1. No category

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Frank H. DeLand
Veterans .4dminisiraiion Medical Center
Syracuse. New York
Effect of Tumor Size on Monoclonal Antibody Uptake
in Tumor Models
@r
FIGURE 2
Vertebral CT concurrent with Fig. 1C. Lytic lesion is seen
in T-i 2 (open arrow)
TO THE EDITOR: The recent paperby Haganet al. (J Nuci
Med. 27:422, 1986) draws attention to the effect oftumor size
on the extent of monoclonal antibody uptake in experimental
systems. Their data, with several different monoclonal anti
bodies, showed that the per gram radiopharmaceutical uptake
by tumor tended to be inversely proportional to tumor size.
They point out the discrepancy between those findings and
ours with a radioiodine-labeled antiosteogenic sarcoma mono
clonal antibody (79lT/36) in a murine-human tumor system
(I ). They are. however.mistaken in the interpretationof our
or decreased (2,7,8) activity on the bone scintigram. Imaging
a lytic lesion by scintigraphy mainly depends on the size of
the lytic area, the degree of reactive bone change (osteoblastic
activity). and its vascularity (2.5,7).
While bone scintigraphy is sensitive enough to depict early
skeletal metastasis. the subsequent manifestations of the scm
tigraphic patterns may persist as increased. or may develop to
decreased or normal uptake. depending on the regional vas
cularity and the balance between blastic and lytic activity in
the bone. To minimize false negative results during interpre
tation of a followup bone scintigraph. the interpreter should
always review the available radiographs, including CT. in
addition
to concurrent
comparison
with previous
skeletal
scintigams.
References
1. Siegel BH. Alazraki NP. McNeil
data with radioiodine-labeled antibody. The data. which has
more recently been published elsewhere in greater detail (2).
did not show any correlation
between tumor size and the
proportion ofthe injected dose of radioiodine/gram of tumor.
Such a correlation was in fact seen between tumor weight and
tumor levels ofradioiodine only when the latter was expressed
as a proportion of the radiolabel retained in the body. The
differences between the results of these two methods of analy
sis was attributed to marked variation in whole-body survival
ofradioiodine from monoclonal antibody (2). This may have
been due to individual differences in rate of catabolism and/
or dehalogenation in tumor-bearing mice, although there was
no correlation between tumor size and whole-body retention
of radiolabel (2).
Overall, however, our studies with radioiodine-Iabeled an
tibody did show, consistently, a statistically significant pro
portionalitybetweentumor sizeand the percent of the avail
BJ. et al: Skeletal system.
In Nuclear Medicine Review Syllabus, Kirchner PT, ed.
New York. The Society of Nuclear Medicine, 1980, pp
555—561
2. Sy WM. WestringDW. WeinbergerG: “Cold―
lesionson
boneimaging.
J Nuc/Med 16:1013—1016,
1975
able dose ofradiolabel(i.e.. that surviving in the whole animal)
which was present within tumors.
This problem of variation of whole-body survival of radio
iodine-labeled 79 1T/36 monoclonal antibody is not seen.
however, with indium-I 1I (‘
‘
‘In)
as the radiolabel (3) and in
view of the comments
3. Manier SM. Van Nostrand D: From “hot
spots―
to “super
of Hagan et al. ( I ), we have now
analyzed data from mice with osteosarcoma xenografts, and
scan.―
C/inNuc/M('d8:624—625.
1983
4. Donnelly B. Johnson PM: Detection ofhypertrophic
pul
which had received ‘
‘
‘In-labeled791T/36
monoclonal
anti
monary osteoarthropathy by skeletal imaging with Tc
body for correlation between tumor weight and uptake of
99m labeled diphosphonate.
I975
administered
Radiology
114:389—391,
5. Thrall JH. Chaed N. Geslien GE. et al: Pitfalls of Tc-99m
polyphosphate skeletal imaging. AJR I2 1:739—747,1974
6. Thrupkaew
WK. Jenkin RE. Quinn JL: False negative
bone scans in disseminated metastatic disease. Radiology
113:383—386.
1974
dose. Here mice had tumors between 0.2—0.7g
and were dissected 3 days after intraperitoneal injection of
I I ‘In-79 lT/36
prepared
as previously
described
(3).
The
mean
whole-bodysurvival of ‘
‘
‘In
at this time was 68% ±2.9%
(s.e.m. n = 16).
Pooled data from 16 individual mice injected with ‘
I‘In
791T/36 is shown in Fig. 1. Tumor levels of ‘
‘
‘Inexpressed
7. Goergen TG, Alazraki NP, Halpern SE, et al: “Cold―
bone lesions: A newly recognized phenomenon of bone as a percent of the injected dose were proportional to tumor
weight (r = 0.79, p < 0.001).
imaging.
J Nuc/Med 15:1
120—1
124.1974
Overall these data, with both iodine-labeled antibody, but
8. PendergrassHP, PotsaidMS. CastronovoFP: The clinical
use of Tc-99m diphosphonate. Radiologi' 107:557—562. where tumor levels are expressed in relation to “available―
radiolabel. and with ‘
‘
‘In
label, where tumor levels need only
I973
be expressed in relation to dose, demonstrate that in this
Wei-Jen Shih
particular model system tumor uptake ofradiolabel is propor
Marguerite Purcell
Peggy A. Domstad
VA and University of Keniucki'
Medical Center
Lexington. Kenticky
1 788
Letters to the Editor
tional to tumor
size. Why this differs from several other
systems is unclear. A multitude of parameters can potentially
affect the relationship between tumor size and antibody up
take. These include changes in blood flow, degree of necrosis,
The Journal of Nuclear Medicine
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man osteogenic sarcoma xenografts. Eur J Cancer C/in
22
20
Oncol20:515—524,
1984
3. Pimm MV, Perkins AC, Baldwin RW: Differences
.
