Should We Use Cimetidine In Cancer Patients?

Should we use cimetidine in cancer patients?

A review

Tomas Koltai M.D.

Instituto Nacional de Seguridad Social para Jubilados y Pensionados de la República Argentina (I.N.S.S.J.P.)

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Tomas Koltai M.D.

República Argentina

tkoltai@hotmail.com

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Headings: Cimetidine, Cancer, Colorectal carcinoma, Gastric Cancer

Should we use cimetidine in cancer patients?

A review

Tomas Koltai M.D.

Instituto de Servicios Sociales para Jubilados y Pensionados. República Argentina.

Abstract

Background: Since 1979 there is growing evidence that cimetidine may improve the survival of gastrointestinal cancer patients, when used as an adjuvant. It has been proposed also as adjuvant treatment in other types of cancer like melanoma, glioblastoma and ovary. In the last ten years it has been elucidated the mechanisms of action of cimetidine on tumor biology.

Objective: To determine the usefulness of cimetidine in the management of cancer and it´s indications.

Method: The literature was reviewed concerning potencial cimetidine anticancer activity and the proposed mechanisms of this activity.

Conclusions: There is clear evidence favouring the use of cimetidine as an adjuvant therapy in tumors that overexpress sialyl Lewis-A and sialyl Lewis-X, mostly in the gastric and colorectal regions and in patients with colorectal cancer Dukes C and patients with non resectable colorectal carcinoma. Cimetidine should also be used in the preoperative period. Patients with ovarian cancer that overexpresses COX-2 may be benefited by cimetidine. The rest of tumors like head and neck squamous cell carcinoma, glioblastoma and melanoma need further research.

Introduction

The histamine type 2 (H2) receptor antagonist cimetidine was first proposed by Armitage and Sidner as an anti-cancer agent in 1979 (Armitage 1979). They followed the spontaneous remission of two patients with metastatic carcinoma after coincidental use of the drug. Since then there have been several clinical trials assessing cimetidine in a range of malignancies with varied and inconclusive results.

Cimetidine has been shown to improve the survival of patients with colorectal cancer, melanoma, and renal cell cancer (2–10) . Cimetidine has also been proposed as a potential tool for the treatment of glioblastoma (11) and ovarian cancer (24).

This review shall provide a presentation of the currently available clinical evidence that shows cimetidine´s anticancer properties and it´s mechanisms of action. It shall also consider those papers that deny cimetidine´s benefits in patients with cancer.

Mechanisms of cimetidine´s anti-tumoral action

Different mechanisms of anti-tumoral action for cimetidine have been identified:

1) Gifford and Tilberg in 1987 (12) showed that cimetidine is capable of increasing IL-2 production after lymphocyte activation. IL-2 is the most potent growth factor and activator of T lymphocytes and induces the release of mediators such as IFN-y.

2) Takahashi et al demonstrated an increased production of interleukin 18 (IL-18) by human monocytes and dendritic cells (29).

3) Cimetidine effectively inhibits suppressor T-cell function and thus enhances the immune response against cancer, as has been demonstrated by Osband et al (13), Sahasrabudhe et al (14), Adams et al (21).

4) Increases tumor infiltrating lymphocytes and natural killer cells (28, 67).

5) Cimetidine enhances the host`s antitumor cell mediated immunity by improving the suppressed dendritic cell function in patients with advanced cancer (15).

6) Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression (31, 64, 66 and 68). Expression of E-selectin on endothelial cells has been shown to be essential in models of transendothelial migration of colon carcinoma cells (71)

7) Cimetidine inhibits epidermal growth factor induced cell proliferation and migration in hepatocellular carcinoma cell lines by decreasing the concentration of intracellular cAMP levels (16).

8) It was demonstrated that cimetidine inhibits neural cell adhesion molecule (NCAM) expression and induces apoptosis in salivary gland tumor cells (19)

9) Cimetidine has antiangiogenic effects by reducing VEGF levels in tumor tissues (23, 69).

10) Cimetidine has an inhibitory effect on platelet-derived endothelial growth factor (PDEGF). (69)

11) Cimetidine reverses the histamine inhibition of the production of interferon-induced protein of 10 kDa in human squamous cell carcinoma and melanoma (70). Interferon-induced protein (IP-10) inhibits tumor progresión.

