Download Prevention of Hepatic Metastases by Intravenous Radioactive Gold`

[CANCER RESEARCH 38, 2740-2744, September 1978]
0008-5472/78/0038-0000$02.00
Prevention of Hepatic Metastases by Intravenous Radioactive Gold'
Antonio E. Aifonso,2 All Hassan, Bernard Gardner,3Sidney Stein, Joseph Path, Nathan A. Solomon,
Joseph McCarthy,and Joseph Steigman
Divisions of Surgical Oncology (A. E. A., A. H., B. G., S. S., J. P.1 and Nuclear Medicine (N. A. S., J. M., J. S.), State University of New York, Downstate
MedicalCenter,Brooklyn,New York11203
ABSTRACT
This investigationwas designed to determine whether
livertumorgrowthcan be preventedby localizedradioac
tivfty through radioactive
gold (198Au) infusion. Colloidal
198Auis phagocytosedby Kupifer cells and emits I@-and
a-radiation. Measurementof a-radiation showedmarked
198Auliver concentration. Liver chemistries, histology,
and isolated hepatocyte function studies that measure
[14C]acetateincorporationinto bile acid and cholesterol
formationafter doses from 200 to 3000 gtCiwere serially
determined.A 4OO-@zCi
dose (2944rads)providedsubstan
tial local radiation in the liver for 9 days withouttoxicity.
Three hundredtwenty-sevenmale 150-gSprague-Dawley
rats received either stable (“cold―)
colloidalgold, 198Au,
intraportallyor through a peripheral vein within 10 mm
following intraportal infusion of 10,000,000 Walker 256
sarcoma cells. In 66 other rats intraportal 198Auadminis
trationwas delayed for 2 weeks after tumorimplantation.
In rat livers that received ‘98Au
early following tumor
injection, significantly
fewer tumors were observed than
in controls(p < 109). When radiationwas delayed for 2
weeks after tumor infusion,the differenceswere not as
significant.
Intraportal or systemic 198Augiven within 10 mm follow
ing tumor infusion can protect an animal from hepatic
tumor growth without significant liver toxicity. That he
patic radiation may prevent tumor growth may have im
portant clinical implications.
INTRODUCTION
liver metastases that utilized adjuvant modalities of therapy
(1—3,17). Previous studies demonstrating that radioactive
colloids injected into either a splanchnic or peripheral vein
selectively concentrate in the liver (5, 13, 18, 21, 22) have
prompted our interest in utilizing prophylactic internal na
dionuclide therapy to prevent clinical liven metastases.
Considerable data have already been accumulated con
cerning the biochemical properties, tissue distribution, ef
fects, and metabolism of radioactive colloidal gold (198Au)
after systemic administration in both humans (16) and
experimental animal models (19). After i.v. administration
198Auremains insoluble in serum, does not cause capillary
microaggregation, becomes rapidly phagocytosed by retic
uloendothelial cells in the liver (Kupffer cells), and can
provide a selective temporary homogeneous field of hepatic
radioactivity without systemic radioactive isotope spillover.
Radioactive colloidal gold was also ideally suited for our
investigation since it emits both 1@-and a-radiation and
possesses a relatively short half-life. /3-Radiation from ‘98Au
has an ionizing tumonicidal range of 8 mm in tissue and
water, and its concomitant a emission permits measure
ment of the isotope distribution in other organs of the body.
Preliminary studies were performed to establish the mm
imum effective i.v. dose of ‘98Au
that would prevent liver
tumor “takes―
in rats after introduction of tumor cells into
the portal circulation, to determine tissue distribution of the
isotope following either splanchnic or peripheral vein injec
tion, and to observe for associated hepatic toxicity of the
proposed treatment regimen. The main experiment was
designed to evaluate the efficacy of internal hepatic radio
nuclide therapy with respect to reducing the incidence of
hepatic ‘
‘metastases―
after either splanchnic or systemic
injection of radioactive colloidal gold.
