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Clinical Trials |
Department of Medicine, Section of Hematology-Oncology, Cancer Research Center and Committee on Clinical Pharmacology, University of Chicago, Chicago, Illinois 60637
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There was no toxicity attributable to BG alone at any dose tested. Bone marrow suppression was the primary and dose-limiting toxicity of BG combined with carmustine and was cumulative in some patients. The neutrophil nadir occurred at a median of day 27, with complete recovery in most patients by day 43. Nonhematological toxicity included fatigue, anorexia, increased bilirubin, and transaminase elevation. Recommended doses for Phase II testing are 120 mg/m2 BG given with carmustine at 40 mg/m2. BG rapidly disappeared from plasma and was converted to a major metabolite, O6-benzyl-8-oxoguanine, which has a 2.4-fold higher maximal concentration and 20-fold higher area under the concentration versus time curve than BG. AGT activity in peripheral blood mononuclear cells was rapidly and completely suppressed at all of the BG doses. The rate of AGT regeneration was more rapid for patients treated with the lowest dose of BG but was similar for BG doses ranging from 20–120 mg/m2. In conclusion, coadministration of BG and carmustine is feasible in cancer patients, but the maximal dose of carmustine that can be safely administered with BG is approximately one-third of the standard clinical dose. Bone marrow suppression, which may be cumulative, is the dose-limiting toxicity of the combination. Prolonged AGT suppression is likely attributable primarily to the effect of O6-benzyl-8-oxoguanine.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There is an inverse relationship between the level of AGT and the sensitivity of tumor cells grown in culture and as xenografts to the cytotoxic effects of alkylnitrosoureas (1) . Increased AGT activity has been found in many human solid tumors including colon cancer (2) , malignant melanoma (3) , lung cancer, gliomas (4 , 5) , and others (6) , and may account for the relative ineffectiveness of nitrosourea therapy in these diseases. Inactivation of AGT leads to an enhancement of the cytotoxic effects of chloroethylnitrosoureas (e.g., carmustine) and methylating agents (e.g., dacarbazine, temozolomide) in both cell culture and animal tumor xenograft models (7, 8, 9) . Therefore, various strategies have been attempted to deplete cells of AGT and thereby increase the sensitivity of tumor cells to carmustine and related agents.
Agents that methylate DNA, such as streptozotocin and dacarbazine, deplete AGT activity incompletely and produce significant clinical toxicity (10) . BG, a low-molecular-weight AGT substrate, binds readily to the same cysteine residue on AGT that is used for alkyl group transfer and inactivates the protein stoichiometrically, requiring micromolar concentrations and only minutes of exposure to completely inactivate AGT (11 , 12) . Once AGT is inactivated, cells become vulnerable to killing by nitrosoureas because lesions that are present at the O6 position of guanine cannot be repaired until new AGT synthesis occurs (13, 14, 15, 16) . There is a strong correlation between the degree of sensitization that can be achieved and the level of AGT activity in cells, with little or no BG-induced enhancement of BCNU cytotoxicity occurring in cells that express low levels of AGT and the greatest enhancement observed in cells with high AGT activity (13) . BCNU preceded by BG treatment results in significantly greater growth inhibition of human brain and colon tumor xenografts in nude mice compared with that observed in animals treated with BCNU alone (8 , 17) .
Preclinical toxicology studies in mice and dogs revealed BG alone to be nontoxic. When combined with BCNU, bone marrow toxicity was dose-limiting, and the MTD of BCNU was 2- to 3-fold lower in mice and 6-fold lower in dogs than in the absence of BG (18 , 19) .
On the basis of the strong preclinical evidence that BG administration could potentially reverse resistance to alkylnitrosoureas, we conducted a Phase I study of the combination of BG and BCNU in patients with advanced cancer. The major objectives of the study were to define the optimal modulatory dose and associated acute and cumulative toxicities of BG administered alone and in combination with BCNU; to define the MTD and associated acute and cumulative toxicities of BCNU administered with BG; to determine the time course of AGT depletion and recovery in PBMCs after administration of BG; and to describe the pharmacokinetics of BG in humans.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study Design.
