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Advances in Brief |
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 [S. V. K., Y. B., R. K. J., H. D. S.], and Department of Immunology, ImClone Systems, Incorporated, New York, New York 10014 [D. J. H., P. B.].
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionConclusionREFERENCES |
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In most tumors, VEGF is the main secreted molecule that signals via VEGFR2 on the membrane of endothelial cells and leads to a whole spectrum of vascular responses (10, 11, 12) . Various strategies to disrupt the VEGF/VEGFR2 signaling pathway have demonstrated a significant inhibition of tumor angiogenesis and growth via mechanisms that include a decrease in vascular density and killing of both endothelial and parenchymal cells in tumors, mainly by apoptosis (e.g., Refs. 8 , 10 , 13, 14, 15 ). In particular, DC101 has been effective against several murine and human tumors grafted into mice, alone (10 , 14) or combined with chemotherapy (7) . However, DC101 has not been used in combination with radiation. Here DC101 and fractionated radiation were administered to two human tumor xenografts growing in the legs of nude mice. These two tumors were the moderately radiosensitive small cell lung carcinoma 54A, and the highly radioresistant glioblastoma multiforme U87. Both tumor and normal tissue responses were evaluated. Because of the dependence of radiation sensitivity on pO2 and previous work with TNP-470 (3) , we evaluated changes in tumor oxygenation after DC101 administration. We also investigated any potential interaction between DC101 and WBI of mice.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionConclusionREFERENCES |
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3–4 weeks later when individual tumors
reached a mean diameter of 8 mm (day 0).
Treatment of Tumors by Fractionated Radiation and DC101.
Starting on day 0, DC101 was given i.p. every 3 days, as determined
previously (10)
, for a total of six injections; the
dose/injection was 20 or 40 mg/kg. Irradiation of tumors commenced on
day 0 for radiation-alone groups or the day after the first DC101
injection for combined-treatment groups, and continued on a daily
basis. Five equal fractions (graded from 5 to 24 Gy each) were given at
a dose rate of 5.4 Gy/min, using a specially designed
137Cs irradiator (17)
. During
irradiation, mice were immobilized on a brass plate such that the tumor
was held in the center of a 3-cm diameter radiation field. In combined
treatment on day 3, radiation was given immediately prior to DC101
injection.
Evaluation of Tumor Response to Therapy.
Tumor size was measured with a caliper three times a week. The time
taken for a tumor to triple its initial volume (from 260 to 780
mm3
) was determined. The difference between mean
values of this parameter for individual tumors in treatment and control
groups was defined as the tumor growth delay achieved as a result of
therapy. The mice were sacrificed when a tumor reached 12 mm in
diameter. The TCD50 was evaluated for radiation
alone or in combination with DC101. The mice with locally controlled
tumors were followed for 90 days after the last tumor recurrence
observed in any group. The TCD50 values were
calculated by regression analysis on a log-dose grid, correcting for
censored animals (18)
.
Evaluation of Skin Response.
Acute skin reaction in the field of tumor irradiation was evaluated
using a slightly modified standard scoring scale (19)
. A
skin reaction score of 0.5–1 corresponded to minor dry abnormalities
(reddening, white scales), and 1.5–3.5 corresponded to increasing
severity/areas of moist desquamation. The normal tissue response was
evaluated in parallel with tumor size measurements during the first 30
days after the beginning of radiotherapy (with or without DC101), and
the maximum scores of individual mice of a group were then averaged.
Because adjacent irradiated tumors complicated the scoring of skin
reaction, especially minor ones at lower radiation doses, the same
treatments were also performed in non-WBI mice not bearing any
transplanted tumors. In this case, using the same scoring scale, we
evaluated the reactions every 1–2 days over 9–30 days after the start
of leg irradiation. Average skin reaction over this period of time was
calculated and plotted as a function of radiation dose.
Single-Dose Irradiation under Different Tumor pO2.
To examine for possible interactions between radiation and
DC101-induced effects in tumors, including antibody-induced changes in
tumor oxygenation, an additional study was performed with 54A
xenografts (in WBI mice). We compared their response to single-dose
irradiation performed under normal blood flow and respiration
versus clamp hypoxia tumor conditions. In the latter case,
the animals were anesthetized with ketamine/xylazine (100/10 mg/kg,
i.m.), and a heavy clamp was placed across the thigh above the tumor
beginning 2 min prior to and continuing during irradiation. A single
injection of DC101 was administered 2 days before or immediately after
irradiation under normoxic or hypoxic conditions.
