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Advances in Brief |
Department of Human Oncology, University of Wisconsin School of Medicine and Comprehensive Cancer Center, Madison, Wisconsin 53792-0600
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Although C225 augmentation of antitumor activity for several chemotherapeutic agents in mouse xenograft models has been demonstrated (7, 8, 9) , in vivo characterization of C225/radiation interactions have not been well established. Several preliminary findings regarding the capacity of C225 to inhibit cellular proliferation (10) , to inhibit DNA damage repair (11) , and to inhibit tumor angiogenesis (12) suggest mechanisms whereby EGFR blockade might enhance antitumor responses. The experimental studies presented herein were conducted to examine the in vivo response of SCC xenografts in athymic mice to dual treatment with radiation and C225, and to explore various mechanisms of C225-mediated enhancement of radiosensitivity.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-tubulin antibody
was obtained from Oncogene Research Products (Cambridge, MA). The
enhanced chemiluminescence detection system was purchased from Amersham
(Arlington Heights, IL). All other chemicals were purchased from Sigma
(St. Louis, MO). C225 was generously provided by ImClone Systems
incorporated (New York, NY).
Cell Lines and Cell Culture.
Human SCC cell lines were established from biopsies of H&N cancer
patients. The SCC-13Y cell line was derived from the facial epidermis
and was provided by Dr. B. Lynn Allen-Hoffman (University of
Wisconsin). The SCC-1 cell line (floor of mouth) and SCC-6 cell line
(tongue) were provided by Dr. Thomas E. Carey (University of Michigan).
The relative expression of EGFR on the cell surface of our SCC cell
lines was evaluated via immunofluorescent staining with C225 and
subsequent flow cytometry analysis. These SCC cell lines expressed EGFR
at essentially comparable levels to those expressed in A431 cells,
which are well known to overexpress the EGFR with several million
receptors per cell. SCC cells were cultured routinely in DMEM
supplemented with 10% Fetal Clone-II serum (Hyclone, Logan, UT), 1
µg/ml hydrocortisone, 1% penicillin, and streptomycin.
Assay of Tumor Growth in Athymic Nude Mice.
Athymic Sprague Dawley nude mice (3–4-week-old females) were obtained
from Harlan Bioproducts for Science (Indianapolis, IN) and maintained
in a laminar air-flow cabinet under aseptic conditions. The care and
treatment of experimental animals were in accordance with institutional
guidelines. Human SCC cells (
1 x 106)
were injected s.c. into the right (SCC-6) and left (SCC-1) flank area
of the mice at day 0. Tumor volume was determined by direct measurement
with calipers and calculated by the formula: 
/6 x (large
diameter) x (small diameter)2. Animal
experiments included four treatment groups: control, radiation alone,
C225 alone, and radiation in combination with C225. Control animals
received injections of PBS. Radiation treatment was delivered via a
precision electron beam from a Varian linear accelerator using
custom-designed mouse jigs. These jigs immobilized the animals and
specifically exposed the dorsal flank (harboring tumor xenografts) for
irradiation without exposing non-tumor-bearing normal tissues. C225 was
administered by i.p. injection at the specified doses and intervals.
Immunohistochemical Determination of PCNA, VEGF, and FVIII.
The expression of proliferative and angiogenic factors were detected in
histological sections of SCC xenografts. Briefly, excised tumor
specimens were fixed in 10% neutral-buffered formalin. After embedding
in paraffin, 5-µm sections were cut, and tissue sections were
mounted. Sections were dried, deparaffinized, and rehydrated. After
quenching endogenous peroxidase activity and blocking nonspecific
binding sites, slides were incubated at 4°C overnight with 1:100
dilution of primary antibody directed against PCNA, VEGF, or FVIII
followed by a 30-min incubation of biotinylated goat antimouse
secondary antibody. Slides were then incubated with streptavidin
peroxidase and visualized using the DAB chromogen (Lab Vision Corp.,
Fremont, CA).
Cell Cycle Analysis.
