Cimetidine for cancer

One of the commonest and cheapest of over-the-counter medicines, cimetidine (Tagamet®) is an anticancer?  This is one of the most surprising things to most of my patients, and I believe that many of my oncology colleagues don’t know this one either!

The following is the most comprehensive review of cimetidine use in cancer that one can currently find online.

Cimetidine, an H2-antagonist whose research and development as an stomach acid inhibitor for the treatment of peptic ulcers started its life in the early 60’s, and was approved and marketed from the 70’s as a treatment for heartburn and stomach ulcers. It went on to become the first drug to hit a billion US dollars per year sales and was a true block buster.  I still remember ordering it for patients with acute intestinal bleeding as an intravenous injection when I was training as a resident.

This is a particularly interesting drug from an off-label perspective, because it has been study for a large range of off-label uses, including for parathyroid storm, warts, herpes (shingles), weight loss, fibromyalgia, hives, HIV, conjunctival papillomatosis and irritable bowel syndrome.  There is also an accumulation of evidence suggesting that cimetidine enhances immune responsiveness (accounting at least in part for its potential use as an antiviral and for cancer).

Cimetidine for cancer?

Cimetidine’s possible anti-tumor action has been noticed as early as 1979 ( Also see below; Armitage JO and Sidney RD, Antitumor effect of cimetidine, Lancet 1(8121), pp. 882-3, 1979), the same year it was approved for use by the US FDA.  And reports of cimetidine’s immunomodulatory actions were soon after reported and it was about the same time that growth of colorectal cancer was reportedly retarded in vitro by cimetidine (JNCI, 67:6, pp. 1207-11, 1981). Since then, it 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) it acts against metastases via inhibition of tumor cell adhesivenes; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; and cimetidine antagonizes this effect as an anti-histamine; c) Cimetidine acts as an immunomodulator by enhancing the host’s immune response to tumor cells, via inhibition on T-cell suppressor activity; d) acts as an antiangiogenic.

a) In vitro (test tube) evidence:

Cimetidine and inhibit Caco-2 cancer cells in vitro, independently of the H2 receptor.

Cimetidine enhances the efficacy of 5 FU chemo on colon cancer SW620 cells.

Cimetidine was able to block the adhesion of gastric, esophageal and breast cancerto vascular endothelium via suppression of e-selectin (Gan To Kagaku Ryoho. 11, pp.1788-90, 2003. Japanese).

In vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells derived from advanced colorectal cancer patients suggest that cimetidine may enhance the host’s antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patient (Br J Cancer 86:8, pp.1257-61, 2002).

b) In vitro (animal) evidence:

Suppresses VEGF and exerts antiangiogenic action on growth of colon cancer implants in mice (Tomita, K 2003; Natori T, 2005).

Tagamet added to chemo was superior in vivo when compared to chemo alone in extending survival of nude mice with human glioblastoma (Lefranc F et al. Int J Oncol 28:5, pp. 1021-1030, 2006)

Cimetidine diminished tumour proliferation in immunodeficient mice xenotransplanted with a human melanoma cell line.

Cimetidine antagonised the trophic effect of histamine on colorectal cancer cell lines in vivo and in vitro, possibly mediated via tumour histamine type 2 receptors

Cimetidine synergistically enhanced IL-2-induced NK and LAK cell activities in tumor-bearing rodents, and significantly prolonged their survival.

c) Clinical (human) evidence:

Armitage and Sidney first reported on possible anticancer effect of cimetidine in humans (Lancet, 1979) but they didn’t know why it would work.  They had two cases of cancer. One was a man with a head and neck cancer with presumed lung metastases but refused chemotherapy.  On cimetidine alone for tummy upsets, his metastases disappeared after two years.  The second case was a woman with metastatic lung cancer to the brain who was placed on cimetidine for heartburn and whose cancer grew smaller.

In 1982, four cases of metastatic melanoma responding to cimetidine alone was reported, and this was followed by a report from Sweden than cimetidine administered to six metastatic melanoma patients who were not responding to interferon alone resulted in complete remission in 2 and response/stability in another 2.  Subsequent reports on cancers of the oesophagus, stomach, liver, ovary, kidney and gallbladder treated with cimetidine noted improvement in 5 out of 7 cases.