Successful treatment following an adequate wide-field
colon cancer resection has often been frustrated by the
subsequent occurrence of hepatic metastases (14). Unfor
tunately, once overt metastases become firmly established
MATERIALSAND METHODS
in the liver, current treatment modalities to date have
All experiments were performed on male Sprague-Dawley
yielded extremely poor overall results. The likelihood of the
rats weighing 200 g and kept under standard laboratory and
development of hepatic metastases reflected by the ad
diet conditions. Operations were performed under i.m.
vanced stage of the local tumor at the time of initial surgical
resection can be predicted in a majority of cases. Such sodium pentobarbital anesthesia, 0.05 mg/g body weight,
and with sterile techniques. Tumor cells were prepared
patients could be greatly benefitted if there were a practical
from homogenates of solid i.p. Walker 256 carcinoma
and effective method of preventing liver tumor “takes―
without the significant local and systemic side effects of implants. The homogenates were appropriately diluted with
sterile 0.9% NaCI solution, and separated cells were ob
external or internal hepatic radiation and systemic or infu
tamed
to provide a constant dose of 10,000,000 cells!
sional chemotherapy.
injection. Cells were counted in a hemocytometer, viability
Recent interest has focused on the prevention of clinical
was confirmed by trypan blue exclusion (>90%), and sub
sequent growths of aliquots were implanted s.c. Previous
results from our laboratory have consistently confirmed an
‘Supported
in
2 To
requests
whom
part
by
Alan
for
Foss
Memorial
reprints
should
Fund
be
Grant
addressed
Clarkson Avenue, Brooklyn, N. Y. 11203.
3 John
and
Mary
Markle
Scholar
in
Academic
Medicine.
ReceivedJanuary27, 1978;acceptedMay17,1978.
2740
1779.
at
Box
40,
450
80 to 85% liver tumor
‘
‘take―
after this dose of Walker 256
carcinoma was given through a portal vein. Radioactive
CANCER
RESEARCH
VOL. 38
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Prevention of Hepatic Metastasesby i.v. 198Au
colloidal gold obtained from Amensham/Seanle Corp. , Ar
“takes―“Au
‘Au
on liver tumor
Effect of increasTable
ing dosesof “1
lington Heights, Ill., with an average fairly uniform particle
size (20 to 40 nm), and calibrated to 25 mCi/mI was used.
for
tumor%Control
of ratsPositive
dose (MCi)No.
Colloidal ‘98Au
after it had been allowed to decay for at
least 60 days to negligible levels of radioactivity (“cold―
4
4
100
colloidal gold) was used for the control animals.
4
4
200
4
2
300
RESULTS
48
0100
4008
100
100
50
0
Minimal Effective Dose of ‘98Au.
Twenty-fourrats re
ceived either “cold―
colloidal gold (8) on 100 (4), 200 (4),
300 (4), or 400 (4)
tributary
@Ciof ‘“Au
through
a mesentenic
5 to 15 mm after intraportal
10,000,000
Walker
256
carcinoma
cells.
vein
introduction
All
animals
of
were
sacrificed at 28 days and examined for liver tumor growths.
As shown
in Table
1 , there was complete
Walker
256
‘U
U)
Cl)
I.
‘a-
0
sarcoma tumor hepatic growth inhibition at 28 days follow
4
ing a 4OO-@Cidose of ‘98Au.
Dosages of 100 and 200 @.tCi CD
were completely ineffective, while the 300-MCi dose pre
‘U
0.
vented liven tumor growth in only 2 of 4 rats. In the 8 control
‘U
Ianimals that received “cold―
gold colloid, a 100% liver
z
tumor “take―
was observed.
Isotope Tissue Distribution. Thirty-six rats were divided
a.
into equal groups. In 18 rats 400 @Ci
of 198Auwere injected
U)
aintraportally through a mesentenic vein tributary. The re
z
mainder had a similar dose administered systemically
0
U
through the femoral vein. Pained rats from each group were
sacrificed at 4 h and 1, 2, 3, 5, 6, 7, 10, and 15 days. The
‘@ota 2 3 4 5 6 7 8 9 lOll
2
following organs were dissected out, weighed, and pre
pared for counting: liver, spleen, lung, brain, and gastroin
Chart 1. Distribution of ‘@Au
in different organs after portal
vein) injection.
testinal tract. A sample of muscle and bone with marrow
‘U
4HR
3
45
DAYS
(mesenteric
was also taken. The specimenswere immediatelyplaced
in appropriately shielded a-scintillation counters, and mdi
vidual radioactivity in terms of cpm/g weight of tissue was
determined. These data obtained on tissue distribution of
‘15Au
as measured by the decay of a emissions at sequential
time intervals from 4 h to 14 days are presented in Charts 1
and 2. Confirming previous work by others with radioactive
colloidal gold particles, the liven and spleen preferentially
concentrated the gold particles after introduction through
either an intraportal or systemic route. Other phagocytic
tissues, like lung, bone, and marrow, were significantly less
active in the removal of gold particles from the blood.