Cell cycle phase distribution after radiation and/or C225 treatment was
analyzed by flow cytometry using PI staining. Briefly, control or
treated cells were harvested by trypsinization, washed with PBS, then
fixed in 95% ethanol and stored at 4°C for up to 7 days before DNA
analysis. After the removal of ethanol by centrifugation, cells were
incubated with phosphate-citric acid buffer [0.2 M
Na2HPO4 and 4
mM citric acid (pH 7.8)] at room temperature for 45 min.
Cells were then stained with a solution containing 33 µg/ml PI, 0.13
mg/ml RNase A, 10 mM EDTA, and 0.5% Triton X-100 at 4°C
for 24 h. Stained nuclei were analyzed for DNA-PI fluorescence
using a Becton Dickinson FACScan flow cytometer. Resulting DNA
distributions were analyzed by Modfit (Verity Software House Inc.,
Topsham, ME) for the proportions of cells in
G0-G1, S phase, and
G2-M phases of the cell cycle.
Immunoblotting Analysis.
After treatment, cells were lysed with Tween 20 lysis buffer [50
mM HEPES (pH 7.4), 150 mM NaCl, 0.1% Tween 20,
10% glycerol, 2.5 mM EGTA, 1 mM EDTA, 1
mM DTT, 1 mM PMSF, and 10 µg/ml leupeptin and
aprotinin] and sonicated. Equal amounts of protein were analyzed by
SDS-PAGE. Thereafter, proteins were transferred to nitrocellulose
membranes and analyzed by specific primary antibodies against DNA-PK.
Proteins were detected via incubation with horseradish
peroxidase-conjugated secondary antibodies and enhanced
chemiluminescence detection system.
Subcellular Fractionation.
To examine the effect of C225 on the subcellular distribution of DNA-PK
after radiation, control or C225-treated SCC cells were collected and
separated into cytoplasmic and nuclear extracts. Briefly, after
centrifugation, cells were resuspended in 150 µl of buffer A [10
mM HEPES (pH 7.9), 1.5 mM
MgCl2, 10 mM KCl, 0.5 mM
DTT, 0.5 mM PMSF, and 10 µg/ml leupeptin and aprotinin]
and incubated on ice for 10 min. The lysate was spun for 30 s to
separate the nuclei and supernatant. For cytosol preparation, the
supernatant was further centrifuged at 14,000 rpm for 10 min to remove
subcellular debris. For nuclear extraction, the nuclei pellet was
resuspended in 100 µl of nuclear extraction buffer [20
mM HEPES (pH 7.9), 0.45 M NaCl, 1.5
mM MgCl2, 0.2 mM EDTA,
0.5 mM DTT, 25% glycerol, 0.5 mM PMSF, and 10
µg/ml leupeptin and aprotinin] and incubated for 30 min. Thereafter,
the solution was centrifuged at 14,000 rpm for 10 min, and the
supernatant (nuclear extracts) was isolated.
Clonogenic Survival Assay.
Clonogenic survival was defined as the ability of the cells to maintain
their clonogenic capacity and to form colonies. Briefly, after exposure
to radiation, cells were trypsinized, counted, and seeded for colony
formation in 35-mm dishes at 50–5000 cells/dish. After incubation
intervals of 14–21 days, colonies were stained with crystal violet and
manually counted. Colonies consisting of 
50 cells were scored, and
4–10 replicate dishes containing 10–150 colonies/dish were counted
for each treatment.
SLDR and PLDR.
