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Experimental Therapeutics, Preclinical Pharmacology |
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università degli Studi di Napoli Federico II, 5-80131 Naples, Italy
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TGF-) is an autocrine growth factor for human
cancer. Overexpression of TGF- and its specific receptor, the
epidermal growth factor receptor (EGFR), is associated with aggressive
disease and poor prognosis. The EGFR has been proposed as a target for
anticancer therapy. Compounds that block ligand-induced EGFR activation
have been developed. ZD-1839 (Iressa) is a p.o.-active, quinazoline
derivative that selectively inhibits the EGFR tyrosine kinase and is
under clinical development in cancer patients. The antiproliferative
activity of ZD-1839 alone or in combination with cytotoxic drugs
differing in mechanism(s) of action, such as cisplatin, carboplatin,
oxaliplatin, paclitaxel, docetaxel, doxorubicin, etoposide, topotecan,
and raltitrexed, was evaluated in human ovarian (OVCAR-3), breast
(ZR-75–1, MCF-10A ras), and colon cancer (GEO) cells
that coexpress EGFR and TGF-. ZD-1839 inhibited colony formation in
soft agar in a dose-dependent manner in all cancer cell lines. The
antiproliferative effect was mainly cytostatic. However, treatment with
higher doses resulted in a 2–4-fold increase in apoptosis. A
dose-dependent supra-additive increase in growth inhibition was
observed when cancer cells were treated with each cytotoxic drug and
ZD-1839. The combined treatment markedly enhanced apoptotic cell death
induced by single-agent treatment. ZD-1839 treatment of nude mice
bearing established human GEO colon cancer xenografts revealed a
reversible dose-dependent inhibition of tumor growth because GEO tumors
resumed the growth rate of controls at the end of the treatment. In
contrast, the combined treatment with a cytotoxic agent, such as
topotecan, raltitrexed, or paclitaxel, and ZD-1839 produced tumor
growth arrest in all mice. Tumors grew slowly for approximately 4–8
weeks after the end of treatment, when they finally resumed a growth
rate similar to controls. GEO tumors reached a size not compatible with
normal life in all control mice within 4–6 weeks and in all single
agent-treated mice within 6–8 weeks after GEO cell injection. In
contrast, 50% of mice treated with ZD-1839 plus topotecan,
raltitrexed, or paclitaxel were still alive 10, 12, and 15 weeks after
cancer cell injection, respectively. These results demonstrate the
antitumor effect of this EGFR-selective tyrosine kinase inhibitor and
provide a rationale for its clinical evaluation in combination with
cytotoxic drugs. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, are potent mitogens for several human
epithelial cell types including breast, colon, ovary, kidney, prostate,
and lung, and have been implicated in cancer development and
progression through autocrine and paracrine pathways (1)
.
TGF- binds to the extracellular domain of the EGFR and activates its
intracellular tyrosine kinase domain (1)
. The EGFR is a
Mr 170,000 transmembrane glycoprotein
with an external binding domain and an intracellular tyrosine kinase
domain (1)
. Ligand binding induces dimerization of the
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 signaling through the
ras/raf/mitogen-activated protein kinase pathway
(2)
. Enhanced expression of TGF- and/or EGFR has been
detected in the majority of human carcinomas (1)
and has
been associated with poor prognosis in several human tumor types, such
as breast cancer (3)
. EGFR overexpression has been also
found in human cancer cell lines that are resistant to different
cytotoxic drugs (4)
. For these reasons, the blockade of
the TGF-/EGFR autocrine pathway has been proposed as a potential
therapeutic modality (5, 6, 7)
. Several pharmacological and
biological approaches have been developed for blocking EGFR activation
and/or function in cancer cells. In the past 10 years, various
anti-EGFR blocking MAbs, recombinant proteins containing TGF- or EGF
fused to toxins, and tyrosine kinase inhibitors have been generated and
characterized for their biological and potentially therapeutic
properties (8, 9, 10, 11, 12, 13, 14, 15)
. One of these agents, MAb C225, a
chimeric human-mouse IgG1 MAb, has recently started Phase II and Phase
III clinical evaluation in cancer patients (8
, 16, 17, 18, 19)
.