Muscle, brain, and intestines did not significantly concen
trate the isotope. Interestingly, transient higher concentra
tion of intestinal 198Au followed intraportal injection as
compared with systemic administration.
Toxicity. Following intraportal 1Au administration in
increasing dose increments (400, 1200, and 2000 MCi),
serum levels of bilirubin, alkaline phosphatase, SGOT,4 and
SGPT were determined and liver histological examinations
were performed in 18 rats that were sequentially sacrificed
at 7 and 21 days. Ten other rats consisting of pairs that
received 400, 1200, 2000, 3000, and 6000 @Ci“Auwere
observed clinically for 6 months and then autopsied. All
livers were examined microscopically for morphological
alterations. Bile acid secretion from isolated hepatocytes
4 The
abbreviations
used
are:
SGOT,
serum
glutamic-oxaloacetic
aminase; SGPT, serum glutamic-pyruvic transaminase.
SEPTEMBER
1978
trans
‘U
U)
U)
aIa.
0
4
CD
‘U
a.
‘U
az
‘U
a.
U)
az
0
U
01
4CC
a
2
3
4
5
6
7
8
9
0
II
2
3
4
DAYS
Chart 2. Distribution of “Auin different organs after systemic (femoral
vein) injection.
with culture techniques previously described in our labora
tory (4), after 2 h of incubation with [‘@C]acetate,
was
measured in 2 rat livers that were exposed to 400 pCi of
internal hepatic radiation 1 week before and compared with
pained normal rat livers. No significant alterations in serum
levels of bilirubin, alkaline phosphatase, SGOT, and SGPT
were found at 7 and 21 days after hepatic radiation dosages
2741
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A. E. Alfonso et al.
Table 2
Liver function
studies obtained
Intraportal
‘“Au
dose
at 7 and 21 days after intraportal
injections
of increasing
doses of
of
ratsBilirubinAlkaline
phosphataseSGOTSGPTControl
(MCi)DayNo.
±0.2@
4007
3
0.2
±0.1
±76
196.6 ±40.4
±161
147.3±99.8
±18
57.3 ± 2.5
199.7±86.852
55.7±
812007
218
30.4 0.13±0.06231
203
13.620007
213
±0.057
30.13 0.2 ±0180
±58
±45.6
190 ±26303 303 ±75109
213
±44
±20.5
30.17±0.057
0.17±0.057129 160 ±10152 196.7±2577.7±36.8
69
±35a
±25237
±10
104.7 ±
Mean ±S.D.
@
of 400, 1200, and 2000 @Ci
(Table 2). None of the animals
observed for 6 months developed any clinical signs of
cirrhosis. At autopsy gross liver nodulanity, hypenemia, and
hepatomegaly were observed in both rats that received
6000 MCi. These were accompanied by distortion of lobular
pattern, hepatic cell ballooning, and necrosis on histologi
cal examination. Similar microscopic alterations were also
observed at 6 months in rats that received 3000 @tCi.None
of the livers of animals that received dosages of 2000 pCi or
less showed either gross or histological alterations at 6
months. The average total bile acid secretion rates in mol/g
liver cells from isolated hepatocyte cultures from 2 rat livers
exposed to 400 @tCiat 2 hr (18.71 ) were comparable to a
pair that received “cold―
colloidal gold and to values
derived from normal rat hepatocytes (19.15).
Table 3
Effect of “Au
colloid on prevention of liver metastasesafter
intraportal andadministrationPortal
systemic
vein
Systemic
Tumor
Tumor
“take―Control Total
“take―
Total
28(93)d‘“Au149
123(5,3)a.b.c
30
2(8)―Delayed
‘Au
a
19(15)―
66
34 (54)C
25
<
b Numbers
C p
123
<
in parentheses,
percentages.
