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Experimental Therapeutics, Preclinical Pharmacology |
Department of Neurosurgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8855 [D. M. K.]; University of Texas Medical Branch, Sealy Center for Molecular Science, Galveston, Texas 77555 [D. B. B.]; National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 [R. C. M.]; Departments of Cellular and Molecular Physiology and Pharmacology, Pennsylvania State University, College of Medicine, The Milton Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [S. C. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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An additional important issue in combining DNA alkylating agents with AGT inhibitors is whether to include such inhibitors in the treatment of tumors with no or low AGT content, especially because such a combination limits the dose of the alkylating agent. Dose is important for several reasons, including the fact that the alkylating agent itself might quench low levels of AGT. A case in point is TMZ, which at a dose of 100 mg/kg eliminates all of the AGT activity in tumors having moderate AGT levels for a prolonged time period (11) . In addition, the inverse correlation between AGT levels and effectiveness of BCNU against central nervous system tumors (22 , 23) suggest that there may be no benefit in treating AGT-deficient tumors with AGT inhibitors. Determining the threshold of AGT activity that could be overcome by alkylating agents without the use of AGT inactivators may be complicated by tumor heterogeneity in AGT levels in some human tumors. However, such heterogeneity has not been demonstrated conclusively in gliomas, and therefore, conclusions derived from xenograft experiments may also apply in patients with such malignancies.
In this report, we address the question of whether AGT depletion prior to the administration of BCNU or TMZ enhances the response of typical glial tumors having low (<50 fmol/mg protein) to moderate (75 fmol/mg protein) levels of AGT activity. It is expected that AGT inhibitors will not enhance the efficacy of TMZ against tumors with modest AGT levels when this agent is administered at its maximum effective dose. On the other hand, the markedly higher toxicity of BCNU as compared with TMZ is expected to render the combination of AGT inhibitors and BCNU more effective than BCNU itself in the treatment of tumors having modest levels of AGT activity, such as those usually found in the central nervous system.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals.
BALB/c nu/nu athymic mice, 4 weeks of age, were purchased
from Harlan Labs (San Diego, CA). Mice were maintained under barrier
conditions and given sterilized food (Harlan Teklad laboratory diet)
and water.
Tumor Lines.
The tumor lines D-54, SWB39, SWB40, SWB77 (human glioblastomas), and
SWB61 (human anaplastic oligodendroglioma) were chosen for their lack
of genomic instability and effective MMR
repair.4
They were grown in 5% fetal bovine serum (Life Technologies, Inc.,
Gaithersburg, MD) in Eagle’s MEM (Life Technologies, Inc.)
supplemented with lysine, valine, methionine, and leucine (100
µM each), nonessential amino acids (1:100 dilution of
stock from Life Technologies, Inc.), 1 mM sodium pyruvate,
1 µM 
- hydroxocobalamin, 10 µM folic
acid, and 0.2 mg/ml gentamicin. s.c. tumors grew upon injection of 3–4
million cells/animal. Tumor xenografts D-54, SWB39, SWB40, SWB77, and
SWB61 had AGT activities of <10, 10, 45, 75, and 16 fmol/mg protein,
respectively, as determined by the biochemical assay (26)
.
Respective mitotic indices in xenografts were 5.5, 8.2, 12.1, 5.7, and
12.9 m/high-powered field. Extensive necrosis was observed in growing
xenografts SWB40 and SWB61, which is in agreement with their rapid
growth patterns.
Drug Treatment.
All treatments were administered i.p. BG and dBG were dissolved in 40%
PEG 400:60% PBS. The pH of the solvent was corrected to 7.0 with
sodium bicarbonate before the addition of the drug. BCNU was
administered in 5% ethanol in water from a stock solution of 20 mg/ml
of anhydrous ethanol. Depending on the dose of BCNU, the injected
ethanol carrier varied from 10 to 15% ethanol. TMZ was dissolved in
100% DMSO. AGT inhibitors were administered at volumes of 30
ml/m2 and alkylating drugs at 20
ml/m2. Drug doses were calculated as
mg/m2 using the formula: meters (m) = weight
(g)2/3 x K x
10-4, where K is 10.5 for mice
(27)
. In animals of 20 ± 2 g used in this
study, the weight (kg) of the animal is 
2.6 times the area surface
(m2).
