Clinical Cancer Research Prevention Award Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dolan, M. E.
Right arrow Articles by Ratain, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dolan, M. E.
Right arrow Articles by Ratain, M. J.
Clinical Cancer Research Vol. 8, 2519-2523, August 2002
© 2002 American Association for Cancer Research

Clinical Trials

Determination of the Optimal Modulatory Dose of O6-Benzylguanine in Patients with Surgically Resectable Tumors1

M. Eileen Dolan2, Mitchell Posner, Theodore Karrison, Jonathan Radosta, Gary Steinberg, Donna Bertucci, Lucky Vujasin and Mark J. Ratain

Departments of Medicine [M.E.D., J.R., D.B., L.V., M.J.R.], Surgery [M.P., G.S.], and Health Studies [T.K.]; Committees on Clinical Pharmacology [M.E.D., M.J.R.] and Cancer Biology [M.E.D.]; and Cancer Research Center [M.E.D., M.P., T.K., G.S., M.J.R.], University of Chicago, Chicago, Illinois 60637


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: O6-Benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG.

Experimental Design: BG was administered to patients as an i.v. infusion 16 ± 4 h before surgical resection of their systemic tumor. AGT activity was measured in the tumor using a methylated DNA substrate. The target end point was defined as >=11 of 13 patients with undetectable tumor AGT levels (<10 fmol/mg protein).

Results: Of the 28 patients enrolled, 25 of whom were analyzed for AGT activity, the most common primary sites of cancer included the colon (n = 11), bladder (n = 3), rectum (n = 4), and stomach (n = 3). Positive (DaOY cells) and negative (Chinese hamster ovary cells) control cell lines were included in each assay. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15–147 fmol/mg protein). Only 2 of the 13 patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 12 fmol/mg protein).

Conclusions: From our surgically removed tissue data, a dose of 120 mg/m2 BG is recommended to deplete systemic tumors of AGT activity.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BG3 is a potent, selective inactivator of the DNA repair protein AGT (1, 2, 3, 4) . AGT activity has been found in many human solid tumors and is primarily responsible for the relative ineffectiveness of alkylnitrosoureas (i.e., BCNU) and alkyltriazenes (i.e., temozolomide). There is a strong correlation between the level of AGT protein and clinical resistance to BCNU (5, 6, 7) . AGT removes adducts from the O6 position of guanine in DNA through covalent binding of the alkyl group to a cysteine residue located within the active site of the protein (3 , 8 , 9) . Upon repair, AGT is inactivated, and guanine is left intact in DNA. Based on this one-step repair process followed by irreversible inactivation of the repair protein, BG was designed as a low molecular weight inactivator of the protein (10) . Our laboratory has shown that micromolar concentrations of BG effectively deplete AGT activity, resulting in a higher number of interstrand cross-links and cytotoxicity after exposure to BCNU (10, 11, 12) . BG increases the sensitivity of a variety of tumor cell lines and human tumor xenografts in nude mice to O6-alkylating agents (11 , 13 14 15 16 17 18 19) .

Phase I clinical trials of the combination of BG and BCNU are now complete (20, 21, 22, 23, 24) . Clinical trials of the combination BG and Gliadel or BG and temozolomide and Phase II trials of BG and BCNU are ongoing. Early phase evaluation of anticancer agents has traditionally used toxicity to establish dosing schedules. However, because BG is a biochemical modulatory agent, the dose of BG required to deplete AGT activity in tumor or lymphocytes was considered in its clinical development (20, 21, 22, 23, 24) . Spiro et al. (24) determined that depletion of AGT activity to undetectable levels in lymphocytes was not a reliable predictor for tumor tissue depletion, demonstrating the importance of tumor measurements (24) . They determined the dose required to reduce AGT activity to undetectable levels 18 h after BG treatment as 120 mg/m2, based on AGT activity in needle biopsies from metastatic sites of three patients (24) . Using the same AGT assay on surgical specimens, Freidman et al. (21) determined the dose to be 100 mg/m2 for patients with malignant glioma 18 h after BG treatment. The difference in the biochemical modulatory dose between these studies could reflect differences in the site of the tumor (glioma versus systemic tumors), the limitations in assaying small needle biopsies (24) versus surgical specimens (21) , or random variation. The objective of our study was to expand the number of patients evaluated for AGT activity with systemic tumors and to determine the biochemical modulatory dose of BG by measuring AGT activity in surgical specimens.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility Criteria
Patients who were candidates for a surgical resection of a solid tumor were eligible. All patients were required to have a prior histological or cytological diagnosis of cancer. Patients must have had a serum creatinine and bilirubin <= 1.5 x upper limit of normal. A complete history and physical examination including baseline vital signs and symptoms and documentation of any evaluable or measurable lesions were performed before treatment. All patients were informed of the investigational nature of the study and required to provide informed consent as approved by the Institutional Review Board.