Polarographic Measurements of Tumor pO2.
pO2 in U87 tumors was measured with the
Eppendorf-pO2 Histograph (model no. 6650;
Eppendorf, Hamburg, Germany; Ref. 20
) in anesthetized mice
(ketamine/xylazine, as above). The pO2 probe was
inserted into the tumor to a depth of 1–1.5 mm through a puncture of
the skin made by a 23-gauge needle. An electrocardiogram patch was
attached to the abdominal wall as a reference electrode. The
measurements were performed in four different regions of the tumor; 11
readings were taken per track in 0.4-mm steps.
Western Blot Analysis of Flk-1 Expression in Tumors.
Untreated U87 and 54A tumors, four of each type, were solubilized in
500 µl of TNT lysis buffer [50 mM Tris-HCl (pH 7.4), 150
mM NaCl, 1% Triton]. Tumor lysates were clarified by
centrifugation at 14,000 x g for 10 min and
incubated overnight at 4°C with DC101. Immune complexes were
precipitated with protein G-Sepharose beads (Pharmacia-Amersham,
Piscataway, NJ) and separated on 12% SDS-PAGE gels (Novex, Carlsbad,
CA). Proteins were transferred onto polyvinylidene difluoride membranes
and probed with anti-Flk-1 polyclonal antibody (Santa Cruz
Biotechnology, Inc., Santa Cruz, CA). Membranes were incubated with
antirabbit IgG-horseradish peroxidase (BioSource, Camarillo, CA) and
developed by an enhanced chemiluminescence detection system (ECL;
Pharmacia-Amersham).
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionConclusionREFERENCES |
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. This effect was tumor dependent. For the high dose of DC101 (40 mg/kg
per injection), tumor growth delays were 17.7 ± 1.9 and
7.7 ± 1.0 days (mean ± SE) for 54A and
U87, respectively. Because the tumor volume doubling time in control
groups was 1.3 times greater in U87 than in 54A xenografts, the
difference in specific (normalized to the doubling times) growth delays
for these tumors was 3-fold. It should be mentioned that the U87 used
here was one of the least susceptible to DC101 treatment among several
tumor types that have been studied to date (7
, 10
, 14)
.
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Fig. 1, C and D
, shows the tumor growth delay for
DC101 combined with relatively small doses of fractionated radiation
(five equal daily fractions, of 5–6 Gy each, on days 1–5). Similar to
antibody alone, 54A xenografts responded better than U87 to both
radiation and the combined therapy. In both tumor models, the combined
effect of radiation and DC101 in terms of growth delay was not
significantly different from additive.
It should be noted that the dynamics of tumor volume response after
irradiation, with or without DC101, differed considerably between the
two xenografts (Fig. 2, A and B)
. U87 tumors rarely shrank below the
initial size (at the beginning of treatment), and then only after
1.5–2 months. In contrast, the response of 54A was much faster, and in
the case of combined treatment, the median tumor volume decreased below
the initial level on day 5, was 3-fold lower on day 15, and then
usually continued to decrease.
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, demonstrates the
increasing number of locally controlled tumors of both lines with dose
of radiation combined with the high dose of DC101. Radiation alone in
the same dose range did not however control any tumor. Also for U87
tumors, tumor size measurements during the first month were not
predictive of individual long-term response in the combined-therapy
group with 70 Gy.
The local control rates for 54A and U87 xenografts as a function of
dose of radiation are shown in Fig. 2, C and D
.
The tumor models differed considerably in their radiation response. For
both tumor lines, DC101 substantially shifted the dose-response curves
to the left, i.e., in the direction of lower radiation dose.
These shifts were not statistically significant for the antibody at a
dose/injection of 20 mg/kg but became significant at 40 mg/kg
(P < 0.05 compared with radiation alone).
DC101-induced reduction of TCD50 values was
always equal to or slightly greater than the corresponding difference
in radiation doses that caused identical tumor growth delays with and
without DC101 administration (Fig. 1, C and D)
.
To our knowledge, this is the first demonstration of a decrease in TCD50 by an antiangiogenic agent. In contrast, the only other long-term study with the antiangiogenic agent TNP-470 showed radioprotection of tumors (an increase of the TCD50 values; Ref. 3 ). Those data were consistent with decreasing tumor oxygenation during treatment with TNP-470. Whether DC101 modified oxygen levels in our tumors was evaluated in the following experiments.
DC101 Did Not Modify Tumor Radiosensitivity and Oxygenation.