Tumor Implantation and Treatment.
Two hundred µl containing 3 x 106 cells
of D-54, SWB39, SWB40, SWB77, and SWB61 tumor cells in 5% serum media
were injected at the left flank of athymic mice, 6 weeks of age,
weighing between 18 and 22 g. Visible tumors appeared in most of
the animals within 3 weeks after implantation. The tumors were
subsequently measured in two perpendicular dimensions, and their
volumes were estimated using the formula (2 x
ß)/2, where is the shorter and ß the longer of the two
dimensions. Treatment was administered to animals with tumors ranging
between 150 and 200 mm3
. Tumors were measured
every other day until their volumes exceeded five times the volume of
the tumor at treatment. The data were analyzed using the Wilcoxon rank
sum test, comparing the time from treatment to five times treatment
volume in individual animals in each of the groups. Growth delay was
the difference between the median time to five times treatment volume
in the treatment group minus the median time to five times treatment
volume in the control group. The number of tumor regressions (number of
tumors measuring smaller than the volume on the treatment day)
occurring in each group was also determined. Groups were compared with
the two-tailed Fisher’s exact test. Two control groups received 40%
PEG:60% PBS, followed by 10% ethanol:water in 2 h or 40%
PEG:60% PBS and BCNU in 10% ethanol. Unless otherwise indicated,
10–12 animals were used in each experimental group.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The LD10 for BCNU is between 70 and 75
mg/m2 when the drug was delivered i.p. Treatments
with doses of 70 mg/m2 induced a temporary loss
of weight of 10% and no deaths. All deaths at higher doses occurred
within 72 h from treatment. The AGT inhibitors BG and dBG
sensitized animals to BCNU, and their use necessitated a decrease of
the dose of the chemotherapeutic drug to 30 and 35
mg/m2, respectively. The combination of dBG and
BCNU at 250 and 35 mg/m2, respectively, was the
maximum tolerated exposure to this drug combination, inducing a 12%
weight loss but no deaths. Increasing the dBG dose to 300
mg/m2 depleted the intestinal AGT in mice and
sensitized the animals to the toxicity of BCNU, even at doses <35
mg/m2. At 180 mg/m2 BG, a
dose that is equimolar to 250 mg/m2 dBG, 35
mg/m2 BCNU induced a 40% incidence of death and
a weight loss 2-fold greater than that induced by an equimolar doses of
dBG and 35 mg/m2 BCNU. Animal deaths were
prevented by reducing the dose of BCNU to 30
mg/m2. Therefore, administration of equimolar
doses of BG and dBG required treatment with 30 and 35
mg/m2 BCNU, respectively, to achieve the same
extent of weight loss and no deaths (equitoxic treatments). Comparisons
between BG and dBG at equimolar doses with slight variation in the BCNU
dose to achieve comparable toxicity is justified because such
treatments achieve the best possible tumor response for the combination
of these two AGT inactivators with BCNU without causing any animal
deaths.
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Treatment Efficacy of BCNU against Glial Tumors.
The efficacy of BCNU against glial tumors was tested using the D-54,
SWB39, SWB61, SWB40, and SWB77 xenografts growing s.c. in nude mice.
The median time and range for these tumors to quintuple in size was 8
(7, 8, 9, 10, 11)
, 11 (9, 10, 11, 12)
, 12 (7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
,
11 (9, 10, 11, 12, 13, 14, 15)
, and 11 (9, 10, 11, 12, 13)
days,
respectively. The effect of BCNU at doses ranging between 35 and 75
mg/m2 on growth delay of these xenografts and the
toxicity of BCNU at these doses are shown on Table 2
. A dose of 35 mg/m2 BCNU was ineffective against
all tumor xenografts tested, including those with negligible levels of
AGT activity (D- 54, SWB61, and SWB39). However, SWB61 SWB39, and D-54
tumor xenografts, with AGT activity <20 fmol/mg protein, responded to
a single BCNU treatment at doses of 65–70 mg/m2,
whereas those with higher AGT activities did not respond (SWB77) or
responded weakly (SWB40). Further escalation of the dose induced animal
deaths, as expected from the toxicity data without further delaying
tumor growth in the survivors.
