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May 2007

Concentration of histamine in serum and tissues of the primary ductal breast cancers in women.

The aim of this study was to evaluate the concentration of histamine (HA) and the activities of their enzymes, namely histidine decarboxylase (HDC) and diaminooxydase (DAO) in 95 women with ductal breast cancer and in healthy women. The control group comprised 60 women without any pathological changes in their breasts, in whom mammoplasties were performed. In women with breast cancer the concentration of HA in serum was significantly higher than in healthy controls (9.1+/-3.2 vs. 5.9+/-3.1 nmol/l; P<0.001). The concentration of HA was significantly higher in neoplasmatic tissues of women with breast cancers than in unchanged tissues of healthy subjects in the control group (14.2+/-5.1 vs. 6.3+/-9.1 nmol/g; P<0.001). HDC activity was significantly elevated in cancerous tissues of women with breast cancer relative to unchanged tissues of healthy subjects (54.7+/-17.1 vs. 39.3+/-26.9 pmol/min per mg; P<0.01). However, the activity of DAO was significantly lower (14.0+/-0.4 vs. 36.1+/-9.7 pmol/min per mg; P<0.001) in neoplasmatic tissues than in normal tissues of healthy women. The adjacent healthy tissue of cancer revealed higher concentrations of HA than were found in unchanged tissues of healthy subjects (6.3+/-9.1 vs. 7.5+/-5.4 pmol/min per mg), but this difference did not reach statistical significance. The activity of HDC did not show any significant difference between the healthy tissues adjacent to cancer foci of women with breast cancer and normal tissues obtained from healthy subjects (39.3+/-26.9 vs. 34.5+/-24.3 pmol/min per mg). However, the activity of DAO was markedly lower than in unchanged tissues of healthy women in the control group (36.1+/-9.7 vs. 14.4+/-10.9 pmol/min per mg; P<0.001). The concentration of HA in cancerous tissues was significantly higher than in adjacent healthy tissues (14.2+/-5.1 vs. 7.5+/-5.4 nmol/g; P<0.001). The activity of HDC was significantly higher in cancerous tissues than in adjacent healthy tissues (54.7+/-17.1 vs. 34.5+/-24.3 pmol/min per mg; P<0.001), but there was no difference in the activity of DAO (14.0+/-6.4 vs. 14.4+/-10.9 pmol/min per mg). The significant elevation of HA concentration in cancerous tissues of women with the ductal breast cancers is caused by the increased synthesis and decreased inactivation of HA.

Breast. 2005 Jun;14(3):236-41

Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review).

Cimetidine (CIM), the prototypical histamine H2 receptor antagonist (H2RA), was brought to market based on its ability to accelerate healing of gastrointestinal ulcers 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 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, thereby reducing the development of liver metastasis; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; CIM therefore may antagonize this effect; c) CIM acts as an immunomodulator by enhancing the host’s immune response to tumor cells. With respect to malignant gliomas, CIM added to temozolomide was superior in vivo when compared to temozolomide alone in extending survival of nude mice with human glioblastoma cells orthotopically xenografted into their brain. We review the various mechanisms of action potentially associated with the therapeutic effects of CIM in the case of experimental glioblastomas, observations we hope will encourage clinical investigation of CIM in the management of highly malignant gliomas.

Int J Oncol. 2006 May;28(5):1021-30

Effects of perioperative cimetidine administration on peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: results of a randomized controlled clinical trial.

BACKGROUND/AIMS: Cimetidine (CIM) seems to have positive effects on the immune systems of cancer patients. This study was conducted to investigate the effects of perioperative administration of CIM on the peripheral blood lymphocytes, natural killer (NK) cells and tumor infiltrating lymphocytes (TIL) in patients with gastrointestinal (GI) cancer. METHODOLOGY: Forty-nine GI cancer patients were randomized into a treatment group which took CIM in the perioperative period, and a control group which did not take the drug. The treatment was initiated 7 days (d) before operation and continued until 10 d after surgery. At baseline examination, before operation, on the 2nd and the 10th postoperative d, peripheral blood T lymphocytes, helper T cells, T suppressor cells, and NK cells were measured by immunocytochemical method. The surgical specimens were examined for TIL response, and immunohistochemical study was performed to measure the proportion of T and B lymphocytes in the TIL population. RESULTS: In comparison with normal controls, both the treatment and the control groups had decreased T cells, helper T cells and NK cells at baseline. In the control group, total T cells, helper T cells and NK cells declined progressively with the disease course and the decreases became more profound after operation. From the baseline to the 2nd postoperative d, the proportion of total T cells, helper T cells, and NK cells went down from 60.5+/-4.6 to 56.2+/-3.8 percent, from 33.4+/-3.7 to 28.1+/-3.4 percent, and from 15.0+/-2.8 to 14.2+/-2.2 percent, respectively. On the other hand, there were significant improvements in these parameters after CIM treatment. On the 10th postoperative d, the treatment group had significantly higher percentages of total T cells, helper T cells and NK cells than control group. Moreover, CIM treatment also boosted the TIL response, as was reflected by findings that 68% (17/25) of the patients in the treatment group had significant TIL responses and only 25% (6/24) of the cases had discernible TIL response. CONCLUSIONS: Perioperative application of CIM to GI cancer patients could help restore the diminished cellular immunity boost TIL responses to tumor.

