(CANCER RESEARCH 48, 5805-5809, October 15, 1988]
Bromine-80m Radiotoxicity and the Potential for Estrogen Receptor-directed
Therapy with Auger Electrons1
Eugene R. DeSombre,2 Paul V. Harper, Alun Hughes, Ronnie C. Mease,3 S. John Gatley, Onofre T. DeJesus,4 and
Jeffrey L. Schwartz
Ben May Institute [E. R. D., A. H.J, Franklin McLean Institute [P. V. H., S. J. G., O. T. D.J, and Department of Radiation Oncology ¡J.L. S.J, University of Chicago,
Chicago, Illinois 60637; and Argonne National Laboratory [R. C. M., O. T. D.], Argonne, Illinois 60439
ABSTRACT
MATERIALS
While theoretically feasible, estrogen receptor (ER)-directed radio
therapy of hormone-dependent cancers has not been realized because no
ER-seeking ligand with an appropriate radiotoxic potential has been
identified. Since an appropriate nuclide is a key component we studied
the 4.4-h half-life, Auger electron-emitting nuclide bromine-SOm. When
incorporated into DNA this nuclide was radiotoxic to cells in culture and
caused substantial chromosomal damage, while similar concentrations of
bromine-SOm as bromide, or bromoantipyrine were without effect. The
mean lethal dose for bromine-80m was 45 atoms per nucleus which is
consistent with use in receptor-positive cancers with limited numbers of
ER.
Materials. Chemicals were reagent grade or better. Unlabeled
BrdUrd, thymidine, aphidicolin, colcemid, hematoxylin, and crystal
violet were from Sigma Chemical Co., St. Louis, MO. The 100-mm
plastic culture plates were from Corning, 6-well plates were from Linbro
Division of Flow Laboratories, McLean, VA, and slide culture plates
were from Lab-Tek Division of Miles Laboratories, Napierville, IL.
MEM, McCoys F12, insulin, fetal calf serum, penicillin, streptomycin,
and glutamine were from GIBCO, Grand Island, NY. Emulsion NTB3
was from Kodak. TCA, Giemsa, and Gurr buffer were obtained from
Fisher Scientific, Chicago, IL.
Bromine-SOm Labeled Compounds. Bromine-SOm was prepared by
either the 32Kr(d, n, a) 80mBrreaction (12) or the »°Se(p,
n) 80mBr
reaction ( 13). [80mBr]-4-Bromo-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one (bromoantipyrine) and [80mBr]-5-Bromo-2'-deoxyuridine
([80raBr]BrdUrd)were prepared from antipyrine and 2'-deoxyuridine as
INTRODUCTION
The concept of ER5-directed radiotherapy
was suggested 6
years ago by Bronzert, Hochberg, and Lippman who treated
ER+ MCF-7 cells in culture with [I25l]16a-iodoestradiol and
showed reduced cloning efficiency of the cells stored frozen to
accumulate sufficient disintegrations (1). However, the long
half-life (60 days) makes iodine-125 a poor nuclide for such use
in patients. There is good evidence that electrons emitted in the
nucleus as a result of nonradiative Auger and Coster-Kronig
processes can be highly effective in causing double stranded
DNA breaks (2-4) with minimum radiation hazard outside the
affected cells (5, 6). Since estrogen, when complexed with ER,
is tightly associated with nuclear DNA and chromatin (7-10),
such a ligand is an attractive vehicle to carry an Auger electronemitting isotope to the nuclei of ER+ cancer cells. An appro
priate estrogen receptor-directed ligand must have a sufficiently
short half-life to decay while associated with the ER, known to
itself have a biological half-life of only around 4 h (11). We
have recently reported the synthesis of several estrogens labeled
with bromine-80m (12, 13), a nuclide with a half-life of 4.4 h
which, on the basis of its Auger electron-emission spectrum
(14, 15), would be expected to be highly radiotoxic when
associated with cellular DNA. However to establish the feasi
bility of such an approach using a bromine-80m-labeled estro
gen it is necessary to demonstrate the radiotoxicity of this
nuclide, and especially to determine that the number of decays
per cell needed for cell killing is compatible with the number
of ER molecules found in ER-positive cancers.
Received 3/16/88; revised 7/6/88; accepted 7/15/88.
The costs of publication of this article were defrayed in pan 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.
1These studies were supported by the NIH (CA27476 and HD1S5I3), DOE
(contract W-31-109-Eng-38), and by the Julius J. Reingold Fellowship Fund.