These studies were designed to examine the influence of C225 on
radiation damage repair. SLDR was demonstrated with classic split dose
radiation design using a 137Cs irradiator
(J. L. Shepherd & Associates, Glendale, CA). Exponentially growing
SCC cells received a dose of 3 Gy at time 0 and a second dose of 3 Gy
at time points ranging from 2–48 h thereafter. The time 0 point shown
in Fig. 4
represents the response to a single dose of 6 Gy. During the
time interval between successive 3-Gy fractions, cultures were
incubated in the absence (control) or presence of 30 nM
C225. After the second radiation exposure, cells were harvested and
replated for clonogenic survival analysis as described above. PLDR was
demonstrated by single-dose irradiation of confluent cultures, and cell
survival was measured by clonogenic assay. The time 0 point shown in
the left panel of Fig. 5
represents the survival of cells that were
plated immediately after radiation. The remaining data points depict
the survival of cells with delayed plating at various time points after
their exposure to radiation at time 0.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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20 mm3 in volume. As
shown in Fig. 1
, treatment with radiation
alone or with C225 alone produced modest inhibition of tumor growth in
both SCC-1 and SCC-6 xenografts. In contrast, combined treatment with
radiation and C225 produced a marked inhibition in tumor growth over
the 55-day observation period in comparison with single modality
treatment or control (P < 0.01 for all comparisons).
In an attempt to examine the in vivo interaction of C225 and
radiation, low doses of both agents were specifically selected so that
their independent effects on tumor growth inhibition would be modest.
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, C225 was
then administered via i.p. injection on day 23 at a dose of 0.2 mg once
a week for 4 consecutive weeks. Radiation fractions were delivered
24 h after each injection of C225 at a dose of 8 Gy. In mice
receiving single modality treatment with either radiation or C225,
inhibition of tumor growth was observed during the first few weeks
after treatment. Thereafter, the tumor growth profile resumed the same
growth rate/slope as that of the controls. In contrast, combined
treatment with radiation and C225 resulted in dramatic tumor growth
inhibition and, in all cases (n = 8 mice), complete
tumor regression for up to 100 days of study.
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.
Immunostaining for VEGF was far more pronounced in control and
radiation groups when compared with groups receiving C225. Using FVIII
antibodies directed against endothelial cells, vessel formation was
shown to be significantly reduced in the group receiving combined
treatment with C225 and radiation compared with that of the remaining
groups (Fig. 3)
. Taken together, these results suggest that C225 may
also inhibit tumor angiogenesis in addition to its cell cycle
inhibition of proliferation.
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depicts the effect of C225
on SLDR after split-dose radiation exposure. Cell survival in control
cells shows a steady increase as the time interval between the two
radiation fractions increased, which is indicative of SLDR. However,
when cells were exposed to C225 during the interval between radiation
fractions, cell survival was significantly less (P <
0.05) compared with corresponding controls, which is indicative of SLDR
inhibition.
The capacity of C225 to influence PLDR was examined under delayed
plating conditions for clonogenic survival. The left panel of Fig. 5
shows the time-dependent response of
PLDR in SCC-13Y cells. After a single 9-Gy radiation exposure, delayed
plating of control cells between 6–48 h resulted in an increased cell
survival compared with that observed with immediate plating. In
contrast, treatment with C225 before radiation resulted in a reduced
survival (P < 0.02) in comparison with controls. We
further examined the influence of C225 on PLDR when varying doses of
radiation (e.g., 0, 3, 6, and 9 Gy) were applied, as shown
in the right panel of Fig. 5
. As expected, control cells showed a
greater survival when they were plated 24 h after radiation rather
than immediately after radiation. Conversely, in cells treated with
C225, cell survival was not increased by delayed plating, suggesting
that PLDR was inhibited by C225. Taken together, these results suggest
that C225 compromises the capacity of SCCs to accomplish effective
repair after radiation-induced damage.
Subcellular Distribution of DNA-PK.
The DNA repair enzyme DNA-PK is known to reside primarily in the
nucleus where it exerts a major role in repairing double-strand DNA
breaks (13
, 14)
. To examine the effect of C225 on the
subcellular localization of DNA-PK after radiation, SCC cells were
treated with C225 for 1 h followed by radiation. As expected, a
major fraction of DNA-PK was localized in the nucleus, and a minor
fraction was localized in the cytosol after radiation exposure (Fig. 6)
. However, dual treatment with
radiation and C225 resulted in a readily measurable shift in the DNA-PK
distribution ratio, with an increase in the cytosolic level of DNA-PK
and a concurrent reduction in the nucleus. The reduction in the level
of DNA-PK in the nucleus suggests a potential mechanism whereby the
repair of double-strand DNA after radiation may be impaired by C225.