The initial goal of the study was to define the dose of BG that
produced maximal AGT suppression in human PBMCs without excessive
toxicity and to define the time course of this inhibition. Once this
dose of BG was defined, cohorts of patients were to be treated at a
fixed dose of BG and at increasing doses of BCNU to determine the MTD
of BCNU given with BG. Thus, patients who were enrolled in the study
initially received BG as a 1-h i.v. infusion without BCNU. After a
14-day washout period, patients received the assigned dose of BG
as a 1-h i.v. infusion followed, 1 h later, by a 15-min i.v.
infusion of BCNU. Cycles of chemotherapy were repeated every 6 weeks as
long as the patient’s tumor was stable or responding to treatment and
the patient did not experience DLT.
The starting dose of BG was 10 mg/m2. Escalation of the BG dose occurred in increments of 100% until maximal AGT suppression was observed in PBMCs 6 h after dosing or until the appearance of grade 1–2 toxicity attributable to BG. Dose escalation of BG was to continue until AGT suppression of at least 90% was observed in at least two of three patients in two successive dose cohorts (BG max). During the period of BG dose escalation, all of the patients received a fixed dose of BCNU of 13 mg/m2. Once BG max was defined, all of the subsequent patients were to receive BG max, and the BCNU dose was to be escalated in cohorts of at least three patients until the MTD of BCNU was defined. Planned BCNU dose levels were 25 mg/m2, 40 mg/m2, 60 mg/m2, 80 mg/m2, and 100 mg/m2. No intrapatient dose escalation was permitted. Midway through the study, we became aware of data from other trials that suggested that AGT suppression in PBMCs did not correlate with the extent of AGT suppression in solid tumor tissues; that BG doses greater than 80 mg/m2 were required to completely suppress AGT activity in tumor tissue; and that doses of at least 100 mg/m2 were required to completely suppress AGT activity in brain tumors (20 , 21) . We, therefore, studied additional cohorts of patients at BG doses higher than those determined to be BG max in PBMCs.
Definition of Study End Points.
BG max was defined as stated above. DLT of BCNU was defined as the dose
of BCNU that produced at least grade 3 nonhematological toxicity
(except alopecia, nausea, or vomiting) or grade 4 hematological
toxicity lasting more than 3 days, or fever in the presence of an
absolute neutrophil count of less than 1000/µl. The MTD of BCNU was
defined as the dose of BCNU that produced DLT in more than two of six
patients during the first cycle of chemotherapy. The recommended Phase
II dose was one dose level below the MTD of BCNU.
Drug Supply.
BG (NSC 637037) was supplied by the National Cancer Institute, Division
of Cancer Treatment and Diagnosis, in 100-mg vials containing white
lyophilized powder with 670 mg mannitol, USP, and sodium hydroxide to
adjust pH to 7–8.5. Once diluted, each ml 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 (pH 7) phosphate buffer. BCNU was commercially
available from Bristol-Myers Squibb and was prepared for administration
according to package labeling.
Pretreatment and Follow-Up Studies.
Before the initiation of therapy, all of the patients had a history and
physical examination, assessment of Karnofsky performance status, chest
radiograph, 12-lead electrocardiogram, determination of tumor
measurements, dipstick urinalysis, and routine laboratory studies that
included a complete blood count with differential WBC count,
electrolytes, urea, creatinine, glucose, total protein, albumin,
calcium, phosphate, uric acid, alkaline phosphatase, total and direct
bilirubin, and alanine aminotransferase and aspartate aminotransferase
levels. Baseline pulmonary function studies including
DLCO and arterial blood gases were performed on
all of the patients. Complete blood counts were assessed weekly during
therapy and daily if grade 4 neutropenia or thrombocytopenia was
documented. History and physical examination, determination of
performance status, toxicity evaluation, and serum chemistries were
performed every 2 weeks and before each cycle of therapy. Disease
assessment and pulmonary function tests were performed after every two
cycles of therapy. A complete response was defined as the disappearance
of all clinical, biochemical, and radiographic evidence of the tumor
for a minimum of 4 weeks and the absence of no disease-related
symptoms. A partial response was defined as at least a 50% decrease
from baseline in the sum of the products of the perpendicular diameters
of all measurable lesions lasting at least 4 weeks during which time no
new lesions had appeared. Minor response was defined as objective
decrease of disease but less than that required for a partial response.
