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Experimental Therapeutics |
Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women’s Hospital, The Children’s Hospital, and Department of Surgery, Harvard Medical School [T. K., P. R. Z., M. A., P. M. B.], and Department of Microbiology and Molecular Genetics, Harvard Medical School and the Dana-Farber Cancer Institute [J. A. A., P. I., C. D. S.], Boston, Massachusetts 02115, and Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland [T. O., E. B.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Most malignant tumors are curable only when surgery or radiotherapy are used together with adjuvant chemotherapy. Unfortunately, there has been little progress in brain tumor chemotherapy during the past 25 years. At most, 15–20% of all brain tumor patients currently benefit from chemotherapy, and the gains are measured in added months rather than added years of life. Historically, chemotherapy for gliomas has used cytotoxic drugs, the mode of action of which is cell cycle independent (3 , 4) . However, fundamental insights into signal transduction and cell cycle control generated during the past decade are being translated into a new generation of signal transduction/cell cycle inhibitors. These drugs can be very selective in action and may provide opportunities to attack brain cancers on a qualitatively new front.
One of these new drugs is STI571, a small molecule kinase inhibitor of
the 2-phenylaminopyrimidine class (Fig. 1A)
. This p.o.-active pharmaceutical targets the activated Abl
oncoprotein and certain members of the subgroup III receptor tyrosine
kinase family, including the receptors for
PDGF.7
Other non-receptor tyrosine kinases, serine/threonine kinases, and
growth factor receptors (EGF, insulin-like growth factor, insulin, and
fibroblast growth factor) are at least two orders of magnitude more
resistant to the action of STI571 than the Abl oncoprotein and the PDGF
receptors (5)
. Preclinical studies with STI571 on the
growth of BCR-abl-positive cells (5)
culminated in
clinical trials on chronic myelogenous leukemia that are yielding
encouraging results (6)
. A broad body of literature
suggests that gliomas might constitute another target for STI STI571.
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subunit is
overexpressed in virtually all cultured glioma cell lines and in fresh
surgical isolates of human malignant astrocytoma (7, 8, 9)
.
Overexpression of the receptor gene can be detected even within
low-grade astrocytoma (9)
. Thus, overexpression of the
receptor appears as an early event in the "progressive" pathway to
astrocytoma. Because the receptor subunit is the universal PDGF
receptor, sensitive to all three isoforms of PDGF (11
, 12)
, it follows that activation of PDGF receptors through an
autocrine loop may be a pervasive feature of malignant astrocytoma. PDGF autocrine loops could, in theory, be completely incidental to the disease. Alternatively, the closure of PDGF autocrine loops could be an early initiating event that becomes irrelevant to the malignant phenotype as the tumor progresses to acquire additional genetic lesions. However, a broadening base of data indicates that PDGF receptor autocrine loops initiate the transformation process and then continue to contribute to the transformed phenotype of malignant astrocytoma cells. Evidence for an initiating role in glioblastoma comes from studies showing that a retrovirus expression vector encoding PDGF B-chain, the universal PDGF ligand, can induce monoclonal or oligoclonal astrocytoma after injection into the brain of newborn mice (13) . Evidence for a maintenance role in the transformed phenotype is derived from studies showing that disruption of ligand:receptor complex can inhibit PDGF receptor autophosphorylation and revert the transformed phenotype of glioblastoma cell lines that have been in culture for many years. Growth inhibition and reversion of the transformed phenotype have been achieved with suramin, neutralizing antibodies to PDGF, and with dominant-negative mutations of either PDGF ligand or PDGF receptor (14, 15, 16, 17, 18) .
