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INTERNATIONAL JOURNAL OF ONCOLOGY 28: 1021-1030, 2006
Cimetidine, an unexpected anti-tumor agent, and its
potential for the treatment of glioblastoma (Review)
FLORENCE LEFRANC1, PAUL YEATON3, JACQUES BROTCHI1 and ROBERT KISS2
1Department of Neurosurgery, Erasmus University Hospital, 2Laboratory of Toxicology,
Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium;
3Department of Gastroenterology, University of Virginia, Charlotesville, VA, USA
Received November 2, 2005; Accepted December 29, 2005
Cimetidine (CIM), the prototypical histamine H2
3. Cimetidine as an anti-tumor drug
receptor antagonist (H2RA), was brought to market based
4. Mechanisms of action of cimetidine in oncology
on its ability to accelerate healing of gastrointestinal ulcers
5. Cimetidine and malignant gliomas
through the inhibition of gastric acid secretion. Cimetidine,
the most studied H2RA, has been demonstrated to possess
anti-tumor activity against colon, gastric and kidney cancers,
and melanomas. This activity involves a number of different
1. Origin of cimetidine
mechanisms of action: a) CIM antagonizes tumor cell-
mediated interleukin-1-induced activation of selectins in liver
sinusoids, inhibiting tumor cell binding on liver sinusoids,
imidazol-4-yl)methyl)thio)ethyl)guanidine] is a substituted
thereby reducing the development of liver metastasis; b)
imidazole with a specific antagonistic effect on histamine H2
histamine acts as a growth factor in various tumor cell types
receptors. Briefly, cimetidine (CIM) is a weak base with a
via the activation of H2 receptors; CIM therefore may anta-
high level of water solubility which can be measured in
gonize this effect; c) CIM acts as an immunomodulator by
biological fluids including the cephalo-spinal fluid (1). CIM
enhancing the host's immune response to tumor cells. With
is metabolized in the liver by oxidative hydroxylation and
respect to malignant gliomas, CIM added to temozolomide
conjugation. Up to 80% of a single dose of CIM is excreted
was superior in vivo
when compared to temozolomide alone
in the urine (1), with up to 70% in an unchanged form (1). Its
in extending survival of nude mice with human glioblastoma
principal action is on parietal cel histamine H2 receptors, and
cells orthotopically xenografted into their brain. We review
by binding to these receptors, inhibits gastric acid secretion
the various mechanisms of action potentially associated with
stimulated by histamine, pentagastrin, acetylcholine, insulin,
the therapeutic effects of CIM in the case of experimental
food and other secretagogues (2).
glioblastomas, observations we hope will encourage clinical
investigation of CIM in the management of highly malignant
2. Initial therapeutic indications of cimetidine
CIM was the first registered histamine H2RA, its wide
acceptance was based on its clinical effectiveness in the
healing of gastrointestinal ulcers through inhibition of gastric
acid secretion (1-3). CIM was one of the most widely used
1. Origin of cimetidine
H2RA during the 1980s (3). At the time of its introduction in
2. Initial therapeutic indications of cimetidine
the late 1970s, CIM was rarely considered an agent with
clinical utility other than its primary indication (3). A primary
concern was if by virtue of their acid-inhibitory activity,
_ H2RAs increased the risk of developing gastrointestinal
malignancies (3); tiotidine, one of the earliest H2RAs
developed, was abandoned when preclinical toxicity tests
: Dr Robert Kiss, Laboratory of Toxicology,
demonstrated an increased incidence of gastric tumors in rats
Institute of Pharmacy, Université Libre de Bruxelles, Campus de la
(4). CIM inhibits several isozymes of the cytochrome P450
Plaine, Boulevard du Triomphe, 1050 Brussels, Belgium
enzyme system, including CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A4. This inhibition forms the
: CIM, cimetidine; H2RAs, histamine H2 receptor
basis of the numerous drug interactions. While CIM proved
to be a safe medication, its use in peptic ulcer disease was
supplanted by the development of longer-acting H2RAs with
cimetidine, H2RAs, malignant gliomas, cancer
reduced adverse effects and the introduction of highly specific
proton pump inhibitors (2).