Drug Supply
BG (NSC 637037) was supplied by the National Cancer Institute, DCTD in a dual pack with diluent. The active drug (100 mg) was supplied as a white lyophilized powder with 670 mg of mannitol (USP) and sodium hydroxide to adjust the pH to 7.0–8.5. The diluent was provided as a 30-ml vial containing a sterile solution of 40% polyethylene glycol 400 in pH 8 phosphate buffer (106 mg of dibasic sodium phosphate and 102 mg of monobasic potassium phosphate in sterile water for injection; USP). Once the diluent (30 ml) was added to the active drug, each milliliter of solution contained 3.3 mg of BG, 22 mg of mannitol (USP), 0.4 ml of polyethylene glycol 400, and approximately 0.6 ml of pH 7.0 phosphate buffer.

Treatment Design
Patients were admitted to the University of Chicago Clinical Research Center the night before their scheduled surgery. At 16 ± 4 h before surgery, patients received BG as a single agent i.v. in dose cohorts as follows: (a) 100 mg/m2; or (b) 120 mg/m2. During surgery, the tumor was removed and frozen immediately at -80°C until analysis. For control samples, surgical specimens were removed at the time of surgery from 10 patients with tumors in the colon (n = 3), bladder (n = 2), liver (n = 3), and esophagus (n = 2) who did not receive BG and stored at -80°C until analysis. Control samples were run in duplicate.

Statistical Considerations
Statistical considerations followed those described previously (21) . The anticipated occurrence of tumors with undetectable AGT activity (<10 fmol/mg protein) is <20% in the absence of any treatment with BG. Patients were treated with BG before surgery, and the presence of AGT in the resected tumor was determined. The biological modulatory end point of the study was the dose of BG that would produce undetectable AGT levels at approximately 16 h after infusion in >=11 of 13 patients. This criterion was chosen to discriminate between an acceptable rate of AGT inactivation (i.e., >=90%) and an unacceptable rate of <=65%. Specifically, as calculated from the binomial distribution: (a) the chance of concluding that BG inactivates AGT activity when in reality BG is not effective (i.e., the percentage of patients without AGT is 20%) is extremely small (<1 in 106); (b) the chance of concluding that BG inhibits AGT when in reality the rate of inactivation is suboptimal (only 65%) is small (0.11); and (c) when the expected percentage of patients without AGT at the time of surgery is at the desired level (90%), the probability of observing >=11 of 13 patients without AGT is high (0.87).

AGT Activity
Extracts were prepared from tumors by homogenization in 50 mM Tris (pH 7.5), 0.1 mM EDTA, and 5 mM DTT. AGT activity was determined as described previously (10) . Briefly, cell extracts were incubated with 3H-methylated DNA substrate (5.77 Ci/mmol). The DNA was precipitated by adding ice-cold perchloric acid at a final concentration of 0.25 N and hydrolyzed in 0.1 N HCl at 70°C for 30 min. The modified bases were eluted on a C18 reverse phase column using 10% methanol/0.05 M ammonium formate (pH 4.5) at 37°C. Each assay was performed with a positive control cell line (DaOY cell extract) and a negative control (Chinese hamster ovary cell extract). Protein concentration was determined by the method of Bradford (25) . The results were expressed as fmol O6-methylguanine released from DNA/mg protein. Assays were performed in triplicate when there was adequate sample. For those samples listed in Table 2Citation without SD, duplicates were run due to the small sample size.