1To whom requests for reprints should be addressed, at the Ben May Institute,
University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637.
' Current address: Medical Division, Brookhaven National Laboratories, As
sociated Universities, Inc., Upton, Long Island, NY 11973.
4 Current address: Department of Medical Physics, University of Wisconsin
Medical Center, 1300 University Avenue, Madison, WI 53706.
5 The abbreviations used are: ER, estrogen receptor; CHO, Chinese hamster
ovary; BrdUrd, 5-bromo-2'-deoxyuridine; TCA, trichloroacetic acid; MEM, min
imal essential medium; pen/strep, penicillin plus streptomycin; PBS, phosphate
buffered saline.
AND METHODS
reported elsewhere (16) in detail. Briefly they were prepared by oxida
tion of bromine-SOm bromide, in the presence of the antipyrine or 2'deoxyuridine with yV-chlorosuccinimide in either l M sulfuric acid for
10 min at SO'C (BrdUrd) or at room temperature with 2 N HC1 in
acetonitrile (bromoantipyrine), followed by separation of the labeled
products on a Cm reversed-phase high-performance liquid chromatography column, eluting with mixtures of acetonitrile and water. The
radioactive peaks were collected and concentrated by evaporating the
solvents at 50"C under a stream of nitrogen. Specific activities were
determined by relating the measured radioactivity in the eluted radio
active product to the normalized UV absorption of the respective
product on the high-performance liquid chromatography tracing. Radiochemical yields varied from 50 to 90% for these compounds in
various preparations.
MCF-7 Studies. MCF-7 cells were plated at 1000 cells per 100-mm
dish, 24 h prior to exposure to [80nlBr]BrdUrd,specific activity, 465 Ci/
mmol; [80l"Br]bromoantipyrine, specific activity, 2000 Ci/mmol; so
dium [80l"Br]bromide or control medium [Dulbecco's MEM with 5%
fetal calf serum, 100 I ¡/nilpenicillin, 100 iig/rnl streptomycin (pen/
strep) and 2 /ug/nil insulin] each in triplicate. Additional controls
included dishes incubated with 0.5 /uniol unlabeled BrdUrd (10 times
the highest concentration of the radioactive BrdUrd) and the inclusion
of 1 HIM unlabeled thymidine with the 3 ¿tCi/mlconcentration of
[80mBr]BrdUrd,the former to assess possible light-induced damage due
to BrdUrd itself under the actual experimental conditions used, the
latter to determine whether incorporation of bromine-SOm into DNA
was essential for radiotoxicity. The dishes were handled in a darkened
tissue culture hood and kept in an incubator with aluminum foil over
the glass door to minimize exposure to light. After 16 h at 37°Call the
media were replaced with fresh control medium and the dishes returned
to the CO2 incubator for colony growth. After 14 days the cells were
rinsed, fixed with methanohacetic acid (3:1), and stained with crystal
violet. Colonies with more than -50 cells were counted and the results
calculated as the ratio of mean number of colonies in treated cultures
to the number in control cultures.
CHO Studies. Clone AA8 of CHO cells were plated in pentuplicate
at 350 cells per dish in McCoy's F12 medium supplemented with 10%
fetal calf serum, 2 HIMglutamine and pen/strep and incubated with the
indicated concentrations of [""""BrjBrdUrd, specific activity 540 Ci/
mmol, in the dark for 2 or 18 h. In parallel CHO cells, plated at 10,000
cells per chambered slide or 100,000 cells per well, were also incubated
for 2 h with ["'""HrjBrdUrd to assess the labeling index of the cells in
the chambered slides and to assay TCA-precipitable incorporation of
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BROMINE-80m RADIOTOXICITY
bromine-80m with the multiwell plates, respectively. After the incuba
tions the experimental media were removed by aspiration and control
medium added. The 100-mm dishes for colony assays were returned to
the darkened incubator to grow for 7 days and the colonies were fixed,
stained, and counted as described for the MCF-7 cells. The slide cultures
were immediately rinsed in PBS, fixed, washed in PBS, and dried. They
were then dipped in Kodak NTB3 emulsion at 38'C in the dark, allowed
to dry and exposed overnight in a light-tight box. The emulsion was
then developed, and the cells stained with hematoxylin. At least 100
cells were counted from each of several slides to calculate the proportion
of cells with silver grains over nuclei (labeling index). Parallel slide
cultures using ['Hjthymidine to assess the labeling index gave similar
results after 1 week of exposure. To assess the incorporation of bromine80m into DNA, parallel incubations were carried out with 100.000 cells
per well in triplicate in 6-well plates. After the 2-h incubations the cells
were washed, exposed for 15 min to trypsin, scraped, and rinsed with
PBS containing 1 mM unlabeled BrdUrd into 1.5-ml Eppendorf tubes
and centrifuged in the cold. After a second PBS wash the cells were
resuspended in PBS, sonicated, and precipitated by adding an equal
volume of cold 20% TCA. After 20 min in ice to allow precipitation,
the tubes were centrifuged in the cold, decanted, washed with cold 10%
TCA, decanted, and the TCA-precipitated pellet counted in a gamma
counter.