18
16
@
14
C
@
M. V. Pimm
R. W. Baldwin
Cancer Research Campaign Laboratories
University of Nottingham
Nottingham, UK
.
12
10
S
‘I,
S
in
tumour and normal tissue concentrations of iodine- and
indium-labelled monoclonal antibody. Eur J Nucl Med
11:300—304,
1985
4. Hagan PL, Halpern SE, Chen A, et al: In vivo kinetics of
radiolabeled monoclonal anti-CEA antibodies in animal
models.
J NuclMed 26:1418—1423,
1985
S
S
6
Effect of Tumor Size on Monoclonal Antibody Uptake
in Tumor Models
4
2
TO THE EDITOR: The article “Tumor
Size: Effect on
Monoclonal Antibody Uptake in Tumor Models―by Hagan
1i@
20O
300
4(@
5c@
600
7th
8d0
TUMORWEIGHT (MILLIGRAMS)
FIGURE 1
Correlation between tumor weight and uptake of 111In
labeled monoclonal antibody. Sixteen individual nude mice
with xenografts of human osteogenic sarcoma 788T were
injected intraperitoneally with 111ln-labeled 79iT/36
anti
body (mean dose 10 @g)
and killedafter 3 days. r = 0.79;
p<0.OOi
and levels ofcellular and intratumor extravascular antigen as
tumor size increases. In addition, the presence of circulating
tumor-derived
antigen can influence tumor deposition
and
blood survival of antibody (4). In this latter context particu
larly one can envisage that with small doses of antibody a
sufficient amount may be neutralized in animals with larger
tumors to significantly reduce tumor uptake and therefore
destroy any correlation
between tumor
size and extent of
antibody deposition. It is possible in these circumstances that
if antibody dose was increased, a correlation would become
apparent. In the osteosarcoma system, circulating antigen has
not been detected ( 1) and this mechanism cannot operate;
this might explain why here a good correlation between tumor
size and antibody deposition can be seen. Moreover tumors
used in our studies were not I g, but with larger tumors this
relationship could well break down as tumors become ne
crotic.
ACKNOWLEDGMENT
This work was supported
paign, UK.
by the Cancer Research Cam
tumor size on the uptake of “tumor
specific―
antibodies, but
does not relate this to tumor imaging. Mann et al. (2) utilized
nude mice with two implanted tumors (melanoma and lung
carcinoma) and the simultaneous injection of differently Ia
beled monoclonal antibodies for each of these two tumors.
Iodine-l25 and iodine-l3l (‘@‘I)
were utilized and these labels
were reversed in half of the experiments. In vitro studies
demonstrated that these two monoclonal antibodies were
almost completely specific for their corresponding melanoma
or lung carcinoma. Total uptake in vivo increased linearly
with tumor size, but this appeared to be secondary to increased
nonspecific uptake with increased tumor size. The largest
tumor tended to be better visualized, even if the ‘31I-labeled
antibody was “specific―
for the smaller tumor. Both tumors
were often visualized and large tumors were also easily imaged
with a nonspecific, nonimmune lgG.
The use of percent administered dose per gram of tumor
(% admin dose/g) may be misleadingbecausethe uptake in
small tumors must be multiplied to normalize it for I g. This
approach tends to ignore biological changes that may occur
in tumors with increasing size, e.g., necrosis. This is probably
the reason that the highest % admin dose/g in the literature
are almost invariably reported to occur in small tumors that
then are scaled up to 1 g. Percent admin dose per mg or per
100 mg would probably be a more reliable measure of uptake
that could be used for comparisons in tumors of all size.
Hagan's comparison of nonspecific versus specific uptake
in animals bearing both a melanoma and a colon carcinoma
is distorted by the fact that the melanoma is three to four
times the size of the colon carcinoma and is “by
far the more
necrotic of the two.―Nonspecific uptake increases directly
with increased tumor size, but is decreased by necrosis (3).
Mann et al. (2) utilizednude mice that were inoculatedwith
References
I. Baldwin RW, Pimm MV: Antitumor
et al. (1) primarily addressesthe problems of the effect of
monoclonal
anti
bodies for radioimmunodetection of tumors and drug
targeting. (‘ancer
Metab Rev 2:89—106,1983
2. Pimm MV. Baldwin RW: Quantitative evaluation of the
localization of a monoclonal antibody (79lT/36) in hu
Volume27 •
Number 11 •
November1986
the slow growing melanoma 2—3
wk prior to inoculation with
the pulmonary carcinoma. This tends to result in mice with
two different, but similar sized tumors. Under these conditions
both nonspecific uptake and total tumor uptake increased
with increasing tumor size. We find that imaging studies
complement and tend to clarify the results of tissue counting
studies.
1789
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Effect of Tumor Size on Monoclonal Antibody Uptake in Tumor Models
M. V. Pimm and R. W. Baldwin
J Nucl Med. 1986;27:1788-1789.
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