Collectively, these data suggest that PDGF receptors might be a therapeutic target for glioblastoma multiforme. However, the agents that have thus been shown to function as antagonists of PDGF receptor activation are unlikely to be of practical value in the treatment of patients with brain cancer. Even in cell culture studies, some glioblastoma cell lines are refractory to PDGF antagonists that act at the outer cell surface (i.e., suramin and anti-PDGF antibodies), presumably because significant levels of functional PDGF:receptor complex can be formed within the cell cytoplasm (15 , 19) . In clinical applications, this cellular compartmentation problem would be exacerbated by the blood-brain barrier. Within current limitations of gene transfer technology, prospects for therapy with dominant-negative mutations of PDGF ligand or PDGF receptor are likewise bleak. In studies presented here, we show that STI571 selectively disrupts PDGF receptor autocrine loops and has therapeutic potential for malignant astrocytoma.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PDGF Receptor Tyrosine Kinase Inhibitor.
STI571 was synthesized by Novartis Pharmaceuticals and has been
described previously (5
, 20)
. For in vitro
assays and for the initial studies on tumor growth in nude mice, STI571
was solubilized and delivered in DMSO. For later studies on
intracranial tumor growth, STI571 was diluted in water and administered
by oral gavage as indicated.
Clonogenic Growth Assay.
Approximately 103 cells were plated into 60-mm
dishes (Falcon) using DMEM/10% BCS. After 24 h, the
serum-supplemented medium was removed, and cells were shifted to
PDGF-free culture conditions by using 5% PPP as a supplement to DMEM
in place of serum. STI571 was added to the PPP-supplemented medium as
indicated, and thereafter, medium was renewed every 2 days. At day 11,
colonies were fixed and stained with methylene blue.
Cell Proliferation Assay.
Cells were plated into 60-mm culture dishes and processed as for the
clonogenic assays above. At day 11, cells were harvested by trypsin
digestion and counted using either a hemocytometer or a Coulter
counter.
Flow Cytometry.
Approximately 105 cells were plated into DMEM
with 10% BCS. After 24 h (day 1), the medium was changed to
DMEM/5% PPP with or without STI571. Cell cycle distribution was
analyzed by propidium iodide staining and flow cytometry, using an
EPICS752 (Coulter Corp) with the 488-nm laser.
s.c. Tumor Growth.
For all in vivo experiments, male NCr Nude mice (Taconic,
Germantown, NY), 4–6 weeks of age, were used. All animal studies were
performed under the approval of Dana-Farber Cancer Institute Animal
Research Committee in accordance with federal, local, and institutional
guidelines (Protocol number: 98-041). Pooled colonies of
ras-transformed BALB/c 3T3, v-sis-transformed BALB/c 3T3, U87, and U343
were trypsinized and resuspended in DMEM and counted. By using a
tuberculin syringe and a 27-gauge hypodermic needle,
107
cells (0.1 ml) were injected into the s.c.
tissue of the right flank region. Five days after cell implantation
(day 1), STI571 was started at a dose of 50 mg/kg/day, delivered by
i.p. injections in two daily doses. Experimental sets for U343 and U87
consisted of 10 mice for the control and 10 mice for STI571-treated
groups. For ras-transformed BALB/c 3T3 and v-sis-transformed BALB/c
3T3, five mice for each experimental set were studied. Tumor growth was
followed by measuring perpendicular tumor diameters. Tumor volumes were
calculated using the formula 
x L x D2/6,
where L is the longest diameter and D is the
diameter at right angles to it. According to the animal research
protocol, mice having tumors in excess of 2 cm were sacrificed;
otherwise, tumor measurements were continued until day 30.
Intracranial Tumor Growth.
For intracranial implantation, 106 cells in a
volume of 10 µl of PBS were injected into the right frontal
hemisphere, using a stereotactic fixation device (Stoelting, Wood Dale,
IL). After a recovery period of 5 days, animals began receiving either
STI571 or vehicle through an orogastric tube daily. Animals were
examined daily by a veterinarian who was blind to the study and
sacrificed as directed when symptoms of intracranial tumor growth
became evident.
TUNEL Staining and Immunoblotting.