The studies with synchronized cells were carried out in a similar
fashion except that the cells were synchronized by mitotic shake off,
held at the Gl/S border by incubating with 2 ¿ig/mlaphidicolin, and
released from the cell cycle block by replating in fresh medium about 4
h prior to incubation with [80mBr]BrdUrd, specific activity 1180 Ci/
(-TORI
mmol. Colonies were counted after 8 days.
Chromosomal Analyses. Exponentially growing CHO cells (subline
AA8) were seeded at 5 x IO6 cells in 20 ml McCoy's F12 medium
supplemented with 10% fetal calf serum. 2 HIMglutamine. 100 units/
ml penicillin, and 100 Mg/ml streptomycin for 24 h prior to use. The
control media were replaced with similar media containing the indicated
concentration of [80mBr]BrdUrd (specific activity, 540 Ci/mmol) alone
or with l IHMunlabeled thymidine. After 2 h at 37°Cthe cells were
washed and resuspended in 20 ml of control medium with 0.2 fiM
colcemid. At 2-h intervals for 10 h mitotic cells were collected by
shaking and treated with 0.075 M KC1 for 15 min to spread the
chromosomes before fixing in methanol:acetic acid (3:1). The chro
mosomes were stained in a 2% solution of Giemsa in Gurr buffer. One
hundred cells per treatment were analyzed for chromatid-type aberra
tions, classified as chromatid or isochromatid deletions (distinguished
from gaps by displacement of the chromatids) and chromatid ex
changes. Inter- and intra arni and chromatid-isochromatid exchanges
were scored individually, but combined for data analysis.
O
co
*^
CO
0.2
0.3
0.4
pCi/cell
Fig. 2. Survival curve of CHO cells treated with ("""BrlBrdUrd. Top, cells
were treated with ["""BrlBrdUrd for 2 h (x), for 18 h (x in circle) alone, or in the
presence of 1 HIMunlabeled thymidine (A, TdR). Dashed line, approximates the
extension of the curve derived from the low concentrations (< S ¿iCi/ml).Labeling
index was found to be 29%. Bottom, synchronized CHO cells as described in
"Materials and Methods." Labeling index was found to be 75%.
£
RESULTS
S/S0
AND DISCUSSION
Fig. 1 shows the survival curve of MCF-7 cells, treated for
16 h with [80mBr]BrdUrd. The toxicity is clearly due to the
/¿Ci "Br/ml
Fig. 1. Cytotoxicity of bromine-80m in MCF-7 cells. MCF-7 cells were
exposed to """BrdUrd (solid line), [80"Br]bromoantipyrine (dotted line), or Na
"""'Hr (dashed line) at the concentrations indicated, for 16 h as described in
"Materials and Methods." After replacing the media the cells were grown for 14
days in the dark, and the resultant colonies stained and counted. Results presented
as the ratio of the number of colonies in the treated (S) and control (50) cultures.