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shows the effect of depletion of AGT prior to BCNU treatment. Depletion
of AGT was accomplished with dBG, which has been shown previously to
suppress AGT activity to <2% of its baseline for a period lasting for
at least 16 h after its administration (21)
. BCNU was
administered at 2 h after 250 mg/m2 dBG,
which is approximately the molar equivalent to a dose of 180
mg/m2 BG. Escalation of the dBG dose above this
level did not cause toxicity by itself but resulted in
unacceptable toxicity by BCNU with no increase in tumor growth delay.
The increased toxicity of BCNU with higher doses of dBG is likely
attributable to depletion of intestinal AGT (9)
and the
exposing of the brush epithelium to cross-linking DNA damage. The
toxicity of the optimal dBG/BCNU combination, as determined from acute
loss of weight, was similar to that achieved for the maximum tolerated
dose of BCNU alone. However, the tumor growth delay was markedly
enhanced in glioblastomas expressing AGT activity at levels >45
fmol/mg protein. Although the increase in tumor growth delay induced by
dBG (250 mg/m2) and BCNU (35
mg/m2) observed in tumors with low AGT activity
(<20 fmol/mg protein) was not statistically significant as compared
with an equitoxic dose of BCNU alone (70 mg/m2),
there was a definite benefit (P < 0.025) as compared
with 35 mg/m2 BCNU alone (Tables 2
and 3)
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. Treatments with either dBG-BCNU (at 250 and 35
mg/m2) or BG-BCNU (at 180 and 30
mg/m2) were isotoxic to a treatment with 70
mg/m2 BCNU alone (Tables 2
and 4)
. Tumor delays
with either drug combination were markedly greater than those observed
when the same tumors were treated with the full dose (70
mg/m2 of BCNU alone, but dBG was more effective
than BG (P < 0.001) in enhancing the efficacy of BCNU.
A statistically significant difference (P < 0.001)
between BG and dBG was also determined when these two compounds were
used in combination with BCNU against SWB40 tumor xenografts (Table 4)
. It was noted that dBG-BCNU caused similar delays in SWB77 and SWB40,
but BG increased the efficacy of BCNU, more notably in SWB40 than in
SWB77. There was a small but statistically significant
(P < 0.05) advantage in using the reduced dose of BCNU
and AGT inhibitors rather than the maximum tolerated dose of BCNU
without AGT inhibition (70 mg/m2) against the
SWB61 tumor xenografts, which have marginal AGT activity, but not
against D-54, which has negligible AGT levels.
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. Although none of the implanted tumors were eradicated by TMZ
treatment alone, the growth of SWB61 and SWB40 was retarded for >50
days. TMZ induced a moderate response in SWB77, where tumor growth
delay was 20 days. There were no statistical differences in the
tumor response between the doses of 200 and 300
mg/m2 TMZ in any of the tumors treated, despite
evident greater toxicity of the latter dose. Further escalation of the
dose to 600 mg/m2 against SWB61 did not delay
growth but had a rather profound effect in toxicity. It was concluded
that the maximum therapeutic effect of TMZ (single-dose i.p.) was
achieved at 200–300 mg/m2.