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LEFRANC et al
: CIMETIDINE AND MALIGNANT GLIOMAS
Table I. Description of the various clinical trials using cimetidine in oncology.
Post-operative 800 mg/d
Tonnesen et al
Burtin et al
5 d pre-/2 d post-operative 800 mg/d
Adams and Morris (7)
5FU+/-post-operative 800 mg/d, 1 y
Post-operative 400 mg twice/d, 2 y
45 (Dukes C) Significant increase
Svendsen et al
Pre-operative, 7 d
3-y survival benefit
Adams and Morris (10)
Pre-operative 800 mg twice/d, 5 d
Kelly et al
Non-randomized 5FU+/-post-operative 800 mg/d, 1 y
10-y survival benefit
Matsumoto et al
Advanced melanoma Phase II
Morton et al
Advanced melanoma Phase II
Creagan et al
Non-randomized Coumarin + 300 mg, 4x/d upd
Marshall et al
Coumarin + 300 mg 4x/d
Dexeus et al
Non-randomized 600 mg/d upd
Inhorn et al
INF +/- (coumarin + 400 mg 3x/d)
No significant increase Sagaster et al
upd, until progression of disease; d, day; y, year; CR, complete response; PR, partial response; INF, interferon; RCC, renal cell carcinoma.
3. Cimetidine as an anti-tumor drug
The use of CIM also has intriguing implications in the
management of advanced malignant melanomas (14-16) and
The first reports suggesting CIM exhibited a clinical onco-
metastatic renal cell carcinomas (17-20) (Table I).
logic effect appeared in 1988 in the context of gastric cancer
Our group (21) has demonstrated that CIM complements
(5,6). In a randomized study including 65 patients selected
the cytotoxic agent temozolomide in experimental glio-
because their condition contraindicated all other forms of
blastomas, a point detailed in the section entitled Cimetidine
treatment, Burtin et al
(5) found that a course of CIM (1-1.2 g/
and malignant gliomas.
day) or ranitidine (450-900 mg/day) significantly improved
the patients' survival rates. These patients survived six times 4. Mechanisms of action of cimetidine in oncology
longer than others receiving pal iative treatment with analgesics
(5). Another multicenter, randomized, double-blind, placebo-
Studies of the anti-tumor effects of CIM indicate multiple
controlled study carried out by Tonnesen et al
(6) on 181
potential mechanisms of action, characterized by three overal
patients showed that a post-operative course of CIM at a
characteristics: a) a direct inhibitory effect on tumor growth
normal therapeutic dosage (800 mg/day) significantly
by blocking the cell growth-promoting activity of histamine
prolonged the survival of gastric cancer patients.
(22-24) (Fig. 1) and an indirect effect by inhibiting tumor-
In colorectal cancer patients, Adams and Morris (7) were
associated angiogenesis (Fig. 2) (25); b) a cell-mediated
the first to demonstrate the beneficial effect of a short-course
immunomodulation by enhancing the host's immune response
perioperative treatment with CIM on surgically-induced
to tumor cells (Fig. 1) (26-28); c) an inhibition of cancer cell
immunosuppression. Their randomized study involving 34
migration (21) and adhesion to endothelial cells (29) and
patients showed a strong trend towards enhanced survival in
therefore an inhibition of tumor neo-angiogenesis (25) (Fig. 2)
the patients treated with CIM (800 mg/day) when compared
and metastasis development (29) (Fig. 3).
to controls, a finding correlated with an increase of lymphocyte
infiltration into the tumors (7).
Inhibitory effects on tumor growth
. While the mechanisms
Matsumoto (8) performed a multicenter randomized
involved are incompletely understood, CIM is known to inhibit
controlled study in 64 colorectal cancer patients receiving
the growth of several types of tumors, including gastro-
postoperative 5-fluorouracil. Post-operative treatment with
intestinal cancers, both in vitro
and in vivo
in animal models
CIM (800 mg/day) and 5-fluorouracil (150 mg/day) for about
(23,24). An active role is strongly suggested for histamine of
a year was efficacious, increasing the disease-free period and
autocrine or paracrine origins in malignant cell proliferation
survival when compared to the treatment with 5-fluoro-
(Fig. 1) (12).
uracil alone (8).
