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Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy [C. B., R. B., G. T., V. D., S. D. P., A. R. B., F. C.]; Divisione di Radioterapia, Azienda Ospedaliera di Cosenza, Cosenza 77100, Italy [C. B., P. G., P. M.]; University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 [J. M.]
ABSTRACT
Recent
studies have suggested that selective inhibition of mitogenic pathways
may improve the antitumor activity of ionizing radiation. The epidermal
growth factor receptor (EGFR) is overexpressed and is involved in
autocrine growth control in the majority of human carcinomas. Protein
kinase A type I (PKAI) plays a key role in neoplastic transformation
and is overexpressed in cancer cells in which an EGFR autocrine pathway
is activated. We used two specific inhibitors of EGFR and PKAI that are
under clinical evaluation in cancer patients: C225, an anti-EGFR
chimeric human-mouse monoclonal antibody (MAb); and a mixed-backbone
antisense oligonucleotide targeting the PKAI RI
subunit (PKAI
AS). We tested in human colon cancer (GEO) and ovarian cancer (OVCAR-3)
cell lines the antiproliferative activity of MAb C225 and/or PKAI AS in
combination with ionizing radiation. In vivo antitumor
activity was evaluated in nude mice bearing established GEO xenografts.
Dose-dependent inhibition of soft agar growth was observed in both
cancer cell lines with ionizing radiation, C225, or PKAI AS
oligonucleotide. A cooperative antiproliferative effect was obtained
when cancer cells were treated with ionizing radiation followed by MAb
C225 or PKAI AS oligonucleotide. This effect was observed at all doses
tested in both GEO and OVCAR-3 cancer cell lines. A combination of the
three treatments at the lowest doses produced an even greater effect
than that observed when two modalities were combined. Treatment of mice
bearing established human GEO colon cancer xenografts with radiotherapy
(RT), MAb C225, or PKAI AS oligonucleotide produced dose-dependent
tumor growth inhibition that was reversible upon treatment cessation. A
potentiation of the antitumor activity was observed in all mice treated
with RT in combination with MAb C225 or PKAI AS oligonucleotide.
Long-term GEO tumor growth regression was obtained following treatment
with ionizing radiation in combination with MAb C225 plus PKAI AS
oligonucleotide, which produced a significant improvement in survival
compared with controls (P < 0.001), the RT-treated
group (P < 0.001), or the group treated with MAb
C225 plus PKAI AS oligonucleotide (P < 0.001). All
mice of the RT + MAb C225 + PKAI AS group were alive 26 weeks
after tumor cell injection. Furthermore, 50% of mice in this group
were alive and tumor-free after 35 weeks. This study provides a
rationale for evaluating in cancer patients the combination of ionizing
radiation and selective drugs that block EGFR and PKAI pathways.
INTRODUCTION
Treatment with ionizing radiation induces different biochemical
effects in cancer cells, with activation of multiple signaling pathways
that lead to either programmed cell death or cell proliferation. The
latter effect is probably the result of activation of various mitogenic
pathways (1
, 2)
. It has recently been demonstrated that
ionizing radiation induces the
EGFR3
/ras/raf/MAPK
pathways through the direct activation of the EGFR tyrosine kinase and
the release of TGF, a specific ligand for EGFR (1
, 2)
.
This may be clinically relevant because it could represent a mechanism
by which cancer cells become able to escape radiation-induced cell
death. In this respect, EGF-related growth factors, such as TGF,
have been implicated in human cancer development and progression
through autocrine and paracrine pathways (3)
. TGF binds
to the extracellular domain of EGFR and activates its intracellular
tyrosine kinase domain (3)
. Ligand binding induces
dimerization of EGFR and its autophosphorylation on several tyrosine
residues in the intracellular domain, creating a series of
high-affinity binding sites for various transducing molecules that are
involved in transmitting the mitogenic signal through the
ras/raf/MAPK pathway (3)
.