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. A significant advantage in using lower levels of TMZ in combination
with BG or dBG rather than greater doses of TMZ alone was also seen in
SWB40 tumor xenografts. However, with SWB40, the difference between BG
and dBG in enhancing the efficacy of TMZ (Fig. 2
; Table 6
) was not statistically significant. There was no enhancement
of TMZ efficacy against SWB61 by BG or dBG (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DNA repair of the damage induced by alkylating agents occurs with the aid of several systems (28) , such as direct reversal of O6-alkylguanine, nucleotide excision repair, MMR, base excision repair, error-free and error-prone tolerance during DNA replication, and recombinational repair. Although BCNU is toxic via the formation of cross-links, DNA excision repair seems to be of minor importance as compared with O6-alkylguanine reversal (29) . However, BCNU ultimately bridges the N1 of G and N3 of C residues via the intermediate formation of O6-N1 cycloethyl derivative of guanine yielding cross-links that are not subject to repair by either excision or by AGT (30) . Inhibition of the O6-2-chloroethyl reversal for a period of at least 18 h, which is required for the cross-links to be formed, is therefore necessary to preserve the cytotoxic effect of BCNU. TMZ, on the other hand, exerts its toxicity by invoking the response of the MMR system via the recognition of O6-methylguanine containing odd bp by the MSH2, MLH1, and PMS2 complexed to MSH3 or MSH6. As a result of the different mechanisms by which BCNU and TMZ exert their toxicities, an inverse correlation between BCNU toxicity and AGT levels is expected with all tumors, whereas such a correlation is expected with TMZ only with tumors that have at least a functional MMR and a rapid rate of turnover. The tumors used in this communication express similar levels of MLH1, MSH2, and PMS2, which migrate to the nucleus after exposure to TMZ and show no apparent instability after TMZ treatment, as determined by microsatellite assays.4 The above indicate the presence of functional MMR systems (31) . Therefore, the resistance of SWB77 and to a lesser extent that of SWB40 to TMZ was attributable, at least partially, to AGT. The poorer response of SWB77 to TMZ, as compared with that of SWB40 and SWB61, even after the depletion of the AGT activity, indicates that SWB77 may resist alkylating damage by mechanisms not yet identified. Different responses of SWB77 on one hand and SWB40 or SWB61 on the other, in cell cycle responses to DNA damage that could determine the efficiency of death via the action of MMR-related mechanisms, could also account for the resistance of SWB77 to TMZ (32) .
Gliomas with low levels of AGT (<20 fmol/mg protein), such as SWB61 and SWB39, were minimally responsive to BCNU, and their resistance to this agent was not improved by pretreatment with AGT inhibitors, indicating the presence of yet unknown mechanisms of resistance. In this regard, SWB39 and SWB61 differ from SWB40 and SWB77, which are resistant to BCNU mainly because of their moderate levels of AGT. SWB39, SWB61, D-54, and even the AGT-effective tumor SWB40 were responsive to TMZ alone in the absence of AGT inhibition, which indicates that AGT activity <45 fmol/mg protein did not significantly contribute to the resistance of these tumors to TMZ. Furthermore, the high efficacy of TMZ against SWB61 suggests that mechanisms of resistance other than AGT, which contribute to the weak response of these tumors to BCNU, can be overcome by TMZ. These data indicate that the threshold of AGT activity required for resistance to TMZ is markedly higher than that determined for BCNU. These experiments also demonstrate that the maximum benefit of the combination of AGT inhibitors and BCNU requires fine adjustments of the doses of these two agents.
In mice, the doses of BG and dBG required for maximum efficacy were 180 and 250 mg/m2, respectively. Doses of BG and dBG can be lowered to 150 and 200 mg/m2 with only a mild decline in the enhancement of antitumor efficacy of the alkylating agents. Doses of 300 dBG induced unacceptable depletion of AGT from normal mouse tissues (21) without improving the suppression of AGT from tumors, and therefore, such doses rendered these tissues extremely sensitive to the alkylating drug, causing severe weight loss and deaths to the treated animals. Overdosing with AGT inhibitors did not improve the tumor response in the survivors, indicating that BG and dBG cause maximal AGT depletion in the tumor when administered at 150–180 and 200–250 mg/m2, respectively.