10-..
d ,@<
Efficacyof ‘98Au.
For establishmentof the effectiveness
of 198Au-induced hepatic local radioactivity in preventing
experimental liver tumor “takes,―
393 rats were divided into
179 control and 214 experimental animals. All animals
received tumor injections of 10,000,000 Walker carcinoma
cells introduced into a mesentenic vein portal tributary. All
experimentally treated animals received 400 @tCiof 198Au.
Five to 10 mm after tumor administration, a comparable
volume of “cold―
colloidal gold was injected either through
a separate mesentenic vein (149 rats) or the femoral vein (30
rats). After a similar time interval, experimental rats re
ceived ‘“Au
colloid through either a mesentenic vein (123
rats)
ora femoralvein(25rats)
injection.
In66 ratsthe198Au
mesentenic vein injection was delayed for 2 weeks following
tumor introduction. All animals either died of tumor after 2
weeks or were sacrificed at 28 days. At autopsy all livers
were examined grossly and microscopically for tumor
growths. A summary of our results is recorded in Table 3. In
149 control rats that received “cold―
colloidal gold through
a mesentenic vein 5 mm after tumor injection, 83% devel
oped bilateral massive liven tumors within 28 days. This
significantly decreased to 15% or 19 of 123 animals in the
treatment group that received intraportal 198Au5 mm after
tumor administration. In the 30 control animals that re
ceived “cold―
colloidal gold through a systemic (femoral
vein) injection 5 mm after tumor injection, there was a 93%
liver tumor “take―
as compared to 8% in the systemically
treated group of rats that received 198Auvia a peripheral
vein 5 mm after the tumor cells. When 198Auadministration
via the portal route was delayed by 2 weeks after tumor
2742
infusion, the tumor “take―
was 54% as compared to 83% in
the comparable control group.
DISCUSSION
Previous experimental and limited clinical experiences
with the use of fJ-emitting 90Y tagged to ceramic micro
spheres have demonstrated that localized interstitial he
patic radiation can be successfully produced with minimal
systemic spillover and result in effective growth prevention
of virulent tumors without significant systemic or liver
toxicity (6, 7, 10, 12). Localization of organ radioactivity,
however, relies on the trapping of microspheres in the size
of 50 to 100 within the pnecapillary vessels by a process of
microembolism and requires operative placement of a he
patic artery catheter.
Other radioactive colloidal compounds that are known to
be selectively concentrated by the reticuloendothelial cells
of the liver after i.v. administration have been studied.
Grady et a!. (5) and Ackerman et al. (1) have separately
reported on encouraging results with the use of radiocolloid
suspensions of 32P-tagged chnomic phosphate in prevent
ing liver “takes―
of Walker 256 carcinoma and the Novikoff
hepatoma injected into the rat portal vein to simulate liver
metastases. A disadvantage of the use of Cr32PO4has been
its reported high bone marrow uptake after systemic i.v.
injection. A radiocolloid suspension of ‘“Au
was chosen as
the particulate matter for our present study. The isotope
was currently available, it is easy to measure quantitatively,
CANCER RESEARCHVOL. 38
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@
Prevention of Hepatic Metastases by i.v. 98AU
and much has been known about its chemical preparation
to small particles of approximately known size (22). A
uniform small particle size (20 to 40 nm) is essential to
avoid capillary aggregation and blockage and to allow
effective reticuloendothelial phagocytosis. Unlike chromic
[32Plphosphate, cumbersome mixing procedures are not
necessary for its preparation. Radioactive gold has a half
life of 2.73 days, emits negative /3 particles with an average
energy of 0.315 MeV, and an a-ray with an energy of 0.411
MeV. Its tissue distribution and radiation effects have been
extensively studied in rats, dogs, guinea pigs, and humans.