Many investigative uses of cimetidine for cancer revolved around colorectal patients. Svendsen LB and colleagues from Denmark were one of the first to report on cimetidine as an adjuvant treatment in colon cancer where there seemed to be a survival benefit for those patients with Duke’s C disease but not for those who had disseminated disease (Dis Colon Rectum 38:5, pp. 514-8, 1995). An Australian team published in the same year a small trial of chemo plus cimetidine vs. chemo alone in metasatatic colon cancer and found a 36% CEA response in the cimetidine arm vs. 0% in the control (Eur J Clin Onc 21:5, pp/ 523-525, 1995). Four years later, the same team did a remarkable randomized controlled study showing that 800mg of cimetidine twice daily for only 5 days preoperatively appeared to have had a positive effect on colorectal cancer patient’s survival (Kelly MD et al. Cancer 85:8, pp.1658-1663, 1995). The best supportive evidence comes from Sumio Matsumoto of Japan. He conducted a clinical trial using 800mg / day of cimetidine for one year in patients with colorectal cases receiving 5-FU chemo after surgery (See Lancet 346, p.115, 1995, also Br J Cancer 86:1,  pp.162-167,2002).  His results were more positive than that reported by the Danish (see above) where at four and ten years, survival in the cimetidine treated patients was 96.3% and 84.6%, compared to 68.8% and 49.8% (p<0.0001) respectively. In patients with cancer of the rectum the results were even better: all of the cimetidine-treated patients were still alive at four years compared to only just over half of the controls.  The Japanese found that survival benefit was seen mainly with tumors expressing sialyl Lewis antigens X and A suggesting an immunomodulatory or cellular adhesion effect of cimetidine (Gan To Kagaku Ryoho. 11, pp.1788-90, 2003).  Another Japanese group recently examined the effect of cimetidine for recurrent colorectal cancer but found found no effect on survival, unless the recurrences was resected (Gan To Kagaku Ryoho 33:12, pp.1730-2, 2006).

Mixed results of efficacy were reported against renal cell cancer: Both American and Japanese reports mentioned complete response to cimetidine treatment alone (Am J Clin Oncol 15:2,pp.157-9, 1992; Nippon Hinyokika Gakkai Zasshi. 87:10, pp.201-4, 1996), and a Japanese study of combined interferon and cimetidine yielded a “definitively good” 40% response (J Urol 157:5,pp.1604-7, 1997), yet more recent trials yielded minimal responses (Am J Clin Oncol 21:5, pp.475-8, 1998).  Studies found no effect of cimetidine on gastric (Br J Cancer 81:9, pp.1356-62, 1999) or hormone refractory prostate cancers (Prostate 17:2, pp.95-9, 1990).

My take

Given its low toxicity and low cost, cimetidine can probably be administered to patients with colorectal cancer and possibly other adenocarcinomas that express the Sialyl Lewis antigens to minimize metastases and recurrence and enhance survival.  Enough supportive data also exist for routinely adding cimetidine in a cocktailed approach to melanoma and renal cell cancers patients. In more recent work, the demonstration that cimetidine may enhance dendritic cell function (See above) suggest that cimetidine should be routinely included in patients undergoing dendritic cell therapy.

Any downsides or concerns?

Generally not, but cimetidine does have occassional side-effects and the drug has a long list of potential interactions that one has to be careful about, and its use in cancer should be under the guidance of a professional.  I do have a concern for use of cimetidine in breast cancer because of its effect to increase serum prolactin which could stimulate breast cancer, although multiple epidemiologic studies have not demonstrated any higher incidence of breast (or other) cancers in cimetidine users (Cancer Epidemiol Biomarkers Prev 17:1, pp.67-72, 2008).

Why not more research?

The simple reason has to do with money and incentive in this capitalism-dominant world we live in.  The patent for cimetidine has long expired and it is a lowly over-the-counter drug these days and drug research (especially trials) is prohibitively expensive.  No drug company in its right mind would spare funds to study a drug they do not own just for the sake of benefitting mankind. It would be up to universities, government research centers, and other non-profits to pursue which is why the more recent studies are mostly from coutries (eg Japan, Scandanavia, China) with socialized healthcare systems and/or low cost to do trials and whose governments may be more interested in saving money ( read: looking for cheaper alternatives) to study this kind of “lowly” drug.  It is unfortunate but a reality in the world we live in.