Histamine is a receptor-dependent growth factor in some,
Several subsequent studies, summarized in Table I, have but not all, human colon cancer cell lines, as well as in some
been published showing considerably enhanced survival rates
gastric, breast and melanoma cell lines (23,24,30,31). In a
in gastric and colorectal cancer patients treated with CIM (9-13).
culture study of four different colorectal tumor cell lines
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INTERNATIONAL JOURNAL OF ONCOLOGY 28: 1021-1030, 2006
Figure 1. CIM inhibitory effect on tumor growth and CIM-mediated immunomodulation. CIM blocks the cell growth-promoting activity of histamine. The
mechanisms proposed for the cell-mediated immunomodulation of CIM include the inhibition of suppressor T lymphocyte activity, the stimulation of natural
killer cell (NKc) activity, an increase in interleukin-2 (IL-2) and interleukin-12 (IL-12) production in helper T lymphocytes, an increase in tumor inhibitory
cytokines and the enhancement of the host's anti-tumor cell-mediated immunity.
Figure 2. CIM-mediated neo-angiogenesis inhibition. CIM induces a significant decrease in VEGF expression levels and the vascular-like tube formation by
endothelial cells is significantly impaired.
(C170, Lovo, LIM2412 and LIM2405) histamine was found
absence (23). When the C170 cell line was grown in nude
to stimulate cell proliferation in two of them (C170 and
mice as a subcutaneous xenograft, CIM had a significant
LIM2412) in a dose-dependent manner (23). This effect was
dose-dependent growth-inhibitoring effect leveling out at a
reversed by CIM in the presence of histamine, but not in its
dose of 50 mg/kg/day (23).
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LEFRANC et al: CIMETIDINE AND MALIGNANT GLIOMAS
Figure 3. CIM-mediated inhibition of cancer cel migration and the development of liver metastasis. Epithelial cel s detaching themselves from primary epithelial
tumors (tumoral bulk) and migrating through the lymphatic or the blood vessels eventual y colonize the liver because epithelial cancer cel s exhibiting Lewis
antigens on their surfaces are able to adhere to endothelial cells in liver sinusoids due to the presence of selectins (the ligands for Lewis antigens) in these
endothelial liver cells. CIM prevents liver metastasis of colon cancer cells by blocking E-selectin activation by means of the inhibition of interleukin-1 (IL-1)
secretion by the tumor cells.
Rajendra et al (32) demonstrated that CIM at 10 µM
of the H2-mediated actions of endogeneous histamine.
inhibited the in vitro proliferation of the Caco-2 colorectal
Curiously, ranitine did not seem to exert most of the in vitro
cancer cell line in the presence of histamine by causing
and in vivo effects mentioned, an observation which would
apoptotic cell death. In the human gastric tumor cell lines
argue against H2 receptors playing a role in the effects of
MKN45 and MKN45G, CIM (10 µM) reversed the
CIM, since ranitine is marginally more potent as an H2
histamine-stimulated proliferation (30). CIM also inhibited
receptor antagonist (36). In fact, in a prospective randomized
the proliferation of MKN45 subcutaneous xenografts in nude
controlled study, the use of ranitidine in patients with gastric
mice (100 mg/kg/day, given in the drinking water) (30). In
cancer did not show any significant increase in their survival
another in vitro study, histamine significantly stimulated
rates (37). In contrast, roxatidine significantly decreased the
cells proliferating in a dose-dependent manner on the gastric
in vivo growth of colon 38 implants in mice (38). In their
cancer cell lines KATO-III and AGS, with the maximum
study, Tomita et al (38) showed that in vitro, histamine,
effect again occurring around a 10 µM concentration (31).
roxatidine, and CIM failed to achieve any growth-promotive
CIM reversed the histamine-stimulated cell proliferation,
or suppressive effects in the case of the colon 38 cell line, a
with the maximum effect at concentrations above 10 µM
cell line that lacks H2 receptors, although roxatidine and CIM
(31). Ranitidine and famotidine did not show such an effect
suppressed the in vivo growth of the tumor tissue implants.