The greatest part of its i .v. administered dose (80 to 90%) is
concentrated by the liver. Only 5 to 15% is taken up by the
spleen, which is relatively radionesistant, and very small
quantities reach other tissues of the body. The compound
is cleared from the blood within minutes inasmuch as most
of the gold given becomes firmly lodged within Kupffer cells
and distribution is in a fairly homogeneous pattern through
out the liver parenchyma (16, 18, 19, 21). The administration
of ‘98Au
in larger i.v. doses has not been associated with
untoward effects in humans (16). There is also virtually no
problem of bone marrow depression following injection of
the material. No immediate or long-term hepatic damage
has been described following radiation of the organ with
2500 R. After massive experimental doses in rats, liver
necrosis had occurred but the doses were considerably
higher (50 times) than were those used in our present study.
The smallest amount of 198Aureported in the literature that
has caused liver damage is 12,000 equivalent R, this sug
gests that the threshold for necroses in rat livers is between
to 19 and 8% after mesentenic or femoral vein ‘98Au
treat
ment, respectively, is significant (p < 10@). These results
have paralleled other studies with respect to optimal time
of isotope administration, which was within 48 hr after
tumor injection (1, 5). Treatment results were poorer when
198Auadministration was delayed for 2 weeks but signifi
cantly different from control values. This observation is
correlated with the fact that clinically obvious liver tumor
growths were usually established after this time interval (2
weeks) in our experimental rat livers. Root (16) has similarly
achieved poor therapeutic results in the treatment of estab
lished
liver tumors
after
i.v. administered
colloidal
radi
ogold. In the areas of discrete “takes―
where reticuloendo
thelial tissues have been replaced, the radionuclide is not
concentrated in the hepatic tissue immediately adjacent to
the tumor nodules. This is in striking contrast to the very
high levels of radioactivity in the remaining grossly normal
liver panenchyma.
While showers of viable malignant cells have been iso
lated from the portal venous effluent area of the primary
tumor after surgical manipulations, the cause of liver me
tastases may be in the presence of already disseminated
occult tumor microfoci at the time of initial resection.
Current knowledge of tumor population growth kinetics
suggests that micrometastases are rendered cytotoxically
more sensitive after removal of all gross disease as the
fraction of remaining actively dividing viable tumor cells
increases in an inverse relationship to total tumor popula
tion size (17). It is therefore logical to treat the disease in its
earlier stages rather than wait until a point at which, to
25,000 and 12,000 A (11).Four hundred @Ciof 198Aucolloid date, only palliative results may be expected at best. Unfor
with t112physical assumed equal to t112effective were calcu
tunately, external irradiation and infusion or systemic
lated to deliver 2944 rads to the liver (2840 from f3-radiation, chemotherapy leave much to be desired in an adjuvent
104 from a-radiation) and in our study appeared to be the setting because of inherent accompanying systemic and
minimal effective dose in preventing liven “metastases.―
local toxicity.
The human threshold for hepatic damage that is secondary
It is apparent that this radionuclide
offers a means of
to total fractionated hepatic radiation is approximately 3000 achieving localized radiation distribution to the liver follow
rads (9, 20), although dramatic recovery of liver morphology
ing i.v. administration with minimal systemic and local
and function has been noted in humans who have received untoward effects. The chief therapeutic use reported for
198Auhas been in the treatment of leukemia and lymphoma
3000 to 5900 rads after fractionated hepatic radiotherapy
(15). Dosage increments of 198Aucolloid from 400 to 2000 (16). While therapeutic possibilities of i.v. administered
@.tCi
did not cause significant changes in several parameters radiogold colloid in the treatment of established hepatic
of nat liver function that were monitored at 7 and 21 days: metastases has appeared exceedingly limited, the unique
serum bilinubin, alkaline phosphatase, SGOT and SGPT. characteristics of colloidal radionuclides and their prefer
Bile acid secretion rates in the isolated hepatocyte after ential concentration in the reticuloendothelial tissues of the
exposure to 400 @tCiwere unaltered . Morphological liver liver suggest that they may prove advantageous in the
damage was produced only at significantly higher doses treatment of disseminated micnometastatic hepatic tumor
(3000 MCi) at 6 months. The nadiocolloid tissue distribution
foci.
also remained similarto previously described patterns (16,
18, 19).
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CANCER RESEARCH VOL. 38
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Prevention of Hepatic Metastases by Intravenous Radioactive
Gold
Antonio E. Alfonso, Ali Hassan, Bernard Gardner, et al.
Cancer Res 1978;38:2740-2744.
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