To reveal possible interactions between radiation and DC101, in
particular to assess DC101-induced changes in tumor
pO2, additional studies were performed based on a
standard radiobiological "paired-curve" analysis (21
, 22)
. 54A tumors received a single irradiation at different doses
under normoxic or clamp hypoxia conditions. Tumor growth delays after
the following six treatments were compared: radiation alone (group I);
radiation 1–2 min before (group II) or 2 days after (group III) a
single DC101 injection (40 mg/kg); and the same three regimens
but with clamp hypoxia (groups IV–VI) of tumors during irradiation.
The results obtained are presented in Fig. 3
and suggest two conclusions. First, regardless of tumor oxygen status
during irradiation, DC101 did not significantly change the shape of the
dose-response curves, rather it only shifted them up. Furthermore, no
effect of sequencing of agents on tumor growth delay was observed
(DC101 prior to versus after radiation). Hence, the combined
effect of single-dose radiation and DC101 was additive and not
associated with a detectable DC101-induced radiosensitization of
tumors. The latter is not consistent with the substantial role of VEGF
signaling in radioresistance of endothelial cells in
vivo, as would be expected on the basis of in vitro
experiments (5)
. It may be that DC101-induced
sensitization of the endothelial cells was not large enough to be of
considerable therapeutic importance.
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, clamp hypoxia equally displaced all three
dose-response curves for radiation, without or with DC101, horizontally
to the right. This suggests that the antibody did not significantly
modify the fraction of radiobiologically hypoxic tumor cells 2 days
after a single injection. Because of the lesser effect of DC101 on U87, a similar experiment with this tumor model would have had a smaller resolution and therefore was not performed. However, polarographic measurements using the Eppendorf technique showed no significant effect of the antibody on oxygenation of this tumor model. Two days after DC101 injection (40 mg/kg), the median pO2 value did not differ significantly from that in the control group (4.0 ± 0.3 versus 4.3 ± 0.4 mm Hg, respectively, mean of medians ± SE from 15 mice in each group).
These results for tumor pO2, together with the data on TCD50, are very encouraging because they show no significant decrease of tumor oxygenation by 1–2 doses of DC101, despite the antivascular effect of the antibody (7 , 10 , 14) . The comparison of our findings with those using TNP-470 (3) suggests that different antiangiogenic agents may have different effects on tumor oxygenation. Thus, inhibitors of the VEGF pathway that either block VEGFR2 (as described in this study) or neutralize VEGF (8) may be preferable to angiogenesis inhibitors such as TNP-470 in this respect. However, the changes in oxygenation may also depend on tumor type (8 , 14) as well as duration and dose fractionation of both antiangiogenic and radiation treatments. Tumor cell apoptosis by DC101 (7 , 12) could also contribute to the improved tumor response resulting from combined DC101 and radiation. Further studies on oxygenation and apoptosis in various tumors during combined treatments with different antiangiogenic agents and radiation are now needed to optimize this approach.
Anti-VEGFR2 Therapy Did Not Modify Radiation Response of Skin.
Acute moist skin desquamation in the field of tumor irradiation was
always observed after fractionated doses 
60 Gy. Typically starting
11–14 days after the beginning of irradiation, the reaction peaked
several days later and then gradually decreased. Importantly, and in
contrast to tumor response, DC101 did not significantly change the
radiation-induced skin damage (Fig. 4A)
. In an experiment on non-WBI mice without tumors, complete
radiation dose-response curves were obtained for such treatments (Fig. 4B)
. Here there also was no effect of DC101 on the acute
skin reaction to radiation.
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Animal Weight Changes.
Importantly, the treatments only minimally affected the weight of the
animals. Weight temporally decreased under the influence of both
fractionated radiation and DC101, typically toward the end of treatment
or shortly thereafter. The antibody and radiation alone decreased body
weight by 2–4% and 6%, respectively, and their combined effect on
weight loss was approximately additive (8–10%).
Tumor- and Dose-dependent Intestinal Toxicity.
Unexpectedly, a tumor type-dependent toxicity at the high dose of DC101
(without or with fractionated radiation) was observed in mice bearing
54A xenografts: 44% of the 80 animals developed ascites, with the
maximum response occurring typically 15–25 days after the last DC101
injection at a dose of 40 mg/kg. In Fig. 2A
, such mice are
identified by stars. Twenty-four percent of mice recovered,
whereas the remaining 20% eventually died. At necropsy, 5 ml or more
of clear ascites fluid were aspirated from the abdominal cavity.