Disease progression was defined as 
25% increase in the sum of the
products of the perpendicular diameters of all of the measured lesions
over the smallest sum observed or as the appearance of any new lesions
or the clear worsening of assessable disease.
Plasma Sampling and Pharmacokinetic Studies.
Patients were admitted to the General Clinical Research Center at the
University of Chicago for administration of the initial dose of BG.
Whole-blood samples were collected in sodium-heparinized vacutainers
before treatment, at 30 and 60 min during the infusion of BG and at
0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8, 24, and 48 h after the
completion of the infusion. Plasma was obtained by centrifugation at
2500 rpm for 10 min. Urine was collected at various time periods
up to 48 h after completion of the infusion. Samples were stored
at -70°C until analysis. Total plasma and urine concentrations of BG
and 8-oxo-BG were measured by high-pressure liquid chromatography using
methods that have been described previously (22)
. For
determination of AGT activity in PBMCs, blood (40 ml) was collected
twice before the BG infusion was begun and at 1, 6, 10, 24, 48, 72,
168, and 336 h postinfusion. Within an hour of collection, an
equal volume of RPMI medium was added, and the diluted blood was
layered on Ficoll-Paque (Histopaque 1077). After centrifugation at
400 x g for 30 min, the lymphocyte layer was removed
and resuspended in 15 ml PBS and centrifuged at 250 x
g for 10 min at room temperature. RBCs were lysed by the
addition of 6 ml of deionized water for 15 s after which 2 ml of
3.6% NaCl and 15 ml of PBS were added. The samples were centrifuged at
250 x g for 10 min. Final pellets were resuspended in
50 mM Tris (pH7.5), 0.1 mM
EDTA, and 5 mM DTT.
The pharmacokinetics of BG were analyzed using noncompartmental methods
with WinNonlin (PharSight Corp., Apex, NC). The terminal elimination
t1/2 of BG was estimated from the slope of the
terminal concentration-time curve of individual patients. The AUC for
the study period, AUClast, for BG and
8-oxo-BG were calculated by the linear trapezoidal method. The AUC to
infinity (AUC0-inf) was calculated as the
sum of AUClast and
Clast/
, where
Clast is the final measured
concentration and is the terminal elimination rate constant. The
latter was based on visual inspection of the data. When
Clast was below the limit of
quantitation, a concentration of BG (15 ng/ml) or 8-oxo-BG (10 ng/ml)
equivalent to one-half of the limit of quantitation was used for the
calculation of the AUC.
AGT Activity.
The assay for alkyltransferase activity was performed as described
previously (22)
. Briefly, alkyltransferase activity was
measured as the removal of
O6-[3H]methylguanine
from a 3H-methylated DNA substrate (5.8 Ci/mmol)
after incubation with extract at 37°C for 30 min. The DNA was
precipitated by adding ice-cold perchloric acid (0.25
N) and was hydrolyzed by the addition of 0.1
N HCl at 70°C for 30 min. The modified bases
were separated by reverse-phase high-pressure liquid chromatography
with 0.05 M ammonium formate (pH 4.5) containing
10% methanol. Each assay was performed with a positive control cell
line (DaOY cell extract) and lymphocytes from three normal volunteers.
Protein was determined by the method of Bradford (23)
, and
the results were expressed as fmol of
O6-methylguanine released from the DNA
substrate per mg of protein.
Statistical Considerations.
Comparisons of DLCO postcycle 2 to baseline were
performed using a paired t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Sixteen patients did not complete the first cycle of therapy and are,
therefore, not assessable for toxicity or response; toxicity data on
the remaining 62 patients form the basis of this report. In most cases,
failure to complete the first cycle of therapy was attributable to
rapid disease progression. Table 2
lists the dose levels evaluated in this study. A total of 121 cycles of
chemotherapy were administered at BG doses ranging from 10 to 120
mg/m2 and BCNU doses ranging from 13 to 50
mg/m2.