View this table:
[in this window]
[in a new window]

  		Table 2 Patient demographics, average AGT activity, and time between BG bolus and procurement of tissue of each patient

 

   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics
Twenty-eight patients were enrolled in the study; their characteristics are listed in Table 1Citation . Three patients treated with BG were not analyzed due to compromised tissue. One stomach cancer was not analyzed because the tumor was fixed in formalin before analysis, one bladder cancer was not analyzed because the pathologist found no visible tumor, and one colon cancer was not analyzed because the pathologist determined the tumor sample was not viable.


View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of patients recruited for study including the number of patients, number of males and females, mean age, and frequency of diagnosis

 
Tumor AGT Activity
Patients enrolled in this study received either 100 or 120 mg/m2 BG before surgery (Table 2)Citation . The patients with evaluable tumor treated with 100 mg/m2 had an average time between BG administration and tissue procurement of 17 h and 2 min (range, 13 h to 20 h and 15 min). The patients treated with 120 mg/m2 had an average time between BG administration and tissue procurement of 15 h and 56 min (range, 11 h and 10 min to 19 h and 20 min). The time between BG administration and tissue procurement was not significantly different between the two dose groups (t = 1.22; P = 0.24). Two patients, one from the 100 mg/m2 cohort and one from the 120 mg/m2 cohort, received drug a little outside this window (at 20 h and 15 min and 11 h and 10 min, respectively). Controls included cells known to be positive for AGT (DAOY; 302 ± 51 fmol/mg; n = 10) and negative for AGT (Chinese hamster ovary; 0 ± 0 fmol/mg protein; n = 10). Seven of the 12 evaluable patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15–97 fmol/mg protein). Two of the 13 evaluable patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 19 fmol/mg protein; (Table 2Citation ; Fig. 1Citation ), fulfilling our criterion for the optimal BG dose. The AGT levels of the tumors from the 10 patients who were not treated with BG were as follows, based on tumor site: (a) colon, 249 ± 62 fmol/mg protein; (b) esophagus, 234 ± 47 fmol/mg protein; (c) liver, 171 ± 16 fmol/mg protein; and (d) bladder, 68 ± 119 fmol/mg protein (Fig. 1)Citation .



View larger version (63K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Effect of BG on the AGT activity of systemic tumors according to tumor type. Patients were treated with either 100 or 120 mg/m2 BG over 1 h. Tumors were removed surgically 16 ± 4 h after BG treatment and immediately frozen for AGT analysis. Data represent the average AGT activity in tumor removed for each patient treated with 0, 100, or 120 mg/m2 BG in colon, liver, esophagus, or bladder. Patients 2, 8, 11, 17, 20, and 23 are not shown.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was designed to discern the dose of BG required to inactivate AGT activity in surgically removed tumors after BG administration. Our previous experience relied on the use of surrogate tissue (peripheral blood mononuclear cells), which was later shown to be a poor indicator of tumor activity (20 , 23 , 24) . Two Phase I clinical trials report different doses of BG to obtain adequate AGT depletion in tumors. One study evaluating gliomas indicated that 100 mg/m2 BG depletes AGT activity to undetectable levels using surgical specimens from 11 patients (21) . A separate study relying on needle core biopsies from three patients (24) concluded that 120 mg/m2 was the appropriate dose, although 100 mg/m2 was not evaluated in this study. Using tumor specimens, our data are in agreement with a dose of 120 mg/m2 BG for depletion of AGT activity to undetectable levels in systemic tumors 16.5 h after BG administration.

Although our objective to determine the dose of BG required for AGT depletion was the same as that of Spiro et al. (24) , our trial design was different in several respects. To avoid the need for invasive biopsies, we measured AGT activity in tumors from patients undergoing surgery to remove histologically confirmed cancer. In addition, the number of tumor samples evaluated from patients treated with 120 mg/m2 BG was extended from 3 in the previous study to 13 in our study. Approximately, 69% (18 of 26 evaluable samples) of our total samples were removed from the primary site of cancer, whereas only 11% of samples in the previous study represented primary disease, with the remainder representing metastatic disease. Despite these differences, the dose recommended for Phase II studies is in agreement.