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,
G1 cell cycle arrest was induced in cells exposed
to C225 alone, and G2-M cell cycle arrest was
induced in cells receiving radiation alone. Dual treatment with
radiation and C225 resulted in the accumulation of cells in both the
G1 and G2-M phases, with a
concurrent reduction of cells within S phase. These results suggest
that one potential mechanism whereby C225 may enhance radiosensitivity
involves the accumulation of cells in more radiosensitive cell cycle
phases, such as G1 and G2-M
phases.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. The profound
antitumor effect observed with combined C225 and radiation (more potent
than that observed in cell culture) strongly suggests that mechanisms
beyond simple proliferative growth inhibition are operational in the
in vivo setting. These mechanisms may include (among others)
C225-induced inhibition of DNA damage repair, increased
radiosensitivity deriving from specific perturbations in cell cycle
phase distribution, enhancement of radiation-induced apoptosis, and
inhibition of tumor angiogenesis. From the standpoint of cell line
variability, recent evidence also identifies a significant inverse
relationship between the magnitude of EGFR expression and both
radiocurability and radiation-induced apoptosis (15)
. In the present studies, the influence of C225 on radiation damage repair was reflected by the capacity of C225 to inhibit PLDR and SLDR. The precise molecular mechanisms that underlie SLDR and PLDR are not clear. Operationally, SLDR is described as that cellular recovery that occurs during the interfraction interval between split-dose radiation exposure, whereas PLDR is described as that cellular recovery that occurs dependent on postradiation conditions after single-dose exposure (16) . Both SLDR and PLDR have been shown to be affected by growth factors (17 , 18) . For example, bFGF has been shown to induce PLDR in bovine aortic endothelial cells, and such induction was inhibited by using a neutralizing mAb against bFGF (17) . It may be that down-regulation of selected mitogenic signal transduction pathways can inhibit cellular recovery processes after radiation damage, but no precise mechanistic scheme is presently appreciated. A similar postulation has recently been put forth in the HER-2/breast cancer system wherein enhanced radiation response and diminished DNA repair is observed in human MCF-7/HER-2 breast cancer cells after mAb blockade of the HER-2 receptor (19) .
Recent evidence has suggested a link between the repair of DNA double-strand breaks and SLDR or PLDR (20) . Li et al. (21) reported that severe combined immunodeficiency fibroblasts, which were deficient in repairing DNA double-strand breaks, demonstrated a lack of PLDR. Using two isogenic human malignant glioma cell lines, Allalunis-Turner et al. (22) demonstrated that cell lines lacking the catalytic domain of DNA-PK did not exhibit SLDR. In our studies, C225 induced a redistribution of DNA-PK with a reduction in the level of DNA-PK in the nucleus of SCC cells exposed to radiation. This finding is consistent with a recent report demonstrating a redistribution of DNA-PK from nucleus to cytosol after exposure to C225 as measured by immunohistochemical analysis (11) . Therefore, it is possible that the observed inhibitory effects of C225 on PLDR and SLDR were mediated in part by impairing the function or activity of DNA-PK within the nucleus of SCCs.
The general profile of cell cycle perturbation, which results after exposure to radiation, has been well established (23, 24, 25) . In general, cells damaged by radiation will arrest in the G2-M phase presumably to initiate repair of DNA damage before proceeding (26) . However, treatment of tumor cells with C225 induces growth arrest primarily in the G1 phase (10 , 27) . When tumor cells are simultaneously exposed to modest doses of radiation plus C225 (exposures that individually produced only transient responses in SCC tumor xenografts), profound tumor cell kill is observed, which may reflect a cellular intolerance to concurrent blockade at these two distinct cell cycle checkpoints. Cellular damage induced by radiation signals proliferating cells to pause to initiate repair, and many repair processes require growth factors to proceed effectively. It may be that cells attempting to repair radiation-induced damage, that simultaneously undergo molecular blockade of the EGFR system with agents such as C225, are unable to facilitate effective repair and recovery, thereby contributing to cell death.