Takahashi et al (59) analyzed an experimental syngenic tumor model using a colon adenocarcinoma cell line, CT-26, in Balb/c mice. In this model, distinct tumor growth was observed around 6 days after inoculation of histamine. Daily administration of cimetidine (0.12 mg/kg/day) significantly suppressed the increases in tumor volume and weight. On day 6 and day 7, histidine decarboxylase (HDC) activity was markedly increased. To examine the alterations in the local immune system, the cytokine expressions in the tumor tissue were measured by ribonuclease protection assay. The cytokine expression levels such as lymphotoxin-β, tumor necrosis factor-α, interferon-γ, interleukin-10, and interleukin-15 were considerably lower in tissues on day 14 than those on day 6. These decreased expressions were all restored by cimetidine. The authors concluded that these results indicated that the effects of cimetidine on tumor growth in this model might be mediated by restoration of the decreased local cytokine expression, which exerts antitumoral effects.

As direct consequence of the above mentioned mechanisms, it may be stated that cimetidine has an immunorestorative effect in patients with immunodepression due to cancer (26), has an antiangiogenic effect and reduces the possibility of metastasis (31).

Reynolds et al (65) found that the high concentration of histamine in colon cancer is enough to be locally immunosuppressive.

It has been proposed that cimetidine has a telomerase inhibitor action (63) but there is only one research performed on this subject with no further confirmation.

There are at least 2 different patent claims in the United States in which cimetidine is used with other chemicals in order to treat cancer:

1) US Patent Application 2003/0158118 in which cimetidine is used with cysteine derivatives (73).

2) US Patent Application 2009/0318391 where cimetidine is used with an antinflammatory agent and a cytotoxic agent.

3) US Patent Application 2010/7838513 which is very similar as the previous one (72).

Cimetidine in colorectal cancer

a) Experimental evidence

Adams et al in 1994, found that cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth (32) in four colorectal cancer cell lines. The same research group (33) found that cimetidine inhibited the growth of carcinogen induced colonic tumours in rats with corresponding reductions in the cellular proliferative indices.

Cimetidine used before surgery might promote tumour infiltration by lymphocytes and increase HLA-DR expression in stroma cells in patients with colorectal carcinoma, leading to enhanced host immunity against tumor (37).

Natori et al (38) investigated the effects of cimetidine on tumor growth and angiogenesis in syngeneic colon cancer cells and observed that cimetidine markedly suppressed tumor growth with reduced neovascularization in it. They concluded that cimetidine suppressed tumor growth by inhibiting tumor associated angiogenesis. 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.

Cimetidine administered in the perioperative period in patients undergoing surgery for gastrointestinal cancer showed a statistically significant increase of NK cells (natural killer cells), which was diminished in both groups (cimetidine group and control group) prior to treatment (43). The same results were obtained in colorectal cancer (45). The same research group found that perioperative administration of cimetidine in gastrointestinal cancer patients could decrease the nuclear size and raise the percentage of diploid tumor cells, and convert high aneuploid tumor cells into low-aneuploid tumor cells, which might help reduce the invasiveness of tumor cells (44).

b) Clinical evidence

Cimetidine, has long been known to improve postoperative survival of gastric and, more prominently, colon cancer patients.

In 1994 Adams and Morris reported that a 7 day perioperative course of cimetidine improved 3-year survival from 59 to 93% in 34 colorectal cancer patients (2).

A remarkable improvement in 10-year survival from 49.8% to 84.6% was reported by Matsumoto et al (27). When the cancer cells strongly expressed sialyl Lewis-x or sialyl Lewis-a, the beneficial effect of cimetidine administration was even more prominent. The most pronounced effect was observed with sialyl Lewis-a expression; 10-year survival was improved from 20.1% to 90.9% in patients with cancer cells strongly expressing sialyl Lewis-a by cimetidine treatment, whereas there was virtually no observable effect (90.9% vs. 80.0%) in patients with cancer cells exhibiting little or no expression of sialyl Lewis-a.(27)) The prophylactic

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