Several compounds that block the ligand-induced activation of the EGFR
tyrosine kinase and, in some cases, to a lesser extent that of the
closely related c-erbB-2 receptor have been developed
(15
, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
. Among these, various quinazoline-derived
agents have been synthesized and tested as anticancer agents in
vitro and in preclinical models (6
, 15)
. ZD-1839, an
anilinoquinazoline, is a p.o.-active, selective EGFR-tyrosine kinase
inhibitor that blocks signal transduction pathways implicated in cancer
cell proliferation and other host-dependent processes promoting cancer
growth (26
, 27)
. ZD-1839 is currently under clinical
evaluation in early clinical trials in cancer patients
(30)
.
In the present study, we tested the antiproliferative activity of
ZD-1839 in four human cancer cell lines of different histotypes,
including ovarian, breast, and colon cancer, that express both EGFR and
TGF-. Furthermore, a large body of experimental and clinical
evidence has been recently accumulated on the enhanced antitumor
activity of some chemotherapeutic agents, such as doxorubicin,
cisplatin, paclitaxel, or topotecan, in combination with specific MAbs
that selectively block either the EGFR or the closely related
c-erbB-2 receptor (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)
. For this purpose,
we also evaluated whether ZD-1839 has cooperative effect with cytotoxic
drugs with different mechanism(s) of action and with antitumor activity
in a variety of human malignancies, in which EGFR is generally
overexpressed and a TGF-/EGFR autocrine pathway is operative.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Lines.
GEO human colon cancer, OVCAR-3 human ovarian cancer, and ZR-75-1 human
breast cancer cell lines were obtained from the American Type Culture
Collection (Rockville, MD). MCF-10A Ha-ras cells have been
obtained by cotransfection of human nontransformed MCF-10A cells with
an expression vector plasmid containing the human activated
c-Ha-ras proto-oncogene and an expression vector plasmid
containing the neomycin resistance gene (43)
. GEO,
OVCAR-3, and ZR-75-1 cells were maintained in DMEM supplemented with
10% heat-inactivated fetal bovine serum, 20 mM
HEPES (pH 7.4), 100 UI/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. MCF-10A Ha-ras cells were grown in a 1:1 (v/v) DMEM
and Ham’s F12 mixture, supplemented with 5% heat-inactivated horse
serum, 20 mM HEPES (pH 7.4), 4
mM glutamine, 0.5 µg/ml hydrocortisone (Sigma),
10 ng/ml EGF, 10 µg/ml insulin (Collaborative Research Products,
Bedford, MA), 100 units/ml penicillin, and 100 µg/ml streptomycin in
a humidified atmosphere of 95% air and 5% CO2
at 37°C.
Growth in Soft Agar.
Cells (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 0.5 ml of
0.8% agar-medium base layer in 24 multiwell cluster dishes (Becton
Dickinson, Lincoln Park, NJ) and treated with different concentrations
of ZD-1839 alone and/or in combination with the indicated
concentrations of cytotoxic drugs. After 10–14 days, cells were
stained with nitro blue tetrazolium (Sigma), and colonies >0.05 mm
were counted as described previously (33)
.
Immunoprecipitation and Western Blot Analysis.
Total cell lysates were obtained as described previously
(44)
from serum-starved MCF-10A Ha-ras cells
that were treated for 3 h with the indicated concentrations of
ZD-1839, followed by the addition of complete medium containing EGF (50
ng/ml) for 15 min. Proteins were immunoprecipitated with MAb C225
anti-EGFR monoclonal antibody (kindly provided by Dr. H. Waksal,
ImClone Systems, New York, NY), as reported previously
(44)
. For Western blot analysis, immunoprecipitates were
resolved by a 7.5% SDS-PAGE and probed with either an antihuman EGFR
monoclonal antibody (Transduction Laboratories, Lexington, KY) or the
PY20 anti-P-tyrosine monoclonal antibody (Transduction Laboratories).
Immunoreactive proteins were visualized by enhanced chemiluminescence
(Amersham International, Buckinghamshire, England), as described
previously (44)
.
Apoptosis Assay.