incorporation of the brominated nucleoside into DNA since the
presence of excess thymidine, which inhibited the incorporation
of the labeled precursor into the TCA-precipitable fraction, also
inhibited its effect on survival. Labeled bromide, which is ex
cluded from viable cells, and bromoantipyrine, which distributes
uniformly in cells, were without substantial effect. Furthermore,
while nonradioactive BrdUrd incorporated into DNA is known
to destabilize DNA subject to light-inducible DNA breaks (17),
unlabeled bromodeoxyuridine, at 10 times the highest concen
tration of [80inBr]BrdUrd used, did not reduce the survival of
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BROMINE-SOm RAD1OTOXICITY
5.Op
100
3H-TdR
(% of mon)
90
4.0 -
80
70
«
w
O
60
f
50
o
U
a
a
o
ffl
S
<j
40
#
30
20
IO
4
6
8
Time After Treatment
IO
6
14
(hours)
8
IO
13
Dose
14
16
18 20
22
24
26 28
(MCi/ml)
Fig. 3. (80mBr]BrdUrd-induced chromosome damage in CHO cells. Left, time course of damage. Mitotic cells were obtained by shaking at the times indicated,
following a 2-h exposure to the concentrations (as ^Ci/ml) indicated (to the right of the curves) of ["""BrlBrdUrd. The dotted line gives the percentage of maximum
cell labeling with [3H]thymidine to illustrate the timing of the S phase. Right, chromosome breaks related to the dose of ["""BrlBrdUrd at 10 h. O, data from
incubations including 1 HIMcold thymidine.
Table 1 Induction ofchromatid-type aberrations in CHO cells
CHO cells were exposed to different concentrations of [*0mBr]BrdUrd for 2 h
and then washed and cultured for 10 h before harvest and analysis of aberration
frequency. The results presented are the number of chromatid breaks (Breaks),
isochromatid breaks (ISO), and chromatid-type exchanges (Exchanges) per cell.
Included are also the fraction of cells with more than 10 aberrations per cell (>/0
ABS/cell) and the per cent of cells with aberrations (% with AUS). 100 cells per
experiment were counted.
asymptote of the first curve at about 70% survival. Although
the bromine-80 daughter decays by emission of two hard betas
(approximately 2.0 and 1.38 MeV), the radiation dose calcu
lated for such low linear energy transfer radiation from the
highest concentration during the 2-h exposure is only 60 rads
(assuming uniform distribution of the ßparticles and a 1-cm
maximum range), insufficient by itself to explain the > 90%
% with
Dose
Breaks
ISO
Exchanges
>10 ABS/Cell
ABS
cell kill. However it is also likely that nuclide incorporated into
cellular nucleotide pools, not washed out by media changes,
02.33.56.726.72.331.2+
could explain, in part, the additional cytotoxicity at higher
doses. Since cells for the labeling index were washed and fixed
at 2 h and only cells with nuclear labeling counted, they would
dThd°+
only reflect the proportion of cells which had incorporated the
dThd"0.032.092.674.204.350.120.080.020.190.300.190.410.000.020.000.090.180.460.350.000.020.000.010.130.150.210.000.003.576.075.584.093.212.08.0
labeled precursor into DNA by the end of the 2-h exposure.
°dThd, 1 mM unlabeled thymidine.
The cells for colony assay, no longer incubated with the labeled
precursor, would continue to incorporate nuclide remaining in
the cells (data not shown). Therefore it is clear that brominethe nucleotide pool, although at decreased efficiency due to
80m, like other Auger electron emitters, is radiotoxic when decay and dilution of labeled nucleotide triphosphate from the
complete medium. In the presence of excess thymidine one
incorporated into cellular DNA.
Because the 36-h cell cycle of the MCF-7 cells made dosimwould expect inhibition of killing due to both the nuclide
etry studies difficult with the short-lived [80mBr]BrdUrd, further
incorporated into DNA and incorporation of the nuclide into
studies used 2-h incorporation with the AA8 Chinese hamster
the nucleotide triphosphate pool but not due to the general
emissions of the daughter bromine-80.
ovary cell line which has a 16-h cell cycle (Fig. 2, top). The effect of the energetic ß
survival curve was biphasic with an asymptotic initial curve at As seen in Fig. 2, top, even at > 30 MCi/m! [80mBr]BrdUrd, 1
HIM unlabeled thymidine increased the survival to > 90%.
about 70% survival showing no shoulder, consistent with Auger
electron effects. It is not entirely clear what the reasons are for Indeed, the general cell labeling background was seen to be
the biphasic nature of the survival curve. Autoradiography of reduced substantially in the autoradiograms of cells incubated
cells in slide culture, also treated for 2 h established that the with [80mBr]BrdUrd in the presence of unlabeled thymidine.