Enhanced expression of TGF and/or EGFR has been detected in the
majority of human carcinomas and has been associated with poor
prognosis (3)
. EGFR overexpression has been also found in
human cancer cell lines that are resistant to different cytotoxic drugs
(4
, 5)
. For these reasons, blocking of the TGF-EGFR
autocrine pathway has been proposed as a therapeutic target
(6)
. Several pharmacological and biological approaches
have been developed for blocking EGFR activation and/or function in
cancer cells. Anti-EGFR blocking MAbs, recombinant proteins containing
TGF or EGF fused to toxins, and EGFR-selective tyrosine kinase
inhibitors have been characterized for their biological and potentially
therapeutic properties (7, 8, 9, 10, 11, 12, 13, 14, 15)
. One of these agents, MAb
C225, a chimeric human-mouse IgG1 MAb, has recently entered phase II
and III clinical evaluation in cancer patients (16, 17, 18, 19)
.
The cAMP-dependent PKA is an intracellular enzyme involved in
controlling cell growth and differentiation (20)
. The PKAI
isoform is overexpressed in human cancer and is directly involved in
EGFR mitogenic signaling (21)
. We have shown that PKAI,
through interaction of its RI subunit with Grb2 adapter protein, has
structural interaction with the ligand-activated EGFR, cooperating in
the propagation to MAPK of the mitogenic signal (22)
.
Different PKAI inhibitors are under clinical development.
Down-regulation of PKAI by unmodified or PS-modified antisense
oligonucleotides targeting its RI subunit causes cell growth
inhibition in a variety of human cancer cell lines and has antitumor
activity in nude mice (23, 24, 25)
. Modified oligonucleotides
of a novel class, defined as MBOs, have been synthesized recently and
have significantly improved pharmacokinetic and toxicological
properties in vivo compared with PS oligonucleotides
(26
, 27)
. In this respect, an antisense RI MBO with
hybrid DNA/RNA structure containing
2'-O-methyl-ribonucleosides at the 5' and 3' ends (PKAI AS),
has been synthesized (27)
. This MBO, named GEM231, has
completed phase I clinical trials and has shown an improved safety
profile and metabolic stability compared with first-generation PS
oligonucleotides (28)
.
In recent years, there has been a growing interest in combining conventional chemotherapeutic agents with biological agents that selectively inhibit key intracellular targets involved in the process of neoplastic transformation. Previous studies have shown that treatment with MAb C225 or PKAI AS oligonucleotide potentiates the antitumor activity of several cytotoxic drugs in human cancer cells (25 , 29, 30, 31) . In this study, we evaluated whether a similar cooperative effect could be obtained when two human cancer cell lines (GEO and OVCAR-3) were treated with MAb C225 and PKAI AS oligonucleotide in combination with RT.
MATERIALS AND METHODS
Materials.
MAb C225 is a human-mouse chimeric anti-EGFR IgG1 MAb, whose
biochemical and biological characteristic have been described
previously (16)
. MAb C225 was kindly provided by Dr. H.
Waksal (ImClone Systems, New York, NY). PKAI AS is a hybrid
oligonucleotide, targeted against the N-terminal 8–13 codons of the
RI regulatory subunit of PKA, with the following sequence,
GCGUGCCTCCTCACUGGC. This AS oligonucleotide has
been termed GEM231 (28)
. The control is a scramble MBO
obtained by mixing all four nucleosides in a mixture containing all
possible sequences. The two oligonucleotides contain PS internucleotide
linkages (nucleosides flanking each position are in Roman, and
2'-O-methyl-ribonucleoside modifications are in italics).
The oligonucleotides were synthesized and kindly provided by Dr. S.
Agrawal (Hybridon Inc., Milford, MA).
Cell Lines.
Human GEO colon cancer and OVCAR-3 ovarian cancer cell lines were
obtained from the American Type Culture Collection (Rockville, MD). The
p53 status of the cancer cell lines is the following:
wild-type gene, GEO; point-mutated gene, OVCAR-3 (G-to-A in codon 248).
The cell lines were maintained in DMEM supplemented with 10%
heat-inactivated fetal bovine serum, 20 mM
HEPES (pH 7.4), 100 IU/ml penicillin, 100 µg/ml streptomycin,
and 4 mM glutamine (ICN, Irvine, United Kingdom)
in a humidified atmosphere of 95% air and 5%
CO2 at 37°C.