The induction of programmed cell death was determined as described
previously (45)
by the Cell Death Detection ELISA Plus Kit
(Boehringer Mannheim, Indianapolis, IN). Briefly, 5 x
104 cells/well were seeded into six
multiwell cluster dishes. After appropriate treatment, the cells
were washed once with PBS, and 0.5 ml lysis buffer was added. After a
30-min incubation, the supernatant was recovered and assayed for DNA
fragments as recommended by the manufacturer at 405 nm using a
Microplate Reader Model 3550-UV (Bio-Rad, Milan, Italy). Each treatment
was performed in quadruplicate. Additional plates identically treated
were analyzed for cell number with an hemocytometer to normalize the
values for cell numbers, and the results are expressed relative to
untreated control samples.
GEO Xenografts in Nude Mice.
Female BALB/c athymic (nu+/nu+) mice, 4–6 weeks of
age, were purchased from Charles River Laboratories (Milan, Italy). The
research protocol was approved, and mice were maintained in accordance
with the institutional guidelines of the University of Naples Animal
Care and Use Committee. Mice were acclimatized at the University of
Naples Medical School Animal Facility for 1 week prior to being
injected with cancer cells. Mice were injected s.c. with
107 GEO cells that had been resuspended in 200
µl of Matrigel (Collaborative Biomedical Products, Bedford, MA).
After 7 days, when established tumors of approximately 0.2–0.3
cm3 in diameter were detected, 10 mice/group were
treated i.p. on days 1–5 of each week for 4 weeks with ZD-1839 at the
indicated daily doses. To determine the effects of the combination of
ZD-1839 and cytotoxic drugs, additional groups of 10 mice were treated
i.p. on days 1–5 of each week for 4 weeks with ZD-1839, 2.5
mg/mouse/day, alone or in combination with paclitaxel, 20 mg/kg on day
1 of each week for 4 weeks; with topotecan, 2 mg/kg on day 1 of each
week for 4 weeks; or with raltitrexed, 12.5 mg/kg on day 1 of each week
for 4 weeks. Tumor size was measured using the formula 
/6 x
larger diameter x (smaller diameter)2, as
reported previously (33)
.
Statistical Analysis.
The Student’s t test (46)
and the
Mantel-Cox log-rank test (47)
were used to evaluate the
statistical significance of the results. All Ps 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).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(33)
. Treatment with ZD-1839 determined a
dose-dependent inhibition of colony formation in soft agar with an
IC50 ranging between 0.2 and 0.4
µM in all cancer cell lines tested (Fig. 1A)
. It has been shown that
treatment with agents that selectively inhibit the EGFR, such as
anti-EGFR blocking MAbs, have a cytostatic effect generally with cell
cycle arrest in the G1 phase (5)
.
However, in some cancer cell lines, inhibition of the EGFR function
also caused apoptotic cell death (34
, 48)
. We, therefore,
determined whether the ZD-1839 antiproliferative effect was accompanied
by the induction of programmed cell death. As shown in Fig. 1B,
ZD-1839 treatment induced a dose-dependent 2–4-fold
increase in apoptosis in all cancer cell lines tested with a maximum
effect between 0.1 and 1 µM. Treatment with
ZD-1839 resulted also in a dose-dependent inhibition of EGF-induced
tyrosine autophosphorylation of the EGFR in MCF-10A Ha-ras
cells (Fig. 2)
as well as in the other
three cancer cell lines (data not shown).
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and 4)
. Similar results were obtained in GEO,
MCF-10A Ha-ras, and ZR-75-1 cells (data not shown).
Furthermore, when combinations of lower doses of ZD-1839 and cytotoxic
drugs were used, the antiproliferative effect was clearly cooperative
in all cell lines examined. For example, the cooperativity quotient of
the combined treatment, defined as the ratio between the actual growth
inhibition obtained with the combination of a cytotoxic drug
(paclitaxel, topotecan, doxorubicin, oxaliplatin, or raltitrexed) and
ZD-1839 and the sum of the growth inhibition achieved by each agent was
between 1.5 and 2.5 in all cancer cell lines tested (Fig. 5)
.
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. Treatment with each
cytotoxic drug increased apoptotic cell death in a dose-dependent
manner in both GEO and OVCAR-3 cells. Addition of ZD-1839 at low doses
that induce little or no apoptosis alone potentiated
cytotoxic-induced apoptosis in both cell lines by approximately
2–3.5-fold (Fig. 6)
.