Furthermore, in the experiment in which MCF-7 cells were
labeling index was 29%, in good agreement with the apparent
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BR()MINE-80m RADIOTOXICITY
*v, A •
,
Fig. 4. Effect of ("""BrJBrdUrd on chromosome breakage. Left, normal CHO metaphase; right, metaphase from CHO cells exposed to 26.7 »iCi/ml[*°™Br]BrdUrd for 2 h followed by culture for an additional 10 h before, harvest and chromosome analysis.
exposed for 16 h (Fig. 1), by the end of which time > 90% of
the nuclide would have decayed, such a secondary effect was
not seen. On the other hand, when the CHO cells were exposed
to (""""BrJBrdUrd alone for 18 h, more than one cell cycle, even
at a lower concentration, 3.5 jiCi/ml, survival was less than
10~3 (Fig. 2, top), as would be expected when all cells would
have incorporated the nuclide into DNA.
To increase the proportion of cells incorporating the nuclide
in a 2-h pulse, AA8 cells were synchronized prior to treatment,
Fig. 2, bottom. Again the plateau of the survival curve was
consistent with the labeling index (75%). The greater toxicity
in this experiment allowed direct estimation of the mean lethal
dose (i.e., the 37% survival dose) at about 40 femtocuries per
cell, corresponding to about 45 molecules per cell after correc
tion for labeling index. This compares favorably with the re
ported D37 for bromine-77 of 130 fCi/cell (6). Similar esti
mation of the D37 for the first curve by extrapolation of the
initial linear portion of the curve for the experiment shown in
Fig. 2, top, was about 50 molecules per cell.
Effects of the short [80l"Br]BrdUrd exposure at different times
age was induced after DNA replication. While over half of the
cells exposed to 26.7 ¿/Ci/ml[80mBr]BrdUrd had aberrations 2
h after treatment, it is likely that this was not an Auger electron
effect. These cells were not in S phase during exposure and
cocultivation with cold thymidine failed to significantly reduce
the aberration frequency (Fig. 3, top) unlike the cells in S phase
as shown in Table 1.
While [80mBr]BrdUrd exposure increased chromatid-type
breaks, isochromatid breaks and exchanges, the most prevalent
form of damage was chromatid-type breaks, Table 1. The
number of breaks per cell increased linearly as the dose in
creased from 0 to 6.7 ¿¿Ci/ml
[80mBr]BrdUrd (Fig. 3, bottom).
Although there was little further change as the dose rose above
6.7 Ã-Ã-Ci/ml,
the number of cells with more than 10 breaks per
cell did increase from 15 to 21% as the [80raBr]BrdUrd concen
tration was changed from 6.7 to 26.7 pCi/ml. In fact, nearly
12% of the cells examined in the 26.7 ¿¿Ci/ml
treated cultures
had too many aberrations to score accurately (Fig. 4). There
fore, the failure to see an increase in the frequency of breaks
induced at the high dose may simply reflect an inability to score
in the cell cycle were examined. The frequency of chromosomal
the more heavily damaged cells. It is also likely that cells with
aberrations dramatically increased with time, and the peak greater numbers of aberrations might not be able to progress
effects for each of the four doses of [80mBr]BrdUrd used was 10 from S phase to mitosis or alternatively might be delayed in
h after treatment, which corresponds to mid-S phase as shown
their entry into mitosis.
by the [3H]thymidine incorporation curve, Fig. 3, top. That
We conclude from these studies that bromine-80m, when
induction of aberrations by [80mBr]BrdUrd mirrored [3H]thy- incorporated into DNA, is clearly radiotoxic. This is consistent
midine uptake suggests that [80mBr]BrdUrd acts after incorpo
with the considerable body of evidence for the effectiveness of
Auger electron emissions from iodine-125 (17-23) and the
ration into the DNA. This is supported by the observation that
report on bromide-77 (6) incorporated into DNA. Furthermore,
thymidine inhibited the induction of aberrations (Fig. 3, bot
our studies show that about 50 atoms of bromine-80m are
tom). Furthermore, as shown in Table 1, most of the aberrations
were of the chromatid type, suggesting that chromosome damsufficient to kill cells. This radiotoxicity may thus be compatible
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BROMINE-80m RADIOTOXICITY
77 in the DNA of mammalian cells. Radiât.Res.. 90: 362-373, 1982.
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10. Gorski, J., Welschons, W., Sakai, D., Hansen, J., Walent, J., Kassis, J..
Shull, J., Stack, G., and Campen, C. Evolution of a model of estrogen action.
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2038-2046. 1986.
12. Seevers, R. H., Mease. R. C., Friedman, A. M., and DeSombre, E. R. The
synthesis of non-steroidal estrogen receptor binding compounds labeled with
80mBr.NucÃ-.Med. Biol.. 13: 483-495. 1986.
