochemistry 32:1998-2006, 1993

32. Wedge S, Newlands E: O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine DNA alkyltransferase activity to temozolomide and BCNU. Br J Cancer 73:1049, 1996[Medline]

33. Gerson S, Zborowska E, Norton K, et al: Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea in a human colon cancer xenograft completely resistant to BCNU alone. Biochem Pharmacol 45:483-491, 1993[CrossRef][Medline]

34. Dolan M, Pegg A, Biser N, et al: Effect of O6-benzylguanine on the response to 1,3-bis(2-chloroethyl)-1-nitrosoureas in the Dunning R3327G model of prostatic cancer. Cancer Chemother Pharmacol 32:221-225, 1993[CrossRef][Medline]

35. Mitchell R, Moschel R, Dolan M: Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3 bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation. Cancer Res 52:1171-1175, 1992[Abstract/Free Full Text]

36. Friedman H, Kokkinakis D, Pluda J, et al: Phase I trial of O6-Benzylguanine for patients undergoing surgery for malignant glioma. J Clin Oncol 16:3570-3575, 1998[Abstract]

37. Schold SC Jr, Kokkinakis DM, Chang SM, et al: O6-benzylguanine suppression of O6-alkylguanine-DNA alkyltransferase in anaplastic gliomas. Neuro-oncol 6:28-32, 2004[Abstract]

38. Dolan M, Posner M, Karrison T, et al: Determination of the optimal modulatory dose of O6-benzylguanine in patients with surgically resectable tumors. Clin Cancer Res 8:2519-2523, 2002[Abstract/Free Full Text]

39. Schilsky R, Dolan M, Bertucci D, et al: Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer. Clin Cancer Res 6:3025-3031, 2000[Abstract/Free Full Text]

40. Spiro T, Gerson S, Liu L, et al: O6-benzylguanine: A clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directed DNA repair. Cancer Res 59:2402-2410, 1999[Abstract/Free Full Text]

41. Lashford L, Thiesse P, Jouvet A, et al: Temozolomide in malignant gliomas of childhood: A United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol 20:4684-4691, 2002[Abstract/Free Full Text]

42. Friedman H, Pluda J, Quinn J, et al: Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 18:3522-3528, 2000[Abstract/Free Full Text]

43. Riccardi A, Mazzarella G, Cefalo G, et al: Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol 52:459-464, 2003[CrossRef][Medline]

44. Hammond L, Eckardt J, Baker S, et al: Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol 17:2604-2613, 1999[Abstract/Free Full Text]

45. Middlemas D, Stewart C, Kirstein M: Biochemical correlates of temozolomide sensitivity models. Clin Cancer Res 6:998-1007, 2000[Abstract/Free Full Text]

46. Stupp R, Gander M, Leyvraz S, et al: Current and future developments in the use of temozolomide for the treatment of brain tumours. The Lancet 2, 2001

47. Friedman H, McLendon R, Kerby T, et al: DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851-3857, 1998[Abstract/Free Full Text]

48. O'Reilly S, Newlands E, Glaser M, et al: Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer 29A:940-942, 1993

49. Newlands E, Blackledge G, Slack J, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:2287-2291, 1992

50. Berg S, Gerson S, Godwin K, et al: Plasma and cerebrospinal fluid pharmacokinetics of O6-benzylguanine and time course of peripheral blood mononuclear cell O6-methylguanine-DNA methyltransferase inhibition in the nonhuman primate. Cancer Res 55:4606-4610, 1995[Abstract/Free Full Text]

Submitted April 11, 2005; accepted July 18, 2005.


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