TUNEL stains on tumors removed from mice treated or not with STI571 for
1 week were performed after fixation with 4% paraformaldehyde in PBS
and cryostat sectioning using the Apoptosis Detection System,
Fluorescein (Promega Corp., Madison, WI) according to the
manufacturer’s instructions. For the generation of protein extracts,
tumors were allowed to grow to approximately 0.5 x 0.5
cm in size then the animal was treated (+) or not (-) with 50 mg/kg
STI571 via i.p. injection. Tumors for immunoblots were harvested 2 h after treatment, and extracts were generated immediately. PDGF
receptor was immune-precipitated from 1 mg of protein, resolved on a
7.5% polyacrylamide gel, and transferred to Immobilon, and the
resulting blot was probed as indicated and as described previously
(17)
Statistical Analysis.
Statistical analysis for the s.c. tumor volumes was carried out by
Student’s t test. For the survival rates of the
intracranial tumor implanted mice, Kaplan-Meier analysis using the
STATVIEW software package was used. P < 0.05
was considered to be significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß PDGF receptor subunits, and
they require an exogenous source of PDGF for optimum growth in culture.
In previous studies on the action of PDGF ligand dominant-negative
mutations, we transformed wild-type BALB/c-3T3 cells through stable
expression of PDGF ligand cDNAs (17)
. As controls, we also
transformed these 3T3 cells with oncoproteins that function downstream
of receptor tyrosine kinases, notably H-ras, v-src, and SV 40. As an
initial evaluation of STI571, we conducted a dose-response assay on
this panel of well-characterized BALB/c 3T3 cell lines.
The chemical structure of STI571 is shown in Fig. 1A
. As
shown in Fig. 1B
, the mitogenic response of wild-type 3T3
cells to ectopic PDGF is inhibited by STI571 at concentrations as low
as 3 µM. The 3T3 cells transformed by PDGF A or
PDGF B proliferate in the absence of ectopic PDGF, because expression
of the ligand cDNAs closes a PDGF autocrine loop. However,
proliferation of PDGF A/B 3T3 cells under these conditions is again
inhibited by low (3 µM) concentrations of
STI571. The H-ras, v-src, and SV40 3T3 cells grow well in PDGF-free
medium (DMEM + 5% PPP). However, STI571 does not inhibit the
growth of these cells until much higher concentrations of the drug are
added to the culture medium. Thus, the biological "action spectrum"
of STI571 on these well-characterized 3T3 cells duplicates the action
spectrum of the PDGF dominant-negative mutations noted in our previous
studies (17)
.
In our previous studies, we also examined the action of
dominant-negative PDGF mutations on a panel of human tumor cell lines
(17)
. Accordingly, we tested the action of STI571 on this
same panel of human cell lines. For a frame of reference, we included
cultures of BALB/c 3T3 cells transformed by the PDGF A gene.
As indicated (Fig. 1B)
, all of these human cell lines grow
well in PDGF-free medium. Two different glioblastoma cell lines (U343
and U87) are growth inhibited by STI571 at low (3
µM) concentrations. Under identical conditions,
a human bladder carcinoma (EJ) and a human colon carcinoma (SW 480),
both of which express an activated ras gene, are relatively
resistant to STI571. HeLa cells are sensitive to STI571, a
characteristic that would not be predicted from conventional wisdom
regarding the tissue distribution of PDGF receptors and the cellular
origins of HeLa. However, as noted in our previous studies, the HeLa
cell stocks in our laboratory are growth inhibited by dominant-negative
mutations of PDGF ligand formation (17)
. Thus, human cells
that are sensitive to STI571 are identical to the human cells that
respond to genetic disruption of PDGF autocrine loops. Conversely, the
human cells that are resistant to STI571 are likewise unaffected by
genetic agents that disrupt PDGF autocrine loops (17)
.
A "Therapeutic Window" for STI571.