Ionizing Radiation Treatment and Growth in Soft Agar.
Exponentially growing GEO and OVCAR-3 cells were irradiated in 100-mm
tissue culture dishes (Becton Dickinson, Lincoln Park, NJ) by a 6
MV photon linear accelerator (General Electric). Following
irradiation, cells were trypsinized, and 104
cells/well were suspended in 0.5 ml of 0.3% Difco Noble agar (Difco,
Detroit, MI) supplemented with complete culture medium. This suspension
was layered over a base layer containing 0.5 ml of 0.8% agar-medium in
24-well cluster dishes (Becton Dickinson) and was treated every
day for a total of 3 days with different concentrations of MAb C225
and/or PKAI AS oligonucleotide. After 10–14 days, the cells were
stained with nitroblue tetrazolium (Sigma, St. Louis, MO), and colonies
larger than 0.05 mm were counted as described previously
(31)
.
GEO Xenografts in Nude Mice.
Female BALB/c athymic (nu+/nu+) mice (5–6 weeks of age) were purchased
from Charles River Laboratories (Milan, Italy). The research protocol
was approved, and mice were maintained in accordance to institutional
guidelines of the University of Naples Animal Care and Use Committee.
Mice were acclimated to the University of Naples Medical School Animal
Facility for 1 week prior to receiving injections of cancer cells. Mice
received s.c. injections of 107 GEO cells that
had been resuspended in 200 µl of Matrigel (Collaborative Biomedical
Products, Bedford, MA). After 7 days, when established tumors
0.2–0.3 cm3 in volume were detected,
10 mice/group were treated i.p. with PKAI AS oligonucleotide (5 or 10
mg/kg/dose, injected on days 1–5 of each week for 3 weeks),
scramble control oligonucleotide (10 mg/kg/dose, injected on days 1–5
of each week for 3 weeks), or MAb C225 (0.25, 0.5, or 1 mg/dose,
injected twice weekly on days 1 and 4 for 3 weeks), or received RT
treatment (5, 7.5, or 10 Gy/dose daily, administered on days 1–4). In
a subsequent series of experiments, groups of 10 mice bearing
established GEO tumors 0.2–0.3 cm3 in
volume received RT (10 Gy/dose on days 1–4) and/or were treated
i.p. with PKAI AS oligonucleotide alone (10 mg/kg/dose, injected on
days 1–5 of each week for 3 weeks), with MAb C225 alone (1 mg/dose,
injected twice weekly on days 1 and 4 for 3 weeks), or with both
agents. Tumor size was measured using the formula 
/6 x larger
diameter x (smaller diameter)2, as reported
previously (31)
.
Statistical Analysis.
The Student’s t test and the Mantel-Cox log-rank test were
used to evaluate the statistical significance of the results. All
P values represent two-sided tests of statistical
significance. All analyses were performed with the BMDP New System
statistical package, version 1.0 for Microsoft Windows (BMDP
Statistical Software, Los Angeles, CA) as reported previously
(31)
.
RESULTS
As shown in Fig. 1
, we first
evaluated the effects of ionizing radiation and/or MAb C225 treatment
on the cloning efficiency of two human epithelial cancer cell lines in
soft agar. We selected GEO colon cancer and OVCAR-3 ovarian cancer cell
lines because they have functional EGFRs that have 40,000 (GEO) to
150,000 (OVCAR-3) EGF binding sites/cell and overexpress PKAI
(31)
. GEO cells possess a wild-type p53
gene, whereas OVCAR-3 cells have a mutated p53 gene
(31)
. Ionizing radiation treatment caused a dose-dependent
inhibition in soft agar growth in both cell lines with an
IC50 of 100 cGy. Treatment with the anti-EGFR
blocking MAb C225 revealed dose-dependent colony inhibition with an
IC50 of 0.3–0.5 µg/ml in both GEO and
OVCAR-3 cancer cell lines.
|
10 or 22%
growth inhibition, respectively, whereas sequential treatment caused
80% inhibition of colony formation in soft agar (Fig. 1
A).