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. Grade 3 or higher toxicity was noted at BCNU doses as low as 25
mg/m2 given with BG. As originally defined in the
protocol, a BG dose of 40 mg/m2 was determined to
be BG max based on suppression of AGT activity in PBMCs. At this BG
dose, two of seven patients treated with BCNU at 40
mg/m2 had dose-limiting hematological toxicity
and three of four patients treated at a BCNU dose of 50
mg/m2 had dose-limiting hematological toxicity.
Further escalation of the BG dose was not associated with increased
BCNU toxicity (Table 4)
, which suggests that BG doses of 40 mg/m2
produced maximal AGT suppression in bone marrow progenitor cells. Table 5
summarizes cycle-one hematological toxicity data for BCNU doses of 32
mg/m2, 40 mg/m2, and 50
mg/m2 given with BG at doses of 40
mg/m2 or higher. Dose-limiting hematological
toxicity occurred in 4 of 6 patients treated with BCNU at 50
mg/m2; in 3 of 18 patients treated with BCNU at
40 mg/m2; and in 0 of 12 patients treated with
BCNU at 32 mg/m2. Prior therapy received by the
patients with DLT is summarized in Table 6
. It should be noted that one of the patients with DLT at a BCNU dose of
40 mg/m2 had previously had high-dose
chemotherapy consisting of
1-ß-D-arabinofuranosylcytosine, etoposide,
cyclophosphamide, and carmustine and an autologous stem-cell
transplant as therapy for refractory lymphoma. On the basis of this
information, we recommend doses of BG at 120
mg/m2 with BCNU at 40 mg/m2
for subsequent Phase II studies. The higher BG dose is recommended
based on data reported by other investigators, which suggested that 120
mg/m2 is the optimal dose to completely suppress
AGT in tumor tissue.
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summarizes episodes of grade 3 or higher bone marrow suppression
occurring during cycle 2 in patients treated with BCNU doses of 32
mg/m2, 40 mg/m2, or 50
mg/m2 regardless of the BG dose. Of note is that,
although 1 of 12 patients treated at 32 mg/m2
experienced grade 3 or higher toxicity during cycle one (Table 3)
, 3 of
10 patients who received a second cycle of chemotherapy at this BCNU
dose experienced grade 3 or 4 neutropenia or thrombocytopenia, which
clearly indicated the potential for cumulative hematological toxicity
to occur. One patient, initially thought to have treatment-related
grade 4 bone marrow suppression after his second cycle of chemotherapy
at BG and BCNU doses of 120 and 40 mg/m2,
respectively, was diagnosed with acute promyelocytic leukemia. This
patient had a hepatocellular carcinoma and had previously been treated
with pyrazaloacridine. Cytogenetic examination of the leukemic
blasts revealed a t(15;17) translocation. No other cytogenetic
abnormalities were noted. Given the low cumulative dose of BCNU
received (80 mg/m2) and the short interval from
initiation of therapy until diagnosis (10 weeks), this leukemia was
unlikely to be related to the BG/BCNU therapy.
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Because high cumulative doses of carmustine are known to be
associated with pulmonary toxicity, we monitored
DLCO in these patients after every two cycles of
therapy. Pulmonary function tests were performed prestudy in every
patient, but only 30 patients returned for testing after two cycles of
therapy. Among patients with both baseline and postcycle 2
measurements, mean DLCO uncorrected fell
approximately 9% (P = 0.002) and mean
DLCO corrected fell approximately 10%
(P = 0.006). Twenty of the 30 patients had a decrease
in the percentage of predicted DLCO. Of these,
the median percent decrease in the percentage of predicted
DLCO was 10% (range, 2–46%). Only four
patients had a percent decrease in percentage of predicted
DLCO of 20%. These patients had been treated
with BG/BCNU doses of 40/32, 80/25, 120/25, and 120/32. No patient
experienced clinical signs or symptoms of pulmonary toxicity.
Antitumor Response.
No complete or partial responses were observed.
Pharmacological Studies.