The clonogenic dose-response assays provide a rapid qualitative
assessment of sensitivity to STI571. A more quantitative assessment of
drug sensitivity was conducted using lower concentrations of the drug
and monitoring actual cell number. As shown (Fig. 2)
, cell lines that express PDGF autocrine loops are inhibited by
concentrations of STI571 as low as 1.5 µM. By contrast,
cells transformed by downstream oncoproteins were insensitive to STI571
at concentrations as great as 10 µM.
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, this drug regimen inhibited the formation of tumors from PDGF B 3T3
cells and from the two human glioblastoma cell lines U343 and U87.
However, STI571 did not inhibit the formation of tumors from
ras-transformed 3T3 cells. Thus, the action spectrum of the drug on
tumor formation in animals is similar to the action spectrum for growth
inhibition in vitro in PDGF-free medium. To an outward
appearance, mice receiving STI571 appeared healthy throughout the
course of the experiment.
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. STI571, therefore, is able to interrupt the autocrine loop
responsible for ectopic stimulation of the PDGF receptor in human
glioblastoma.
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, oral administration of STI571 prolongs the survival of mice that
received an intracranial inoculation of PDGF B (sis) 3T3 cells (Fig. 5B)
, U87 glioblastoma cells (Fig. 5, C and E)
, or U343 glioblastoma cells (Fig. 5D)
. As a
negative control, we injected ras-transformed BALB/c 3T3 cells. STI571
could not prolong the survival of mice that had received an
intracranial injection of these cells (Fig. 5A)
. These data
suggest that p.o.-administered STI571 can access the cranium at levels
sufficient to be of therapeutic value in malignant astrocytoma.
Moreover, the target selectivity demonstrated in Figs. 1
2
3
is retained
in the intracranial environment.
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grown in the presence or absence of
PDGF and ras-transformed BALB/c 3T3 cells (Fig. 6D)
,
respectively. As shown (Fig. 6B)
, when STI571 is added to
wild-type 3T3 cells (growing in the presence of PDGF) they become
growth arrested in the
G0-G1 phase of the cell
cycle. The drug-induced growth arrest of wild-type 3T3 cells is
identical to that seen when these cells are deprived of PDGF (Fig. 6A)
. The ras-transformed 3T3 cells grow in the absence of
PDGF as noted previously (Figs. 1
and 2)
and show no change in their
cell cycle distribution profile in the presence of STI571 (Fig. 6D)
. STI571 treated c-sis-transformed BALB/c 3T3 cells
growth arrested in a similar manner as the wild-type cells (Fig. 6C)
, indicating that STI571 is able to interrupt the
PDGF-mediated autocrine loop that allows these cells to grow in the
absence of the growth factor.
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.
Close scrutiny of the glioblastoma FACS profiles reveals no sign of the
sub-G1 cellular debris associated with apoptosis.
As a positive control, we used a well-characterized model for
drug-induced apoptosis. As shown in Fig. 6G
, FACS analysis
of HL-60 cells that had been treated with etoposide shows ample
evidence of the cellular debris associated with apoptosis. The
etoposide-treated cells are also reactive in TUNEL stains (data not
shown). Thus, our assays would have detected STI571-induced apoptosis
in these studies had it occurred. TUNEL staining of small U87-derived
glioblastoma tumor samples excised from STI571-treated nude mice
revealed no sign of STI571-induced apoptosis in vivo (Fig. 7)
. We conclude that the main mechanism of STI571-induced growth
inhibition in vitro and in vivo is that of cell
cycle arrest, rather than apoptosis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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STI571 was developed as an inhibitor of the c-Abl tyrosine kinase. Other non-receptor tyrosine kinases and serine/threonine protein kinases are resistant to STI571. Receptor tyrosine kinases in the EGF, insulin-like growth factor, and fibroblast growth factor families are likewise insensitive to STI571. However, PDGF receptor family tyrosine kinases are as sensitive to STI571 as the original c-Abl target (5 , 20) . Using a well-characterized panel of murine and human cell lines, we show that STI571 selectively inhibits the growth of cells that are driven by activated PDGF receptors. This selective growth inhibition is observed in both tissue culture and nude mice. Moreover, the drug is p.o. active against intracranial implants of human glioblastoma in nude mice.