Of note is that only a 20% increase in the dose of BG results in an increase in the percentage of patients with adequate AGT depletion from 42% to 85%. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15–97 fmol/mg protein). Of those seven, the majority (four of seven) were colon/rectum samples. AGT activity in untreated colon cancer is 249 ± 62 fmol/mg protein, therefore depletion at 100 mg/m2 BG was >60% for all samples. However residual AGT can repair lesions introduced by methylating (i.e., temozolomide) or chloroethylating (i.e., BCNU), causing an outgrowth of resistant cells. The sample size is small for each tumor type; therefore, the possibility exists that higher BG doses may be better in some tumors. We did not look at higher doses in preoperative patients because there were no safety data. Such data should be collected in healthy volunteers, and additional studies should be conducted in a preoperative setting.

Our study used a biochemical assay to measure AGT activity instead of the more convenient immunohistochemical analysis. The biochemical assay measures loss of O6-[3H]methylguanine from a 3H-methylated DNA substrate. Immunohistochemistry determines the content of the AGT protein by measuring the sum of the active and inactivated forms of the protein. Pegg et al. (26) determined a short half-life of the inactivated AGT protein after treatment with BG; therefore, immunohistochemistry is not likely to yield an accurate estimation of the cellular capacity to repair O6-alkylguanine lesions. More recently, Liu et al. (27) extended this observation to clinical samples, showing a poor correlation between the biochemical assay and immunohistochemistry when measuring AGT activity after BG treatment. Therefore, clinical trials of BG using a laboratory component that includes the measurement of AGT should use a biochemical measure of activity.

In vitro data suggest that AGT activity must be low for at least 12 h after treatment with an O6-chloroethylating agent, a time interval in which BCNU-induced adducts are converted to cross-links (28) . The peak cross-link formation occurs at approximately 12 h in vitro; therefore, it is thought that depletion for up to 16 h should allow for cross-links. BG dosing regimens will vary depending on the akylating species. For example, locally implanted BCNU wafers (Gliadel; Rhone-Poulenc Rorer, Cary, NC) release BCNU over days or weeks; therefore, optimal BG dosing regimens will need to be established such that AGT is depleted for the entire period that BCNU is released. Similarly, BG combined with methylating agents including temozolomide (Schering-Plough, Kenilworth, NJ) requires prolonged AGT depletion because temozolomide is given p.o. every day for 5 days. Furthermore, the persistence of O6-methylguanine in DNA is required to trigger an apoptotic response (29) . Under these conditions, optimal dosing regimens need to be established so that AGT will remain low for an extended period of time. Clinical studies to optimize the dosing regimen for these agents are recommended.


   ACKNOWLEDGMENTS
 
We thank Shannon Delaney for excellent technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by NIH Grant CA69852 (to M.J.R.), General Clinical Research Center Grant M01RR00055, and University of Chicago Cancer Research Center Support Grant P30 CA14599. Back

2 To whom requests for reprints should be addressed, at 5841 South Maryland Avenue, Box MC2115, University of Chicago, Chicago, IL 60637. Phone: (773)702-4441; Fax: (773)702-0963; E-mail: edolan{at}medicine.bsd.uchicago.edu Back

3 The abbreviations used are: BG, O6-benzylguanine; AGT, O6-alkylguanine-DNA alkyltransferase; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; USP, United States Pharmacopeia. Back