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, when injected s.c. in
immunodeficient mice (48)
. GEO cells
(107) were injected s.c. into the dorsal flank of
nude mice. After 1 week, when established GEO xenografts were palpable
with a tumor size of 
0.25 cm3, mice were
treated i.p. on days 1–5 of each week for 4 weeks with different
concentrations of ZD-1839 (Fig. 7A)
. ZD-1839 treatment
produced a dose-dependent inhibition of GEO tumor growth that was
almost completely suppressed in mice treated with the 5 mg of daily
dose. This effect was cytostatic rather than cytotoxic. In fact, GEO
tumors resumed a growth rate comparable with controls within 1–2 weeks
by the termination of treatment (data not shown). ZD-1839 treatment was
generally well tolerated by mice with no signs of acute or delayed
toxicity. However, an approximately 5–10% reduction in body weight
that was reversible upon cessation of treatment was observed at the end
of the treatment period in mice receiving the highest ZD-1839 dose.
Although GEO tumor growth was only delayed, mouse survival duration was
significantly increased in the ZD-1839 (5 mg/dose)-treated group
(P < 0.001), as shown in Fig. 7B
.
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50%
inhibition of tumor growth after 4 weeks of treatment and was very well
tolerated. This dose of ZD-1839 was given for 4 weeks in combination
with four weekly administrations of either paclitaxel, topotecan, or
raltitrexed to nude mice bearing established GEO tumors. The maximum
tolerated doses of paclitaxel, topotecan, or raltitrexed using this
schedule were selected. Treatment of mice with each agent significantly
inhibited GEO tumor growth in vivo as compared with control
untreated mice. However, shortly after the end of the treatment with
ZD-1839, paclitaxel, topotecan, or raltitrexed, GEO tumors resumed the
growth rate of untreated tumors (Fig. 8)
. A cooperative
antitumor effect was observed when ZD-1839 was used in combination with
each cytotoxic drug tested with a significant suppression of tumor
growth at the end of the 4 weeks of treatment in all mice as compared
with untreated mice or to single agent-treated mice. As shown in Fig. 8
, GEO tumors reached a size not compatible with normal life in all
untreated mice within 4–6 weeks and in all single agent-treated mice
within 6–8 weeks after GEO cell injection. The delayed GEO tumor
growth in the ZD-1839 plus chemotherapy-treated groups was accompanied
by a prolonged life span of mice that was significantly different from
that of untreated controls or single agent-treated groups. This effect
was more pronounced with the paclitaxel plus ZD-1839 combination. In
fact, 40% of mice treated with this combination were the only mice
alive 16 weeks after tumor cell injection (Fig. 8B)
.
Combined treatments with ZD-1839 and each cytotoxic drug at the dose
and schedule tested were well tolerated by mice, with no weight loss or
other signs of acute or delayed toxicity observed.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, we analyzed the effects of ZD-1839 on cell proliferation, induction of apoptosis, and antitumor activity in several human cancer cell lines with a functional EGFR-driven autocrine pathway. ZD-1839 treatment produced a dose-dependent growth inhibition in vitro in all human cancer cell lines tested. The growth inhibition induced by ZD-1839 was mainly cytostatic, although an increase in programmed cell death was observed with higher doses. Furthermore, ZD-1839 treatment had antitumor activity in vivo against established GEO cancer xenografts in immunodeficient mice. This effect was also dose dependent. At the end of a 4-week treatment period with the highest dose tested (5 mg/dose), GEO tumor growth was almost completely suppressed. ZD-1839 was well tolerated in vivo, because it could be administered to mice for at least 4 weeks without relevant toxicity. A reversible mild reduction in body weight was the only side effect observed with the highest dose used. However, the antitumor effect of ZD-1839 in vivo was reversible upon cessation of treatment. These results were similar to those obtained with the treatment of established human solid tumor xenografts with other types of anti-EGFR agents, such as EGFR blocking MAbs (13 , 31, 32, 33) .