We have previously reported results of pharmacological studies
performed in 25 patients enrolled in this study and treated at BG doses
ranging from 10 to 80 mg/m2 (22)
. BG
is rapidly eliminated from plasma (t1/2 at 120
mg/m2 averaged 1.9 h) and is replaced by a
major metabolite, 8-oxo-BG. This biologically active metabolite of BG
has a longer t1/2 (averaging 4.0 h at 120
mg/m2) and a 12- to 29-fold higher AUC than BG.
Fig. 1
illustrates the relationship between BG dose and AUC for patients
treated at doses ranging from 40 to 120 mg/m2 of
BG. As suggested by Fig. 1
, the BG clearance decreases as the dose
increases from 40 to 120 mg/m2, with values of
40.9 ± 12.1, 34.7 ± 12.9, and 31.6 ± 10.6
liters/h/m2, at BG doses of 40, 80, and 120
mg/m2, respectively.
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provides data for a total of 50 patients.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study design that we used clearly illustrates the advantages and disadvantages of using PBMCs as surrogates for tumor tissue in assessing biochemical events. PBMCs are easily accessible and can be sampled serially with little risk to the patient. PBMCs provide ample cellular material and enable quantitative assays even with relatively insensitive techniques. However, PBMCs cannot be presumed to be an adequate surrogate for the assessment of biochemical events in tumor tissue. Using the definition of BG max described previously, we initially concluded that a BG dose of 40 mg/m2 was sufficient to completely suppress AGT activity. Although this is clearly the case with respect to PBMCs and bone marrow progenitors, Spiro et al. (21) have convincingly demonstrated that AGT suppression in PBMCs does not correlate with AGT suppression in solid tumor tissue. Their study also demonstrated that BG doses >80 mg/m2 are necessary to completely suppress AGT in tumors.
We previously reported (22) linearity in the AUC of BG and nonlinearity in the AUC of 8-oxo-BG with increasing BG dosage based on an initial evaluation of 25 patients. Our updated analysis suggests some nonlinearity in BG pharmacokinetics over a wider dosage range, inasmuch as the mean clearance decreased approximately 23% over a 3-fold increase in dosage. In addition, the 8-oxo-BG AUC increased more than proportionately, despite the apparent saturation of its formation, which suggests that its catabolism is also saturable, as reported previously (22) . The pharmacokinetics of BG are unlikely to require precise titration because the clinical toxicity remains the same when the BG dosage is increased from 40 to 120 mg/m2 at any given BCNU dosage.
Although essentially all of the patients in this study had advanced cancer that was unresponsive to prior therapy, very few patients had received alkylnitrosoureas or alkylating agents of any kind prior to enrollment on this trial. We were disappointed, therefore, that no objective tumor responses were observed among 62 evaluable patients. If AGT is the primary mechanism of resistance to alkylnitrosoureas and if AGT activity is completely suppressed by BG, one might have anticipated that tumor responses would occur. A number of possible explanations exist for the apparent lack of tumor efficacy. Only 24 patients received a BCNU dose of 40 mg/m2 or higher and, of these, only 10 received BG at a dose of 120 mg/m2. Treatment of a heterogeneous group of only 10 patients at the recommended Phase II doses or above is not an adequate test of antitumor efficacy. It is also reasonable to consider whether this schedule of BG administration is sufficient to produce sustained AGT depletion throughout the period of time when BCNU-induced DNA cross-links are most likely to occur, i.e., 12–18 h after BCNU administration (24) . Synthesis of new AGT molecules after BG depletion occurs at different rates in different tissues. Persistence of BG or 8-oxo-BG at sufficient concentration is necessary to insure that newly synthesized AGT is inactivated or the removal of alkylnitrosourea monoadducts from DNA is likely to occur, thereby limiting the effectiveness of BCNU. Pharmacological data from this study demonstrates that plasma concentrations of 8-oxo-BG of at least 100ng/ml are detectable in most patients at 10 h post-BG dosing, and Spiro et al. (21) have demonstrated undetectable AGT activity in tumor biopsies obtained 18 h after a BG dose of 120 mg/m2. Thus, it seems likely that the present schedule of administering BG over a 1-h period prior to BCNU is adequate to suppress AGT throughout the period of BCNU-induced DNA cross-link formation.