Hepatogastroenterology. 2005 Mar-Apr;52(62):504-8

The effect of cimetidine mainly increases CD4+ cells of peripheral blood T lymphocytes

Cimetidine, one of the most popular histamine-2 receptor antagonists, has been reported to improve survival in gastrointestinal cancer patients and to activate cell-mediated immune response in surgical patients. NKT cells are a population of T cells that share characteristics with natural killer cells, and their main functions are production of immunoregulatory cytokines and cytolytic activities. In this study, we aimed to investigate the effect of cimetidine on the cell-mediated immunoresponse. Six healthy adult volunteers were given 800 mg of cimetidine per day orally, and their blood samples were taken prior to and at days 1, 3, 5, and 7 days post-administration of cimetidine. Leukocyte counts and differentials were obtained by the conventional hemogram, and the leukocyte subsets were analyzed by flow cytometry. Cimetidine administration caused leukocytosis, dependent on the increase of neutrophils, as well as of the CD3-positive T lymphocytes, and the subset of CD4-positive cells among them. On the other hand, the NK cell subpopulation was decreased, and the NKT cell subpopulation was not affected. The present results suggest that cimetidine is a modulator of the cellular immunity, and may be used as the activator of the tumor specific immunoresponse.

Gan To Kagaku Ryoho. 2005 Oct;32(11):1576-7

Cimetidine inhibits angiogenesis and suppresses tumor growth.

Cimetidine, a histamine type-2 receptor antagonist, has been reported to improve survival of patients with cancers. However, the exact mechanisms by which cimetidine suppresses development of cancers remain to be elucidated. Solid tumors require neovascularization for their growth. Here, we investigated the effects of cimetidine on tumor growth and angiogenesis. Syngeneic colon cancer cells, CMT93 cells, were inoculated into the subcutaneous space of C57BL/6 mice. Mice were treated with either saline or cimetidine. Tumor size was measured everyday and angiogenesis was evaluated histologically. Cimetidine markedly suppressed tumor growth with reduced neovascularization in the tumor. Cimetidine had no effect on proliferation of CMT93 cells in vitro. Vascular endothelial growth factor production by cancer cells was not affected by cimetidine, while vascular-like tube formation by endothelial cells in vitro was significantly impaired in the presence of cimetidine. Our findings suggest that cimetidine suppresses tumor growth, at least in part, by inhibiting tumor-associated angiogenesis.

Biomed Pharmacother. 2005 Jan-Feb;59(1-2):56-60

Effects of cimetidine on the biological behaviors of human gastric cancer cells

OBJECTIVE: To investigate the effects of cimetidine on the proliferation, apoptosis, adhesion, and invasion of human gastric cancer cells. METHODS: Human gastric cancer cells of the line SGC-790 were cultured. Cimetidine of the concentrations of different concentrations was added into the culture fluid. The survival rate of the cells was calculated. Flow cytometry was used to examine the distribution of cell cycle and apoptosis of the cells. Fluorescence staining was used to observe the morphology of the apoptotic cells. The adhesion of the cells was measured by MTT method and their invasion ability was tested with Millicell chambers. RESULTS: The proliferation of the AGC-7901 cells was inhibited by cimetidine of the concentration of 0.5 to 5 mmol/L time and dose-dependently. Cimetidine of the concentrations of 0.5 - 10 mmol/L retarded the SGC-7901 cells at the stage G(0)/G(1) and increased the number of apoptotic cells dose-dependently (P < 0.05). Cimetidine of the non-toxic concentrations 250, 125, and 62.5 micrommol/L decreased the adhesion and invasion of the SGC-7901 cells to the extracellular matrix. CONCLUSION: Capable of inducing apoptosis and cell cycle arrest, cimetidine is helpful in treatment of cancers of gastric cancer.