Received 1/27/02; revised 5/ 8/02; accepted 5/ 8/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Pegg A. E. Repair of O6-alkylguanine by alkyltransferases. Mutat. Res., 462: 83-100, 2000.[CrossRef][Medline]
  2. Dolan M. E., Pegg A. E. O6-Benzylguanine and its role in chemotherapy. Clin. Cancer Res., 3: 837-847, 1997.[Abstract]
  3. Gerson S. L., Willson J. K. O6-Alkylguanine-DNA alkyltransferase. A target for the modulation of drug resistance. Hematol. Oncol. Clin. N. Am., 9: 431-450, 1995.[Medline]
  4. Koc O. N., Phillips W. P., Jr., Lee K., Liu L., Zaidi N. H., Allay J. A., Gerson S. L. Role of DNA repair in resistance to drugs that alkylate O6 of guanine. Cancer Treat. Res., 87: 123-146, 1996.[Medline]
  5. Esteller M., Garcia-Foncillas J., Andion E., Goodman S. N., Hidalgo O. F., Vanaclocha V., Baylin S. B., Herman J. G. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med., 343: 1350-1354, 2000.[Abstract/Free Full Text]
  6. Jaeckle K. A., Eyre H. J., Townsend J. J., Schulman S., Knudson H. M., Belanich M., Yarosh D. B., Bearman S. I., Giroux D. J., Schold S. C. Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J. Clin. Oncol., 16: 3310-3315, 1998.[Abstract]
  7. Chen Z. P., Yarosh D., Garcia Y., Tampieri D., Mohr G., Malapetsa A., Langleben A., Panasci L. C. Relationship between O6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients. Can. J. Neurol. Sci., 26: 104-109, 1999.[Medline]
  8. O’Connor P. J., Manning F. C., Gordon A. T., Billett M. A., Cooper D. P., Elder R. H., Margison G. P. DNA repair: kinetics and thresholds. Toxicol. Pathol., 28: 375-381, 2000.[Abstract/Free Full Text]
  9. Pegg A. E., Dolan M. E., Moschel R. C. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog. Nucleic Acid Res. Mol. Biol., 51: 167-223, 1995.[Medline]
  10. Dolan M. E., Stine L., Mitchell R. B., Moschel R. C., Pegg A. E. Modulation of mammalian O6-alkylguanine-DNA alkyltransferase in vivo by O6-benzylguanine and its effect on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Cancer Commun., 2: 371-377, 1990.[Medline]
  11. Mitchell R. B., Moschel R. C., Dolan M. E. 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]
  12. Dolan M. E., Mitchell R. B., Mummert C., Moschel R. C., Pegg A. E. Effect of O6-benzylguanine analogues on sensitivity of human tumor cells to the cytotoxic effects of alkylating agents. Cancer Res., 51: 3367-3372, 1991.[Abstract/Free Full Text]
  13. Kreklau E. L., Liu N., Li Z., Cornetta K., Erickson L. C. Comparison of single- versus double-bolus treatments of O6-benzylguanine for depletion of O6-methylguanine DNA methyltransferase (MGMT) activity in vivo: development of a novel fluorometric oligonucleotide assay for measurement of MGMT activity. J. Pharmacol. Exp. Ther., 297: 524-530, 2001.[Abstract/Free Full Text]
  14. Rhines L. D., Sampath P., Dolan M. E., Tyler B. M., Brem H., Weingart J. O6-Benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma. Cancer Res., 60: 6307-6310, 2000.[Abstract/Free Full Text]
  15. Wan Y., Wu D., Gao H., Lu H. Potentiation of BCNU anticancer activity by O6-benzylguanine: a study in vitro and in vivo. J. Environ. Pathol. Toxicol. Oncol., 19: 69-75, 2000.[Medline]
  16. Friedman H. S., Dolan M. E., Moschel R. C., Pegg A. E., Felker G. M., Rich J., Bigner D. D., Schold S. C., Jr. Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. J. Natl. Cancer Inst. (Bethesda), 84: 1926-1931, 1992.[Abstract/Free Full Text]
  17. Felker G. M., Friedman H. S., Dolan M. E., Moschel R. C., Schold C. Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother. Pharmacol., 32: 471-476, 1993.[CrossRef][Medline]
  18. Gerson S. L., Zborowska E., Norton K., Gordon N. H., Willson J. K. Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone. Biochem. Pharmacol., 45: 483-491, 1993.[CrossRef][Medline]
  19. Schold S. C., Jr., Kokkinakis D. M., Rudy J. L., Moschel R. C., Pegg A. E. Treatment of human brain tumor xenografts with O6-benzyl-2’-deoxyguanosine and BCNU. Cancer Res., 56: 2076-2081, 1996.[Abstract/Free Full Text]
