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1021-1030 20/3/06 19:21 Page 1021 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 Abstract. 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 Correspondence to: 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 E-mail: rkiss@ulb.ac.be enzyme system, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. This inhibition forms the Abbreviations: 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 Key words: cimetidine, H2RAs, malignant gliomas, cancer reduced adverse effects and the introduction of highly specific proton pump inhibitors (2).
1021-1030 20/3/06 19:21 Page 1022 LEFRANC et al: CIMETIDINE AND MALIGNANT GLIOMAS Table I. Description of the various clinical trials using cimetidine in oncology.
(patient survival) Post-operative 800 mg/d Significant increase Tonnesen et al (6) Significant increase Burtin et al (5) Colorectal cancer 5 d pre-/2 d post-operative 800 mg/d Significant increase Adams and Morris (7) Colorectal cancer 5FU+/-post-operative 800 mg/d, 1 y Significant increase Colorectal cancer Post-operative 400 mg twice/d, 2 y 45 (Dukes C) Significant increase Svendsen et al (9) Colorectal cancer Pre-operative, 7 d 3-y survival benefit Adams and Morris (10) Colorectal cancer Pre-operative 800 mg twice/d, 5 d Kelly et al (11) Colorectal cancer Non-randomized 5FU+/-post-operative 800 mg/d, 1 y 10-y survival benefit Matsumoto et al (13) Advanced melanoma Phase II Morton et al (16) Advanced melanoma Phase II Creagan et al (15) Non-randomized Coumarin + 300 mg, 4x/d upd Marshall et al (17) Coumarin + 300 mg 4x/d Dexeus et al (18) Non-randomized 600 mg/d upd Inhorn et al (19) INF +/- (coumarin + 400 mg 3x/d) No significant increase Sagaster et al (20) 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



1021-1030 20/3/06 19:21 Page 1023 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).


1021-1030 20/3/06 19:21 Page 1024 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.
1021-1030 20/3/06 19:21 Page 1025 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).
1021-1030 20/3/06 19:21 Page 1026 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 1021-1030 20/3/06 19:21 Page 1027 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.
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VOLUME 2   ISSUE 9   SEPTEMBER 2014   Regional medical practice of concomitant medication CDSCO - REGULATORY MATTERS 1. CONSIDERATION OF ETHNICITY FOR APPROVAL OF NEW DRUGS  Severity distribution of eligible subjects.  Similarity of dose and dosage regimen. Based on the recommendation of the expert committee constituted by the MINISTRY OF HEALTH AND FAMILY

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