The cooperativity quotient of this treatment, defined as the ratio
between the actual growth inhibition obtained with ionizing radiation
followed by MAb C225 and the sum of the growth inhibition achieved by
each treatment, was 2.5. We next evaluated whether a similar
cooperative antiproliferative effect could be achieved by combining RT
with the blockage of PKAI function by a specific PKAI AS
oligonucleotide. As illustrated in Fig. 2
, in both GEO and OVCAR-3 cells,
supra-additive inhibition of cloning efficiency in soft agar was
obtained following sequential treatment with ionizing radiation and
PKAI AS oligonucleotide. This effect was specific for the combined
treatment with the PKAI AS oligonucleotide because treatment with a
scramble control oligonucleotide at doses up to 1
µM did not enhance the antiproliferative effect
of ionizing radiation in either GEO or OVCAR-3 cancer cells
(data not shown).
|
. In fact, at
single-treatment doses that produced only 5–10% inhibition of colony
formation in soft agar, the combination of the three treatments caused
75–85% inhibition of soft agar growth of GEO and OVCAR-3 cells.
|
0.2–0.3
cm3 were detectable, mice were given RT or were
treated i.p. with PKAI AS oligonucleotide or with the anti-EGFR MAb
C225. Fig. 4
shows that each treatment
significantly inhibited GEO tumor growth in vivo in a
dose-dependent fashion. However, this effect was reversible because
shortly after the end of the treatment with RT, MAb C225, or PKAI AS
oligonucleotide, GEO tumors resumed a growth rate similar to that of
untreated controls (data not shown). We next evaluated the
effects of RT in combination with MAb C225 or with PKAI AS
oligonucleotide on mice bearing GEO xenografts. As illustrated in Fig. 5
, treatment with MAb C225 (1 mg/dose
twice weekly for 3 weeks) after ionizing radiation (10 Gy/dose daily,
days 1–4) suppressed tumor growth in all mice. In mice that received
MAb C225 plus RT, GEO tumors grew very slowly for 50–60 days
following the end of treatment; tumors then resumed a growth rate
similar to controls (Fig. 5
A). The delayed GEO tumor growth
in the MAb C225 + RT-treated group of mice was accompanied by a
prolonged life span that was significantly different from controls
(P < 0.001), the MAb C225-treated group
(P < 0.001), or the RT-treated group
(P < 0.001). Furthermore, 20% of mice in this group
were still alive without any evidence of tumor 35 weeks after the GEO
cancer cells were injected (Fig. 5
B). A similar but less
pronounced potentiation of the antitumor activity of RT was observed
when mice were treated with PKAI AS oligonucleotide (10 mg/kg/dose,
injected on days 1–5 of each week for 3 weeks; Fig. 6
).
|
|
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B, GEO tumors reached a
size not compatible with normal life in all untreated mice within 6
weeks. A small increase in mouse survival was observed in the group
treated with RT alone (P < 0.05). Mice treated with
MAb C225 + PKAI AS oligonucleotide survived longer than those in the
control group and the RT-treated group (P <
0.001). Survival was markedly increased in the group of mice
receiving the triple treatment (P < 0.001). In fact,
all mice of this group were alive 26 weeks after injection of GEO tumor
cells. Furthermore, no histological evidence of GEO tumors was observed
in 50% of the mice in this group 35 weeks after tumor cell injection.
|
The possibility of combining conventional anticancer treatments,
such as cytotoxic drugs or RT, with novel drugs that selectively
interfere with important pathways controlling cancer cell survival,
proliferation, invasion, and metastasis has generated a wide clinical
interest. This could be a promising therapeutic approach for several
reasons. First, because the cellular targets for these agents and their
mechanism(s) of action are different from those of cytotoxic drugs and
ionizing radiation, their combination without potential
cross-resistance is conceivable. Second, alterations in the expression
and/or the activity of genes that regulate mitogenic signals not only
can directly cause perturbation of cell growth, but also may affect the
sensitivity of cancer cells to chemotherapy and RT (35)
.