13. DeSombre, E. R.. Mease, R. C., Hughes, A.. DeJesus, O. T.. and Harper. I'.
V. Bromine-80m-labeled estrogens: Auger-electron emitting, estrogen recep
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Carlo treatment of the decay of Br-80m, a novel Auger electron emitting
isotope with potential for therapy. J. Radioanalyt. NucÃ-.Chem. Lett.. 119:
159-170, 1988.
16. Mease, R. C., DeJesus, O. T., Galley, S. J., Thompson. M., and Friedman.
A. R. Labeling of uracil, deoxyuridine and antipyrine with bromine-80ni.
Appi. Radiât.Isotop., in press, 1988.
17. Djordjevic, B., and Szybalski, W. Genetics of human cell lines. III. Incorpo
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18. Bradley, E. W., Chan, P. C., and Adelstein, S. J. The radiotoxicity of iodinc125 in mammalian cells. Radiât.Res., 64: 555-563, 1975.
19. Hofer, K. G., Harris, C. R., and Smith. J. M. Radiotoxicity of intracellular
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effect: biological consequences and implications for therapy. Pathobiology
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1981.
I., radiotoxicity
Sastry, K. S.ofR.,' 'IIand<IKin
Adelstein,
S. J. cells:
Kinetics
of uptake,
23. Kassis,
retention,A. and
mammalian
implications
of
with estrogen receptor-directed therapy, since ER+ cancers
contain from 500 to 20,000 free receptor molecules per cell.
Realistically, however, one must also deal with the fact that
there is heterogeneity in the expression of ER in hormonedependent cancers like breast cancer. Nonetheless, results from
immunohistochemical
assays for ER suggest that improved
prognosis is seen in breast cancer patients whose cancers con
tain at least 40% ER+ cells (24). This implies that even some
cancers with fewer than half of their cells expressing ER act
like hormone-responsive cancers. In this regard, it is becoming
more evident that estrogen may at least in part control growth
of cancer cells by autocrine or paracrine mechanisms (25), so
that ER+ cells, producing estrogen-dependent growth factors,
may regulate the growth of other cancer cells which could be
ER negative but depend on the growth factors produced by the
ER+ cells. Such a mechanism of growth control is likely to be
operating with current endocrine therapies as well. However,
while current endocrine therapies are basically cytostatic, recep
tor-directed therapy with Auger electron-emitting nuclides
should be cytotoxic if the effects are similar to those shown
here for the nuclide incorporated into DNA. Furthermore,
unlike cell cycle-dependent therapeutic agents, ER-directed
therapy should work equally well in all ER+ cells, even those
in Go since all that should be needed is for ER to bind the
nuclide-bearing estrogen and form an intimate association with
nuclear DNA.
An additional advantage to ER-directed therapy with Auger
electron-emitting estrogens is that those cells lacking substan
tial concentrations of nuclear ER, in which any estrogen taken
up would be expected to be largely cytoplasmic (such as liver in
which cytoplasmic enzymes metabolize estrogens), should not
be adversely affected. This was seen with bromine-80m as
sodium bromide and bromoantipyrine (Fig. 1) which were not
concentrated in the nucleus, and has been well-documented
previously (6, 18, 19) for a number of Auger-emitting nuclides.
Clearly the details of the route of administration, tumor uptake
and clearance, potential hazards of the ß
decay of the brominedaughter, etc. must be worked out prior to successful clinical
use. However, as shown by studies in our laboratory (12, 13,
26, 27) and elsewhere (28-32) there are a number of brominecontaining steroidal and nonsteroidal estrogens with good af
finity for the estrogen receptor, likely to be concentrated in
ER+ tissues and tumors, that can now be investigated for this
purpose. Demonstration of the radiotoxicity of bromine-80m
labeled estrogens in vivo awaits higher specific activities of
bromine-80m-labeled estrogens, but it now appears that this
attractive approach to the treatment of estrogen-receptor-posi
tive cancers in humans is feasible.
24.
25.
26.
27.
28.
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Downloaded from cancerres.aacrjournals.org on April 14, 2017. © 1988 American Association for Cancer Research.
Bromine-80m Radiotoxicity and the Potential for Estrogen
Receptor-directed Therapy with Auger Electrons
Eugene R. DeSombre, Paul V. Harper, Alun Hughes, et al.
Cancer Res 1988;48:5805-5809.
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