The markedly increased antitumor potency of C225 and radiation in vivo (over that observed in vitro) suggests that factors beyond the confines of the clonogenic cell may influence the in vivo response. One possible microenvironmental mechanism involves tumor angiogenesis, which may itself be affected by the functional activity of the EGFR system. Recent findings suggest that the use of an angiogenesis inhibitor (angiostatin) during radiation therapy can significantly enhance response in human tumor xenografts (28) . Indeed, several recent associations between the EGFR pathway and tumor angiogenesis have been identified (12 , 29 , 30) . For example, C225 was shown to down-regulate the expression of several angiogenic factors, including VEGF, interleukin 8, and bFGF in A431 and human transitional cell carcinoma of the bladder (12) . This down-regulation was postulated to be mediated via reduction of AP-1 activity, which was shared by the promoters of VEGF, bFGF, and interleukin 8. In the present studies, we observed an inhibition of VEGF expression and reduced number of tumor vessels via staining with the endothelial cell marker (FVIII) in xenografts after treatment with C225 and radiation. These findings provide indirect evidence that C225 may also inhibit tumor angiogenesis in addition to the observed effects on radiation-induced cytotoxicity. Studies to clarify and augment these findings using complementary in vivo assays of angiogenesis are being developed.
In conclusion, epithelial tumors that are rich in their expression of EGFR hold special promise for the receptor blockade approach. SCCs of the H&N are notably robust in their EGFR expression and therefore represent a logical experimental model for EGFR inhibition. In addition, SCCs of the H&N are particularly rapid proliferators, which lends favorably to the antiproliferative impact of EGFR blockade. The studies presented in this report demonstrate that human H&N cancer cells are particularly sensitive to radiation damage when the EGFR signaling pathway in these cells is blocked by C225. Most impressively, the in vivo tumor response after the combined administration of C225 and radiation is dramatic and long-lasting, as demonstrated within the xenograft model system.4 Such profound antitumor activity in vivo appears to derive from not only proliferative growth inhibition (with associated cell cycle redistribution), but also from inhibition of postradiation damage repair and inhibition of tumor angiogenesis.
Similar to the recent therapy successes in selected breast cancer and lymphoma patients with mAbs that target specific growth receptor blockade (e.g., herceptin, rituxan), C225 plus radiation therapy in SCC of the H&N represents a promising new molecular cancer therapy approach that has recently commenced formal investigation in Phase III clinical trials.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grant CA 66786 (to P. M. H.) from
the National Cancer Institute. P. M. H is the recipient of a
laboratory research award from ImClone Systems Inc., and he holds stock
options in the company. 
2 To whom requests for reprints should be
addressed, at Department of Human Oncology, University of Wisconsin
Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI
53792-0600. Phone: (608) 263-8500; Fax: (608) 263-9167; E-mail: harari{at}mail.humonc.wisc.edu
3 The abbreviations used are: SCC, squamous cell
carcinoma; bFGF, basic fibroblast growth factor; DNA-PK, DNA-dependent
protein kinase; EGFR, epidermal growth factor receptor; FVIII, factor
VIII-related antigen; H&N, head and neck; mAb, monoclonal antibody;
PCNA, proliferating cell nuclear antigen; PI, propidium iodide; PLDR,
potentially lethal damage repair; SLDR, sublethal damage repair; VEGF,
vascular endothelial growth factor; PMSF, phenylmethylsulfonyl
fluoride.
4 Similar results demonstrating enchancement of
tumor xenograft response with radiation plus C225; communicated to
P. M. H. by L. Milas and K. Ang, September 1999.
Received 12/31/99; revised 2/24/00; accepted 2/28/00.
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REFERENCES |
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-rays and 5-fluorouracil. Cancer Lett., 123: 227-232, 1998.[CrossRef][Medline]
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, 
) or 24-h delayed
(
, •) plating for the control group and C225-treated
SCC-13Y cells. Data points, means of duplicates with
five cultures per replicate per point; bars, SD.