In this respect, EGFR overexpression has generally been found in human
cancer cell lines that are resistant to different cytotoxic drugs
(3, 4, 5)
. Furthermore, ionizing radiation induces the
activation of the EGFR tyrosine kinase and the release of its specific
ligand, TGF (2)
. For these reasons, it has been
postulated that EGFR overexpression and activation could be a survival
response to counteract apoptotic signals in cancer cells exposed to
ionizing radiation or to cytotoxic drugs (2
, 35)
. In fact,
it has been proposed that is possible to enhance the anticancer
activity by treatment with maximum tolerated doses of cytotoxic drugs
or of RT in combination with selective inhibitors of signal
transduction pathways instead of increasing chemotherapy or ionizing
radiation doses to supertoxic levels that require complex medical
support for the cancer patient, such as hematopoietic cell rescue
(35)
.
In the present study, we have shown that treatment with the anti-EGFR blocking chimeric human-mouse antibody MAb C225 potentiates the cytotoxic effects of ionizing radiation in human colon and ovarian cancer cell lines that express functional EGFR. The growth-inhibitory effect in vitro is accompanied by a marked increase in antitumor activity in vivo, suggesting that the EGFR blockade is able to overcome cancer cell survival signals induced by ionizing radiation treatment. These data are in agreement with and extend those of recent studies by Huang et al. (36) , who evaluated the effects of MAb C225 on the radiosensitivity of human head-and-neck squamous carcinoma cell lines in vitro, and Milas et al. (37) , who showed in vivo enhancement of tumor radioresponse by MAb C225 treatment in nude mice bearing A431 human epidermoid carcinoma xenografts. Furthermore, our study is the first report of a cooperative antiproliferative effect of blocking of PKAI, a serine-threonine kinase acting downstream to EGFR, in combination with RT. The growth-inhibitory effects of MAb C225 and/or PKAI AS treatment in combination with RT seems to be p53-independent because similar results have been obtained in human cancer cells bearing either a normal wild-type or a mutated p53 gene.
In this study, we also demonstrated that the combined blocking of EGFR and PKAI function and signaling by treatment with MAb C225 and a PKAI AS oligonucleotide following ionizing radiation results in even more efficient cytotoxic activity. In fact, established GEO tumors were eradicated in 50% of mice receiving a relatively short-term treatment with one course of ionizing radiation followed by MAb C225 plus PKAI AS oligonucleotide for 3 weeks.
The results of this study are of potential clinical interest. In fact, they provide a rationale for the combination of MAb C225 and PKAI AS oligonucleotide in the treatment of human epithelial cancers after RT. MAb C225 is in phases II-III clinical development, both alone and in combination with cytotoxic drugs or with RT. In this respect, a pilot phase I study has suggested high antitumor activity of MAb C225 in combination with RT in stage III-IV head-and-neck cancer patients that is maintained as a complete response in 13 of 15 treated patients, with the response lasting 12–27 months (19 , 38) . Furthermore, the PKAI AS oligonucleotide that we used in the present study has completed phase I evaluation in cancer patients and is in phase II trials (28) .
ACKNOWLEDGMENTS
We thank Dr. S. Agrawal for the gift of the MBO oligonucleotides. We also acknowledge the excellent technical assistance of G. Borriello.
FOOTNOTES
The costs of publication of this article were defrayed in part 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.
1 This study was supported by grants from the
Associazione Italiana per la Ricerca sul Cancro (AIRC) and the
Consiglio Nazionale delle Ricerche (CNR) Target Project on
Biotechnologies. 
2 To whom requests for reprints should be
addressed, at Cattedra di Oncologia Medica, Dipartimento di
Endocrinologia e Oncologia Molecolare e Clinica, Facoltà di
Medicina e Chirurgia, Università degli Studi di Napoli
"Federico II," Via S. Pansini 5, 80131 Naples, Italy. Phone:
39-081-7462061; Fax: 39-081-7462066; E-mail: fortunatociardiello{at}yahoo.com
3 The abbreviations used are: EGFR, epidermal
growth factor receptor; MAPK, mitogen-activated protein kinase; TGF,
transforming growth factor ; MAb, monoclonal antibody; PKAI, protein
kinase A type I; PS, phosphorothioate; MBO, mixed-backbone
oligonucleotide; RT, radiotherapy.
Received 5/31/00; revised 8/17/00; accepted .
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