(31). Histamine significantly stimulated growth in two of
Such a finding suggests that in this case, the tumor-suppressive
four human melanoma cell lines, and this effect was inhibited
effects of H2 receptor antagonists do not constitute the product
by CIM in a dose-dependent manner, and also by ranitidine
of any direct action on tumor cel s. Szincsak et al (39) have
and famotidine (24). CIM also inhibited tumor growth of
shown that in vivo tumor proliferation in immunodeficient
human pancreatic cancer xenografts in immunodeficient mice mice xenotransplanted with a human melanoma cell line was
diminished by CIM (50 mg/kg/day), if combined with a
Adams et al (23) suggested a role for H2 receptors located
tamoxifen derivate acting on cytochrome P450 molecules.
either on the tumor cells themselves, on immunocompetent
This suggests again that the effect of CIM cannot be restricted
cells in the host, or both. Using L-histidine decarboxylase
to an H2 receptor blocker alone. The anticancer actions of
(HDC)-deficient mice with undetectable levels of endo-
CIM might not be mediated via histamine antagonist only.
genous histamine, Takahashi et al (34,35) have shown that
Therefore, the mechanisms of action by which CIM prolongs
the daily administration of CIM (0.12 mg/kg/day) failed to
the survival of patients with various forms of cancer remain
suppress the growth of a syngeneic colon adenocarcinoma
to be clarified and are probably multifactorial. The inhibitory
despite the fact that an identical dose of CIM suppressed
effect of CIM on tumor-associated angiogenesis (25,38) is
tumor growth in wild-type mice, as the result of the inhibition developed below.
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INTERNATIONAL JOURNAL OF ONCOLOGY 28: 1021-1030, 2006
Cell-mediated immunomodulation. Many tumors, and par-
remains unclear whether or not H2 receptors are expressed
ticularly colorectal and breast cancer, secrete histamine, a
on dendritic cells, the effect of CIM on the antigen presenting
process that results in high histamine levels within the tumors
ability of dendritic cells appears to increase because of CIM-
(13,40). Moreover, histamine is also frequently secreted in
specific actions (Fig. 1) (44). It also remains unclear whether
response to the surgical resection of colorectal cancers (40). Al
or not the modulating effects of CIM on the dendritic cell
these factors working together create an immunosuppressive
function observed in vitro by Kubota and colleagues (44)
environment both in the area of tumor growth and in the
have any clinical y substantial meaning: the clinical effective-
whole body, and in so doing they facilitate tumor growth. A
ness of CIM against gastrointestinal malignancies is considered
number of clinical studies have shown that the administration
to be due to the combined total of immunological and non-
of CIM may help in reducing the immunosuppression due to
increased histamine levels in a tumor's environment (11,41).
CIM has been reported as having better cell-mediated
Adams and Morris (7) first desribed that pre-operative
immunomodulation than other H2RAs such as famotidine
treatment with CIM (800 mg/day) significantly increased the
and ranitidine, and the differences between CIM and other
proportion of colorectal cancers that elicited a lymphocyte
H2RAs might be due to their structures and/or affinities to
response, and that the presence of tumor-infiltrating lympho-
H2 receptors (22,36).
cytes was associated with a survival advantage. In a pilot
Immunologically based therapies for various types of
study, they showed that CIM enhanced the lymphocyte
cancers are improved by adjuvant CIM therapy (47).
infiltration of human colorectal carcinomas (10). Forty-two
Interestingly enough, one study has reported that a small
patients scheduled for the elective resection of colorectal
number of patients with metastatic renal cell carcinomas
carcinomas were randomized either to receive CIM for one
(5%) responded with long-term remission to CIM mono-
week preoperatively, or to act as control (10). A positive
therapy (19). But, immunologically based therapies for renal
lymphocyte response was observed in 10 of 18 CIM-treated
cell carcinomas or disseminated malignant melanomas have
carcinoma patients compared with only 5 of the 24 control
usually been combined with CIM and the contributions of
patients (p=0.03) (10). Moreover, the presence of a lympho-
CIM have not been adequately controlled (17,20,48,49).
cyte response correlated with improved survival (10). Gastric
cancer patients also have higher levels of suppressor lympho-
Inhibition of cancer cell migration and the development of
cyte activity when compared to normal controls, and these
liver metastasis. In vitro studies have demonstrated that CIM
levels are restored to normal with CIM treatment (42). In a
inhibits the adhesion of some breast (50) and colon (29)
controlled randomized clinical trial, Lin et al (43) recently
cancer cells to human umbilical cord cells, a process that is
showed that pre-operative CIM administration at the dose of
a crucial biological step in tumor neo-angiogenesis and,
400 mg/day promoted peripheral blood lymphocytes and tumor consequently, in tumor progression and metastasis. Tomita et al
infiltrating lymphocytes in patients with gastrointestinal cancer.