Zhonghua Yi Xue Za Zhi. 2006 Jul 11;86(26):1813-6

Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells.

The cytokine-inducible endothelial cell adhesion receptor E-selectin has been implicated in cancer metastasis. Previously, we reported that experimental liver metastasis of Lewis lung carcinoma subline H-59 cells could be abrogated in animals treated with an anti-E-selectin antibody. To gain further insight into the functional relevance of E-selectin expression to liver colonization, we investigated here the time course of cytokine and hepatic E-selectin expression after the intrasplenic/portal inoculation of H-59 cells by using a combination of reverse transcription-PCR, Northern blot analysis, immunohistochemistry, and in situ hybridization. In parallel, we analyzed cytokine induction in response to the injection of Lewis lung carcinoma subline M-27 and murine melanoma B16-F1 cells, which do not spontaneously metastasize to the liver. In livers derived from normal or saline-injected mice, only minimal basal levels of TNF-alpha and IL-1 mRNA were detectable by RT-PCR. Rapid cytokine mRNA induction was noted within 30-60 min of H-59 injection, reaching maximal levels at 4-6 h. This was followed by the appearance of E-selectin mRNA, which was detectable at 2 h after injection and reached maximal levels at 6-8 h, declining to basal levels by 24 h. In situ hybridization analysis and immunohistochemistry localized E-selectin mRNA and protein, respectively, to the sinusoidal endothelium. M-27 cells failed to induce cytokine or E-selectin expression, whereas B-16 cells elicited a delayed and more short-lived response. The results demonstrate that upon entry into the hepatic circulation, tumor cells can rapidly trigger a molecular cascade leading to the induction of E-selectin expression on the sinusoidal endothelium and suggest that E-selectin induction may contribute to the liver-colonizing potential of tumor cells.

Cancer Res. 1999 Mar 15;59(6):1356-61

Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression.

Although the beneficial effect of cimetidine on survival in cancer has been clinically demonstrated in colorectal cancer patients, the mode of action of cimetidine has not been elucidated. In this report, we have demonstrated for the first time that cimetidine can block the adhesion of a colorectal tumor cell line to the endothelial cell monolayer in cell culture and that it can suppress the metastasis of the tumor cell in a nude mouse model. We also demonstrated that these antimetastasis effects of cimetidine might occur through down-regulation of the cell surface expression of E-selectin on endothelial cells, a ligand for sialyl Lewis antigens on tumor cells. We found that the cimetidine-mediated down-regulation of E-selectin did not involve down-regulation of E-selectin mRNA or blocking of the nuclear translocation of nuclear factor kappaB, a transcriptional activator of E-selectin gene expression. Because two other histamine type 2 receptor antagonists, famotidine and ranitidine, did not show any similar effect, these actions of cimetidine probably do not occur via blocking of the histamine receptor. These observations support the idea that cancer metastasis can be blocked by cimetidine administration through blocking the adhesion of tumor cells to the endothelium when an interaction between E-selectin and sialyl-Lewis antigens plays a role.

Cancer Res. 2000 Jul 15;60(14):3978-84

Cimetidine inhibits the adhesion of cancer cells with sialyl Lewis epitope onto the vascular endothelium

The attachment of circulating cancer cells to vascular endothelium is considered an important initial step in hematogenous metastasis. We believe that hematogenous metastasis can be inhibited by blocking the adhesion of cancer cells to vascular endothelium. We demonstrated that cimetidine suppressed the expression of E-selectin on the surface of HUVECs, which was a ligand to the sialyl Lewis (sLe) epitope. Thereby, adhesion of HT-29 cells to HUVECs was inhibited by cimetidine pretreatment. In this study, adhesion between cancer cells and HUVECs was observed by a high-speed video recording system. We examined whether or not cimetidine inhibited the adhesion of cancer cells with the sLe epitope, such as gastric, esophageal and breast cancers, to HUVECs. Cimetidine was able to block the adhesion of gastric, esophageal and breast cancer cells with the sLe epitope. We conclude that cimetidine would be effective for inhibiting hematogenous metastasis on gastric, esophageal and breast cancer cells with the expression of sLe epitope.

Gan To Kagaku Ryoho. 2003 Oct;30(11):1788-90