We also evaluated the potential cooperative antiproliferative effect of the combined treatment with ZD-1839 and cytotoxic drugs. There was a significant dose-dependent potentiation of the proapoptotic effect and of the growth-inhibitory activity of all cytotoxic drugs tested by the EGFR tyrosine kinase inhibitor. Furthermore, mice were treated with weekly injections of cytotoxic drugs and ZD-1839 for 4 weeks in an attempt to develop treatment schedules of combined treatment suitable for testing in cancer patients. With this treatment schedule, an enhancement of antitumor activity was observed in vivo in mice bearing established GEO cancer xenografts when treated with ZD-1839 in combination with paclitaxel, topotecan, or raltitrexed. This effect was accompanied by significantly increased survival in the combined therapy group as compared with the groups treated with a single agent. In fact, in established GEO human colon carcinoma xenografts, treatment with each agent alone transiently inhibited tumor growth as the tumors resumed the growth rate of untreated controls after cessation of therapy. In contrast, the combined treatment with each cytotoxic agent and ZD-1839 produced tumor growth arrest in all mice; tumors grew slowly for approximately 4–8 weeks after the end of treatment, when they finally resumed a growth rate similar to controls. GEO tumors reached a size not compatible with normal life in all control mice within 4–6 weeks and in all single agent-treated mice within 6–8 weeks after GEO cell injection. In contrast, 50% of mice treated with ZD-1839 plus topotecan, raltitrexed, or paclitaxel were still alive 10, 12, and 15 weeks after cancer cell injection, respectively. The combined treatment with these selected doses of ZD-1839 and paclitaxel, topotecan, or raltitrexed was well tolerated by mice without signs of toxicity. Therefore, in an attempt to increase mice survival and possibly to eradicate established tumors, it is conceivable that additional cycles of combined therapy could be administered.
The increase in cytotoxicity and in antitumor efficacy obtained by the blockade of EGFR activation with ZD-1839 treatment seems to be independent of the mechanism(s) of action of the chemotherapeutic agents used in combination. In fact, an enhanced effect was found with structurally and functionally different drugs, such as topoisomerase I- or topoisomerase II-selective inhibitors, taxanes, platinum-derived agents, and a thymidylate synthase inhibitor. These results are in agreement with and extend those of previous reports that have shown a cooperative antitumor activity for different cytotoxic drugs such as cisplatin, doxorubicin, paclitaxel, or topotecan when combined with antibodies generated against the EGFR or the closely related c-erbB-2 type I tyrosine kinase receptor (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42) . Taken together, these studies support the hypothesis that cellular damage by chemotherapy can convert EGFR ligands from growth factors into survival factors for cancer cells that express functional EGFR (51) . In this situation, the blockade of EGFR mitogenic signaling in combination with cytotoxic drugs could cause irreparable cancer cell damage, leading to programmed cell death (51) .
The potentiation of the antitumor activity of cytotoxic drugs by interfering with EGFR activation may have important clinical implications. In fact, it has been proposed that it is possible to enhance anticancer activity by treatment with maximum tolerated doses of cytotoxic drugs in combination with signal transduction inhibitors instead of increasing chemotherapy doses to supertoxic levels that require complex medical support, including hematopoietic rescue (51) . In this respect, the feasibility and antitumor activity of the combined treatment of cisplatin and MAb C225 in patients with advanced head and neck or lung carcinomas has been demonstrated (18) . Similarly, blockade of c-erbB-2 signaling by treatment with a recombinant humanized anti-c-erbB-2 MAb (Herceptin) enhances the antitumor activity of cisplatin in metastatic breast cancer patients (40) . Furthermore, a randomized Phase III trial has recently demonstrated that the addition of Herceptin in advanced breast cancer patients treated with paclitaxel or doxorubicin increases the activity of chemotherapy alone (42) .
In summary, the results of the present study demonstrate the antitumor activity of ZD-1839 and provide a rationale for the evaluation of the anticancer activity of this EGFR-specific tyrosine kinase inhibitor alone and in combination with cytotoxic drugs in cancer patients with epithelial tumors that express functional EGFR. Preliminary results of two independent Phase I studies have been reported recently (52 , 53) . These studies have shown the feasibility of oral administration of ZD-1839 to cancer patients for prolonged periods with no major toxic effects at doses that allowed us to obtain steady-state plasma concentrations that are within the biologically effective concentrations demonstrated in the present study.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from the Associazione
Italiana per la Ricerca sul Cancro and the Consiglio Nazionale delle
Ricerche 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, 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: EGF, epidermal
growth factor; EGFR, EGF receptor; TGF, transforming growth factor;
MAb, monoclonal antibody.
Received 11/19/99; revised 2/14/00; accepted 2/16/00.
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