One of the important findings of this study is that the potential of other AGT inhibitors to enhance the efficacy of chemotherapy with DNA alkylating drugs and theoretically to surpass BG, the prototype AGT inhibitor currently undergoing clinical trials. It has been shown previously that dBG, which has a small but significant advantage to suppress tumor AGT as compared with O6-benzyl-9-cyanomethylguanine and O6-benzylguanosine, is also more effective in enhancing the efficacy of BCNU against human medulloblastoma (Daoy) tumors (21) . Comparisons between these 9-substituted derivatives of BG have shown that small variations in both the extent and also the duration of suppression could translate into marked differences in the response of tumor to BCNU chemotherapy. Careful screening of additional compounds should therefore allow the discovery of AGT inactivators that are more effective than those presently at hand. In this report, we demonstrate that dBG is significantly more effective than BG in enhancing the efficacy of BCNU against two AGT-efficient glioblastomas. This could be attributed to the more prolonged exposure of tumors to AGT inhibitors derived from dBG than from BG metabolism (21) , causing a more protracted AGT suppression. Comparison of BG and 8-oxo-BG levels in plasma and cerebrospinal fluid of primates given systemic BG and dBG, respectively, may suggest a greater potency of BG over dBG (33) . However, the comparisons were made at equal doses and not at equimolar or equitoxic doses that would have allowed direct comparisons between that report and the data presented here. Our results with TMZ contrast with those reported earlier showing marginal benefit on TMZ efficacy by BG in single-administration regimens (7 , 34) . This is probably because of the optimization of the chemotherapeutic regimens and fine adjustment of the TMZ and BG or dBG doses in this study.
Overall, we have shown that for glial tumors with AGT activity <45 fmol/mg protein, there is no significant benefit in using an AGT inhibitor and a reduced dose of BCNU as compared with an isotoxic full dose of BCNU. However, tumors with AGT of 45 fmol/mg protein or greater activity are unresponsive to BCNU alone and require pretreatment with an AGT inhibitor to respond to BCNU treatment. It is interesting that tumors, which are resistant to BCNU because of their AGT content, are more responsive to treatment combining BCNU and AGT inhibitors than tumors with low AGT activity and responsive to BCNU alone. This indicates that the latter may rely on mechanisms of resistance other than the AGT. Unlike BCNU, the performance of TMZ is not as dependent on tumor AGT at the AGT levels tested. Consistent improvement of tumor delay because of AGT inhibition prior to TMZ treatment is observed with SWB77. The similar efficacy of TMZ against SWB61, SWB39, and SWB40 suggests that the (different) mechanisms of resistance these tumors may relay on are easily overcome by a single dose of TMZ. On the other hand, the failure to obtain the same response with SWB77 as with SWB61 and SWB40, even under AGT inhibition conditions, indicates that the efficacy of TMZ may also be limited by yet uncharacterized mechanisms of resistance in some tumors. The tumors tested here are neither rich in AGT nor have MMR defects, which may confer resistance to TMZ.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by National Cancer Institute Grants CA
57725 and CA 78561 and the National Cancer Institute, Department of
Health and Human Services, under contract with ABL and The
Children’s Brain Tumor Foundation of the Southwest. 
2 To whom requests for reprints should be
addressed, at Department of Neurological Surgery, University of Texas
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX
75235-8855. Phone: (214) 648-6314; Fax: (214) 648-2265; E-mail: dkokki{at}mednet.swmed.edu
3 The abbreviations used are: BCNU,
1,3-bis(2-chloroethyl)-1-nitrosourea; AGT,
O6-alkylguanine-DNA alkyltransferase; BG,
O6-benzylguanine; dBG,
O6-benzyl-2'-deoxyguanosine; MMR, mismatch
repair; TMZ, temozolomide; PEG, polyethyleneglycol.
4 D. B. Bocangel, S. Mitra, and D. M.
Kokkinakis, unpublished observations.
Received 7/21/00; revised 11/ 9/00; accepted 11/ 9/00.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, vehicle plus BCNU 35 mg/m2 at 2-h
intervals; 
, BG 180 mg/m2 plus 30 mg/m2
BCNU; •, dBG 250 mg/m2 plus 35 mg/m2
BCNU. Vehicle for dBG and BG was 40% PEG 400 in PBS. BCNU was
administered as a solution in 10% ethanol.
, 40% PEG 400
in PBS vehicle followed in 2 h with 200 mg/m2
temozolomide in DMSO; 
, 40% PEG 400 in PBS vehicle followed in
2 h with 300 mg/m2 temozolomide in DMSO; 
BG 180
mg/m2 plus 200 mg/m2 temozolomide;