Portions of the colon and small intestine of affected animals were
2–3-fold larger in diameter than normal. Histological analysis of the
colon and small intestine demonstrated an enlargement of the lamina
propria and submucosa, most likely because of accumulation of edema
fluid. Modifications to tissue structures were more striking in the
wall of the colon, with large separations between the mucosa and
external muscularis and large folds in the mucosa that projected into
the lumen (Fig. 4C)
. The mucosa was atrophic with obvious
stretching of the columnar epithelium. In animals that recovered from
the ascites, the colon wall had an almost normal appearance but the
separation between the mucosa and external muscularis could still be
observed in discrete areas. In contrast, no apparent toxicity was
observed in the same experiments at the low dose (20 mg/kg per
injection) of DC101. In addition, only 4% of 47 mice bearing U87
tumors and treated with the high dose of antibody developed ascites
(which was eventually resorbed), and no such effect was observed in 20
non-WBI mice without tumors in the skin-reaction experiment. Under
comparable experimental conditions, DC101 did not induce delayed
toxicity in SCID mice with a grafted neuroblastoma (7)
.
Role of WBI in DC101-induced Toxicity.
To examine whether this adverse effect of the high dose of DC101 in
mice bearing the 54A tumor was a result of their WBI at a dose of 5 Gy
1 day before tumor transplantation, we performed the following
experiment. Three groups of nude mice were compared: WBI (5 Gy) animals
with (group I) or without (group II) implanted 54A tumors, and non-WBI
mice grafted with the same tumor (group III). WBI did not
influence the time necessary for tumors to grow to 8 mm in diameter
(when treatment was started). The animals were subjected to the
standard fractionated treatment with DC101 (40 mg/kg x six injections) combined with radiation (5 Gy x five
fractions); in group II, DC101 alone was also used. Results for group I
were consistent with our previous findings: 5 of 10 mice developed
ascites. Virtually the same effect was observed in group II: 9 of 20
mice had ascites. However, none of 11 animals in group III showed such
adverse effect.
Collectively, the results obtained suggest that the whole-body irradiation of mice at dose of 5 Gy almost 1 month before DC101 treatment was responsible for the observed complications in experiments with 54A tumor. The mechanisms of interaction between DC101 and radiation-induced changes in the intestine remain to be elucidated. In addition, the reasons that DC101 interfered with radiation damage in this normal tissue but not in skin need to be determined.
No less puzzling is why the presence of U87 tumors, in contrast to 54A,
alleviated the combined intestinal toxicity of DC101 and WBI. We
speculate that U87 tumors were a significantly more capacious
"sink," eliminating DC101 from the mouse body, than 54A. Two facts
seem to support this idea. First, as shown by our Western blot
analysis, Flk-1 expression was on average at least 3–5-fold higher in
U87 than in 54A untreated tumors (data not shown). Second, the dynamics
of tumor size changes under the influence of DC101 (with or without
radiation) were very different between these two xenografts. The volume
of U87 tumors was larger than the initial volume for the entire DC101
treatment period as well as subsequently (Fig. 2B)
. In
contrast, 54A tumors shrank very fast under the influence of combined
treatment (Fig. 2A)
, thus likely gradually decreasing the
amount of DC101 extraction from the organism. When DC101 was used
without local irradiation, the development of ascites was observed only
among those mice in which 54A tumors responded well to the antibody.
Additional experiments on plasma pharmacokinetics and tissue
distribution of DC101 in WBI and non-WBI animals are needed to test
this hypothesis.
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Conclusion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionConclusionREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by National Cancer Institute
Grants R35-CA-56591 (to R. K. J.) and R37-CA-13111 (to H. D. S.).
S. V. K. is a recipient of National Cancer Institute Training Grant
T32-CA-73479. 
2 To whom requests for reprints should be
addressed, at Department of Radiation Oncology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA 02114.
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; pO2, partial pressure of oxygen;
VEGFR2, VEGF receptor-2; WBI, whole-body irradiation (irradiated);
TCD50, dose of radiation necessary to control 50% of
tumors locally; Flk-1, fetal liver kinase 1 (the specific name of
murine VEGFR2).
Received 7/21/00. Accepted 11/ 9/00.
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) mice and in mice treated with DC101 (• and 
;
arrows indicate the time of DC101 injections).
Data points and bars represent the
mean ± SE from 6–12 tumors per group. C
and D, dependence of tumor growth delay on the total
dose of tumor irradiation given on 5 consecutive days [days 0–4 for
radiotherapy (RT; 
) and
DC-2d-R/H (
)] or immediately after [R-0d-DC (
) and R/H-0d-DC
(