(38) have shown that CIM-induced angiogenesis inhibition
The mechanisms proposed for the cell-mediated immuno-
suppresses the growth of colon cancer implants in syngeneic
modulation of CIM (Fig. 1) include the inhibition of suppressor
mice and is associated with a significant decrease in VEGF
T lymphocyte activity (26), stimulation of natural killer (NK)
expression levels in tumor tissue and the serum of colon
cel activity (27), an increase in interleukin-2 (IL-2) production 38-bearing mice (Fig. 2). In the syngeneic murine colon cancer
in helper T lymphocytes (28), an increase in tumor inhibitory
CMT93 model, CIM also significantly reduced the growth of
cytokines (35) and the enhancement of the host's anti-tumor
the subcutaneously grafted tumor and neovascularization in
cel -mediated immunity by improving the suppressed dendritic the tumor (25). CIM at this dose had no effect on the in vitro
cell function in advanced cancer patients (44).
proliferation of this cel line (25). The cancer cel s' production
Takahashi et al (35) have demonstrated that: a) a daily
of the vascular endothelial growth factor was not affected by
injection of CIM suppressed tumor progression in mice after
CIM, whereas the vascular-like tube formation by endothelial
the syngeneic transplantation of CT-26 cells (a colon adeno-
cells in vitro was significantly impaired in the presence of
carcinoma cell line); and b) decreased expression of TNF-·
CIM (Fig. 2) (25). Their findings suggest that CIM suppresses
and INF-Á associated with the tumor development was restored tumor growth, at least in part by inhibiting tumor-associated
following treatment with CIM. CIM dramatically increased
angiogenesis. One of the major classes of adhesion molecules
IFN-Á production by human lymphocytes (Fig. 1) via a possibly present on the surface of endothelial cells includes selectins
histamine-independent (non-histamine receptor mediated)
(51). The direct implication of P-selectin in endothelial cell
pathway, most likely through cytochrome P450 moieties (45). migration has been reported previously (52) and we recently
High concentrations of INF-Á resulted in the inhibition of cell
suggested a direct implication of E-selectin in human endo-
proliferation by the direct stimulation of natural killer cells
thelial cell migration during tubulogenesis (53). Both E- and
(Fig. 1) (45). The use of CIM also retarded the growth of
P-selectins are induced in endothelial cells by proangiogenic
human melanomas in a nude mouse model and prolonged the
cytokines such as the tumor necrosis factor (TNF)-· or IL-1ß
survival of the tumor-bearing mice by directly inhibiting the
(51). Since Kobayashi et al (29) have shown that CIM
proliferation of tumor cells and indirectly promoting the
prevented liver metastasis of colon cancer cells in nude mice
infiltration of activated macrophages into the tumor site (39).
by blocking the E-selectin expression on the endothelial
It is also reported that H2RAs such as CIM can reverse the
cells, the anti-angiogenic effect of CIM could also be related
inhibition of the secretion of human interleukin-12 (IL-12)
to the decrease in E-selectin expression on endothelial cells
induced by histamine via H2 receptors expressed on mono-
and therefore to its anti-metastatic effect against carcinoma
cytes (the precursors of dendritic cells) (Fig. 1) (46). While it
cells invading the liver (Figs. 2 and 3).