The main mechanism of STI571-induced growth inhibition in
vitro and in vivo is that of cell cycle arrest, rather
than apoptosis. It should be noted, however, that the population of sis
3T3, U343, and U87 cells does decline during an 11-day exposure to
STI571 (Fig. 2A)
. A considerable amount of floating cell
debris can be seen in these long-term drug-treated cultures. Thus, over
an extended time, disruption of PDGF autocrine loops leads to some
degree of cell death, perhaps through nonapoptotic mechanisms or
through low levels of apoptosis. In addition, it should be noted that
these studies involve immortalized cell lines that have grown in
culture for many years. It is possible that primary tumors with PDGF
autocrine loops might respond differently to STI571.
One concern is that STI571, while inhibiting PDGF receptor signaling, might antagonize other signaling pathways that are required for programmed cell death (apoptosis). For example, the other known target for STI571, c-Abl, is known to facilitate the apoptotic response to DNA damage (25, 26, 27) . Myeloid cell lines that have been transformed by Bcr-Abl undergo apoptotic cell death rather than growth arrest when exposed to STI571. Thus, STI571 does not inherently antagonize the process of programmed cell death. Rather, the data suggest that cellular responses to STI571 mimic the effect of growth factor withdrawal from factor-dependent cell lines. Factor-dependent myeloid cell lines generally undergo programmed cell death upon factor withdrawal, whereas nonmyeloid lines, such as 3T3, undergo growth arrest.
Obviously, a cytotoxic response would be preferable to a cytostatic response in a cancer therapeutic. However, cytotoxic agents have proven generally ineffective as therapeutics for glioma. Given the minimal toxicity shown by STI571 thus far in clinical trials on chronic myelogenous leukemia, the possibility emerges that STI571, perhaps used in combination with other therapeutic modalities, might be of some benefit to patients with glioblastoma. As time goes on, other treatment modalities might prove to synergize with STI571 by promoting cell killing in addition to growth arrest.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Grant HD24926 from
the National Institutes of Child Health and Development and a grant
from the June Rockwell Levy Foundation. In compliance with Harvard
Medical School guidelines on potential conflict of interest, we
disclose that one of the authors (C. D. S.) has a consulting
relationship with Novartis Pharmaceuticals. 
2 The first two authors contributed equally to
this work.
3 Present address: Marmara University, Institute
of Neurosciences, Department of Neurosurgery, Istanbul, Turkey
pk53 81532.
4 Present address: Department of Anatomy,
Institute of Biostructure, University Medical School of Warsaw,
Warsaw, Poland 02-004.
5 Present address: Baylor College of Medicine,
Houston, TX 77030.
6 To whom requests for reprints should be
addressed, at Department of Cancer Biology, Dana-Farber Cancer
Institute, 44 Binney Street, Boston MA 02115. E-mail: charles_stiles{at}dfci.harvard.edu
7 The abbreviations used are: PDGF,
platelet-derived growth factor; EGF, epidermal growth factor; BCS,
bovine calf serum; PPP, platelet-poor plasma; TUNEL, terminal
deoxynucleotidyltransferase-mediated nick end labeling; FACS,
fluorescence-activated cell sorter.
Received 3/10/00. Accepted 7/20/00.
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),
c-sis-transformed BALB/c 3T3 cells (
), U87 glioblastoma cells (
),
and U343 glioblastoma cells
(
).
B, cells that failed to respond to STTI571
treatment:ras-transformed BALB/c 3T3 cells (
). The
horizontal line in both reflects the starting (plated)
population. Results were reproduced in at least three independent
experiments. Results from a typical experiment performed in triplicate
are shown; bars, SE.
) by twice daily i.p. injections of 25 mg/kg each. Results
presented here are representative of three independent experiments.