Phase II studies of the combination of BG and BCNU are ongoing or planned in patients with malignant gliomas, myeloma, colorectal cancer, melanoma, soft tissue sarcoma, and pediatric brain tumors. Recommended dosage for these studies is BG 120 mg/m2 given over a period of 1 h followed 1 h later by BCNU 40 mg/m2.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by USPHS Grants CA14599 (to
R. L. S.), CA67098 (to M. E. D.), and CA69852 (to M. J. R.) from
the National Cancer Institute, NIH, Bethesda, MD, and by Grant MO1
RR00055 to The General Clinical Research Center, University of
Chicago. 
2 To whom requests for reprints should be
addressed: Division of the Biological Sciences, University of Chicago,
5841 South Maryland Avenue, MC1000, Chicago, IL 60637. Phone: (773)
834-3914; Fax: (773) 834-3915; E-mail: rschilsk{at}medicine.bsd.uchicago.edu
3 Author has disclosed a financial interest in
Procept, a company that has licensed
O6-benzylguanine.
4 The abbreviations used are: AGT,
O6-alkylguanine-DNA alkyltransferase; BCNU,
bischloronitrosourea, carmustine; BG,
O6-benzylguanine; MTD, maximally tolerated
dose; PBMC, peripheral blood mononuclear cell; BG max, maximal
dose of BG; DLT, dose-limiting toxicity; DLCO, carbon
monoxide diffusion capacity; AUC, area under the concentration
versus time curve; 8-oxo-BG,
O6-benzyl-8-oxoguanine.
Received 12/ 6/99; accepted 2/15/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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M. E. Dolan, M. Posner, T. Karrison, J. Radosta, G. Steinberg, D. Bertucci, L. Vujasin, and M. J. Ratain Determination of the Optimal Modulatory Dose of O6-Benzylguanine in Patients with Surgically Resectable Tumors Clin. Cancer Res., August 1, 2002; 8(8): 2519 - 2523. [Abstract] [Full Text] [PDF]
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 M. Esteller, G. Gaidano, S. N. Goodman, V. Zagonel, D. Capello, B. Botto, D. Rossi, A. Gloghini, U. Vitolo, A. Carbone, et al. Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma J Natl Cancer Inst, January 2, 2002; 94(1): 26 - 32. [Abstract] [Full Text] [PDF]
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L. Long and M. E. Dolan Role of Cytochrome P450 Isoenzymes in Metabolism of O6-Benzylguanine: Implications for Dacarbazine Activation Clin. Cancer Res., December 1, 2001; 7(12): 4239 - 4244. [Abstract] [Full Text] [PDF]
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 L. D. Rhines, P. Sampath, M. E. Dolan, B. M. Tyler, H. Brem, and J. Weingart O6-Benzylguanine Potentiates the Antitumor Effect of Locally Delivered Carmustine against an Intracranial Rat Glioma Cancer Res., November 1, 2000; 60(22): 6307 - 6310. [Abstract] [Full Text]
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H. S. Friedman, J. Pluda, J. A. Quinn, R. B. Ewesuedo, L. Long, A. H. Friedman, I. Cokgor, O. M. Colvin, M. M. Haglund, D. M. Ashley, et al. Phase I Trial of Carmustine Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma J. Clin. Oncol., October 20, 2000; 18(20): 3522 - 3528. [Abstract] [Full Text] [PDF]
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Y. Cai, M. H. Wu, M. Xu-Welliver, A. E. Pegg, S. M. Ludeman, and M. E. Dolan Effect of O6-Benzylguanine on Alkylating Agent-induced Toxicity and Mutagenicity in Chinese Hamster Ovary Cells Expressing Wild-Type and Mutant O6-Alkylguanine-DNA Alkyltransferases Cancer Res., October 1, 2000; 60(19): 5464 - 5469. [Abstract] [Full Text]
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H. S. Friedman Can O6-Alkylguanine-DNA Alkyltransferase Depletion Enhance Alkylator Activity in the Clinic? Clin. Cancer Res., August 1, 2000; 6(8): 2967 - 2968. [Full Text]
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