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LEFRANC et al: CIMETIDINE AND MALIGNANT GLIOMAS
Kobayashi et al (29) have also shown that CIM (daily doses
gliomas (58,68). Because experimental y decreasing migration
of 200 mg/kg) prevented liver metastasis of colon cancer
in apoptosis-resistant migrating tumor astrocytes restores
cells in nude mice by blocking E-selectin expression on the
sensitivity to apoptosis (58,68) and thus to pro-apoptotic drugs,
endothelial cells, a ligand for sialyl Lewis antigens on tumor
it would be interesting to elaborate new therapeutic strategies
cells (Fig. 3). Epithelial cells detaching themselves from
targeting migrating glioma cel s. Cel migration includes very
primary epithelial tumors (carcinomas) and migrating through
complex cellular and molecular processes in which at least
the lymphatic or the blood vessels (Fig. 3) eventual y colonize three independent but highly coordinated biological steps are
the liver due to the fact that epithelial cancer cells exhibiting
involved, i.e.: a) cell adhesion to specific components of the
Lewis antigens [involving CD15 with fucose moieties, i.e.
extracellular matrix (ECM) (72-74); b) modifications to the
fucosyl-N-acetyl-lactosamine (fucosyl-LacNAc)] on their
organization of the actin cytoskeleton (75-77); and c) the
surface are able to adhere to endothelial cel s in liver sinusoids secretion of proteases (78). Gene-expression profiling has
because of the presence of selectins (the ligands for Lewis
implicated numerous genes involved in glioma cel migration,
antigens) in these endothelial liver cells (Fig. 3) (13,54-56).
and many of these genes relate to cell adhesion molecules
Kaji et al (54) and Khatib et al (55) showed that upon entry
that directly interact with specific ECM components (79-84).
into the hepatic circulation, epithelial tumor cells can rapidly
Gladson has detailed the molecular nature of ECM in gliomas
trigger a molecular cascade (involving interleukin-1 secretion (85), the crucial roles of which have been emphasized for the
by tumor cel s) leading to the induction of E-selectin expression first time by Rutka and colleagues (86,87) with respect to
on the sinusoidal endothelium (Fig. 3). Khatib et al (55) thus
gliomas. Apart from integrins (85,88,89), galectins (75,90-92)
suggested that E-selectin induction in liver sinusoids by
also play a number of crucial roles in glioma cell migration.
carcinoma cells contributes to the liver-colonizing potential
While integrins employ protein-protein interactions with ECM
of carcinoma cells (Fig. 3). Again, these actions of CIM
components, galectins use protein-carbohydrate interactions
probably do not occur via the blocking of the histamine
between themselves and ECM glycoproteins, with the core of
receptor because famotidine and ranitidine did not show any
carbohydrate ligands for the galectins being represented by
similar effect. CIM treatment was particularly effective in
LacNAc moieties, i.e. Lewis antigens without fucosylation
colorectal cancer patients with tumors expressing higher levels (58). We have shown that the interactions between the oligo-
of sialyl Lewis-X and sialyl Lewis-A epitopes which are
saccharide moieties present in the glioma ECM and cell
involved in E-selectin mediated cell adhesion with endo-
adhesion molecules present on the surface of glioma cel s play
thelial cells (13).
a number of major roles in glioma cel migration (75,90-93).
Among these oligosaccharide moieties that play a number
5. Cimetidine and malignant gliomas
of major roles in glioma cell migration are fucose and lactose
Malignant gliomas are the most frequently encountered
One major target in the fight against glioma cel migration
primary brain tumors in adults and children (57,58); these
is connected with the successful decrease in protease
malignant gliomas include neoplasms of astrocytic (anaplastic expression by glioma cel s (78). Another major target involves
astrocytomas and glioblastomas) and oligodendroglial (ana-
adhesion molecules and their ligand in the extracellular
plastic oligodendrogliomas) lineages (59). The standard
matrix. By example, tenascin, an integrin ligand, is over-
treatment for these malignant gliomas is typically surgery,
expressed in the extracellular matrix of malignant gliomas
followed by radiotherapy and chemotherapy (58,60-63).
when compared to low-grade gliomas and normal brain
However, only those malignant gliomas that exhibit a loss of
parenchyma (85), and clinical applications serve to specifical y
heterozygosity (LOH) of chromosomes 1p and 19q are
combat this particular feature of glioma cell migration (95).
chemoresponsive (64,65). Unfortunately, gliomas exhibiting
Complementary to conventional chemotherapy, CIM has
1p/19q LOH are mainly malignant oligodendrogliomas, i.e.