  20. Dolan M. E., Roy S. K., Fasanmade A. A., Paras P. R., Schilsky R. L., Ratain M. J. O6-Benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings. J. Clin. Oncol., 16: 1803-1810, 1998.[Abstract]
  21. Friedman H. S., Kokkinakis D. M., Pluda J., Friedman A. H., Cokgor I., Haglund M. M., Ashley D. M., Rich J., Dolan M. E., Pegg A. E., Moschel R. C., McLendon R. E., Kerby T., Herndon J. E., Bigner D. D., Schold S. C., Jr. Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol., 16: 3570-3575, 1998.[Abstract]
  22. Friedman H. S., Pluda J., Quinn J. A., Ewesuedo R. B., Long L., Friedman A. H., Cokgor I., Colvin O. M., Haglund M. M., Ashley D. M., Rich J. N., Sampson J., Pegg A. E., Moschel R. C., McLendon R. E., Provenzale J. M., Stewart E. S., Tourt-Uhlig S., Garcia-Turner A. M., Herndon J. E., II, Bigner D. D., Dolan M. E. 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]
  23. Schilsky R. L., Dolan M. E., Bertucci D., Ewesuedo R. B., Vogelzang N. J., Mani S., Wilson L. R., Ratain M. J. 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]
  24. Spiro T. P., Gerson S. L., Liu L., Majka S., Haaga J., Hoppel C. L., Ingalls S. T., Pluda J. M., Willson J. K. 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]
  25. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72: 248-254, 1976.[CrossRef][Medline]
  26. Pegg A. E., Wiest L., Mummert C., Stine L., Moschel R. C., Dolan M. E. Use of antibodies to human O6-alkylguanine-DNA alkyltransferase to study the content of this protein in cells treated with O6-benzylguanine or N-methyl-N’-nitro-N-nitrosoguanidine. Carcinogenesis (Lond.), 12: 1679-1683, 1991.[Abstract/Free Full Text]
  27. Liu L., Spiro T. P., Qin X., Majka S., Haaga J., Schupp J., Willson J. K., Gerson S. L. Differential degradation rates of inactivated alkyltransferase in blood mononuclear cells and tumors of patients after treatment with O6-benzylguanine. Clin. Cancer Res., 7: 2318-2324, 2001.[Abstract/Free Full Text]
  28. Erickson L. C., Bradley M. O., Ducore J. M., Ewig R. A., Kohn K. W. DNA cross-linking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas. Proc. Natl. Acad. Sci. USA, 77: 467-471, 1980.[Abstract/Free Full Text]
  29. D’Atri S., Tentori L., Lacal P. M., Graziani G., Pagani E., Benincasa E., Zambruno G., Bonmassar E., Jiricny J. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol. Pharmacol., 54: 334-341, 1998.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
L. M. Wagner, R. E. McLendon, K. J. Yoon, B. D. Weiss, C. A. Billups, and M. K. Danks
Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma
Clin. Cancer Res., September 15, 2007; 13(18): 5418 - 5425.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. F. Gajewski, J. Sosman, S. L. Gerson, L. Liu, E. Dolan, S. Lin, and E. E. Vokes
Phase II Trial of the O6-Alkylguanine DNA Alkyltransferase Inhibitor O6-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma
Clin. Cancer Res., November 1, 2005; 11(21): 7861 - 7865.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. E. Warren, A. A. Aikin, M. Libucha, B. C. Widemann, E. Fox, R. J. Packer, and F. M. Balis
Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors
J. Clin. Oncol., October 20, 2005; 23(30): 7646 - 7653.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. A. Quinn, A. Desjardins, J. Weingart, H. Brem, M. E. Dolan, S. M. Delaney, J. Vredenburgh, J. Rich, A. H. Friedman, D. A. Reardon, et al.
Phase I Trial of Temozolomide Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma
J. Clin. Oncol., October 1, 2005; 23(28): 7178 - 7187.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
T. F. Gajewski
Temozolomide for Melanoma: New Toxicities and New Opportunities
J. Clin. Oncol., February 15, 2004; 22(4): 580 - 581.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dolan, M. E.
Right arrow Articles by Ratain, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dolan, M. E.
Right arrow Articles by Ratain, M. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online