been used successfully to inhibit cancer cell migration of
a minor proportion of malignant gliomas (59,66). In other
epithelial origins (carcinomas) towards the liver (13,29). It
words, most malignant gliomas are of astrocytic origin,
should be remembered that metastatic implantation of epi-
without 1p/19q LOH, and are therefore weakly sensitive to
thelial cancers in the liver involves cancer cel -mediated oligo-
any type of chemotherapy if at all (58). Malignant gliomas
saccharide moiety (the fucose moiety present on Lewis
are biologically heterogeneous and include sub-populations
antigens) interactions with cel adhesion molecules (selectins)
of proliferating and migrating cells (58,67,68). While certain
present in liver microvasculatures (13,29,56). In view of the
intracellular signaling pathways specifically control cell
fact that levels of expression of fucose binding activities in
proliferation and/or apoptosis, other intracellular signaling
malignant gliomas differ in relation to the levels of malignancy
pathways control cell migration (58,68-71). For example, the
(91) and that these receptor types could influence the levels
CAS/Crk assembly serves as a ‘molecular switch' for the
of proliferation of human glioma cel s (93), we postulated that
induction of cell migration and appears to contribute to the
addition of CIM to temozolomide treatment would improve
invasive property of tumors (70). Moreover, accumulating
survival of human glioblastoma orthotopic xenograft-bearing
evidence suggests invasive glioma cells associated with high
immunodeficient mice when compared to temozolomide
levels of migration display a decreased proliferation rate and
therapy alone. We chose the human U373 model because it
a relative resistance to apoptosis (57,58,68,70,71), a feature
is of astrocytic origin, devoid of 1p/19q LOH and weakly
that may contribute to chemotherapy and radiotherapy
sensitive to temozolomide (96), and the rat 9L sarcoma model
resistance (71). It is these migrating glioma cells that renders
because of its diffuse invasive abilities with respect to the
dismal the prognosis associated with high-grade malignant
brain parenchyma (97). We observed that combining CIM
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INTERNATIONAL JOURNAL OF ONCOLOGY 28: 1021-1030, 2006
with temozolomide improved survival of the U373 orthotopic
cimetidine has been proven to be a useful adjunct in colon
xenograft-bearing nude mice (21). However, human glio-
cancer chemotherapy because it delays the formation of liver
blastoma U373 cells do not express H2 receptors (98), an
metastasis. Cimetidine also displays anti-tumor effects in
observation which again argues against the possibility of H2
gastric and renal carcinomas, and in melanomas. Cimetidine
receptors on tumor cells playing a role in the CIM-induced
can also act as an immunomodulator by enhancing the host's
immune response to tumor cells. We have recently shown
In vitro colorimetric MTT-based assay have revealed that
that combining CIM with temozolomide improved survival
cimetidine significantly decreased growth of both human U373 when compared to temozolomide alone in human glioblastoma
glioblastoma and rat 9L gliosarcoma cells at concentrations
orthotopic xenograft-bearing nude mice. As reviewed in the
≥100 µM (21). Van der Ven and col eagues (99) and Finn and
present report, various mechanisms of action can be associated
col eagues (100) had previously tested the growth-modulating with the beneficial therapeutic effects contributed by cimetidine
effects of CIM on glioma cultures derived from human brain
in the case of experimental glioblastomas, a fact that should
tumors. They observed that high dose (1 mM) CIM induced
encourage clinical investigators to enter highly malignant
inhibition of in vitro proliferation of gliomas, while lower
gliomas to cimetidine-related clinical trials.
concentrations (1 µM) were less effective (99,100). We
observed that in vitro 0.1-1 µM CIM significantly decreased
migration of both U373 and 9L brain tumor cells (21). We
also demonstrated that 30 daily intraperitoneal injections of
We thank Steven Decorte, the GSK Belgium Medical
30 mg/kg CIM markedly decreased the percentage of 9L
Advisor, for his help with the bibliography. R.K. is a
tumor cel s exhibiting endogenous receptors for fucose moieties Director of Research with the Fonds National de la Recherche
and the concentration of endogenous receptors for fucose
Scientifique (FNRS, Belgium) and F.L. is a Clinical Research
moieties in 9L tumor cells (21). This CIM-mediated decrease
Fellow with the FNRS.
in endogenous receptors for fucose moieties could partly
explain the cimetidine-induced decrease in 9L (and also U373) References
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