Life Extension Magazine May 2007
By Cynthia Haines, MD
Conventional cancer therapies do not always eradicate the cancer, leading patients to seek out adjuvant therapies that may confer additional benefits.
More than two decades ago, Life Extension called attention to the over-the-counter heartburn drug cimetidine—more commonly known by its brand name, Tagamet®—as a complementary cancer treatment. Although cimetidine was developed to relieve heartburn, acid indigestion, and sour stomach, numerous studies demonstrate that this readily available medication may offer powerful support in the fight against cancer.Unfortunately, many cancer patients and even oncologists remain unaware of the compelling evidence demonstrating its efficacy.
By preventing cancer metastasis (spread), slowing or halting tumor growth, and prolonging survival, cimetidine may serve as an important adjuvant therapy for people fighting colon cancer and other malignancies.
What Is Cimetidine?
Cimetidine, or Tagamet®, reduces the production of stomach acid by binding with H2 receptors on the acid-secreting cells of the stomach lining. These receptors normally bind with histamine to produce stomach acid, which helps to break down food. By competing with histamine to bind with H2 receptors, cimetidine reduces the stomach’s production of acid.
This mechanism of action accounts for cimetidine’s use in managing gastroesophageal reflux disease (GERD), a condition marked by an excess of stomach acid. In fact, its use in treating gastric (stomach) disorders dates back several decades.
Anti-emetic drugs are used to prevent or treat nausea and vomiting. Before stronger anti-emetic drugs became available, cimetidine was prescribed to treat nausea associated with chemotherapy. As far back as 1988, scientists observed that colon cancer patients who had been treated with cimetidine had a notably better response to cancer therapy than those who did not receive cimetidine.1 Now, nearly 30 years of published research suggests that cimetidine may exert its most profound effects not as a heartburn remedy, but as an anti-cancer drug.
An Unexpected Anti-Cancer Agent
The first studies to hint at cimetidine’s effectiveness against cancer were published in the late 1970s. Although scientists initially thought that cimetidine worked by enhancing immune function, later studies showed that cimetidine functions via several different pathways to inhibit tumor cell proliferation and metastasis
In a prospective, randomized, placebo-controlled study in 1988, 181 patients with gastric cancer received cimetidine (400 mg, twice daily) or placebo for two years or until death. Those given cimetidine had a significantly prolonged survival rate compared to the placebo group, particularly patients with more serious disease.1
In a 1994 study, just seven days of cimetidine treatment (400 mg twice daily for five days preoperative and intravenously for two days post-operative) in colorectal cancer patients decreased their three-year mortality rate from 41% to 7%. In addition, tumors in the cimetidine-treated patients had a notably higher rate of infiltration by lymphocytes, a type of white blood cell.2 These tumor-infiltrating lymphocytes, part of the body’s immune response to the tumor, serve as a good prognostic indicator. When more tumor-infiltrating lymphocytes are present, the body is more capable of attack-ing and eliminating the tumor.
A report in the British Journal of Cancer examined findings of a collaborative colon cancer study conducted by 15 institutions in Japan. First, all participants had surgery to remove the primary colorectal tumor, followed by intravenous chemotherapy treatment. They were then divided into two groups: one group received 800 mg of oral cimetidine and 200 mg of fluorouracil (a cancer-fighting medication) daily for one year, while a control group received fluorouracil only. The patients were followed for 10 years. Cimetidine greatly improved the 10-year survival rate: 85% of the cimetidine-treated patients survived 10 years, while only 50% of the control group survived.3 Cimetidine produced the greatest survival-enhancing benefits in those whose cancer cells showed markers associated with the tendency to metastasize.
In just the last two years, several other studies have corroborated cimetidine’s benefits for surviving colorectal cancer. For instance, in a Japanese study in 2006, colorectal cancer patients who received cimetidine following surgical removal of recurrent cancer had an improved prognosis compared to those treated with surgery only.4
A groundbreaking study reported in the International Journal of Oncology in 2006 confirms decades of research highlighting cimetidine’s role as an important adjuvant cancer therapy. This study demonstrated that cimetidine may enhance survival in those undergoing conventional treatment for brain tumors.5 The most common primary brain tumors in adults and children, known as malignant gliomas (tumors that begin in the supportive cells of the brain or spinal cord), often fail to respond to chemotherapy, and are frequently fatal. Mice with tissue grafts of human glioblastoma cells that received both cimetidine and the chemotherapy drug temozolomide (Temodar®) demonstrated improved survival rates compared to those that received chemotherapy only. Cimetidine may thus prolong survival in people undergoing chemotherapy for the most prevalent type of brain tumor.
How Does Cimetidine Fight Cancer?
Since cimetidine’s anti-cancer effects were first reported, scientists have proposed several hypotheses to explain how the drug works. Cimetidine’s potential mechanisms of action include:
Cimetidine Modulates the Immune System
Histamine plays many roles in the body—contributing to allergic responses, regulating physiological function in the gut, and acting as a neurotransmitter. Histamine secretion also has the effect of suppressing the immune system.
Many cancers, particularly colorectal and breast tumors, secrete histamine.3,5,6 Histamine secretion also frequently occurs in response to surgical resection of colorectal cancers.6 In the tumor environment, histamine acts to suppress the immune response the body mounts to attack a tumor. This creates an immunosuppressive environment in the area of tumor growth and throughout the body, thus facilitating tumor growth.
Since cimetidine is a histamine receptor antagonist—that is, an agent that binds with a cell receptor without eliciting a biological response—it may help reduce immunosuppression caused by increased histamine levels in a tumor’s environment.6,7 Administering cimetidine may enable the immune system to mount a more effective response, so that it can attack and potentially eliminate the tumor.
While histamine appears to stimulate the growth and proliferation of certain types of cancer cells,8 inhibiting histamine’s action may be only one mechanism by which cimetidine fights cancer.9 Researchers have found evidence that cimetidine has many different effects on the immune system and the body’s ability to respond to a tumor.
In 1972, for example, scientists discovered that T-suppressor cells in the immune system express receptors for histamine on their surface.10,11 T-suppressor cells accelerate the growth of tumors,12 and by activating these cells, histamine suppresses the immune response.13 Several studies have shown that cimetidine inhibits this immune suppression and helps restore a normal immune response.7,14-16 Compared to normal controls, gastric cancer patients also have higher levels of suppressor lymphocyte activity, and cimetidine treatment helps restore these levels to normal.17
During surgery, some cancer cells may be released into the bloodstream. A suppressed immune system may contribute to the ability of these residual cancer cells to escape immune surveillance and establish metastatic lesions.7,15,16 Cimetidine’s ability to reverse immune suppression could thus help the immune system to remain alert to challenges such as spreading cancer cells.
In addition, many tumors are infiltrated with lymphocytes as a part of the body’s immune response. The presence of tumor-infiltrating lymphocytes in a tumor indicates a better prognosis than for tumors that lack these white blood cells.2,17 With more tumor-infiltrating lymphocytes present, the body is more capable of attacking and eliminating the tumor. Administering cimetidine greatly elevated the proportion of colorectal cancers with tumor-infiltrating lymphocytes, probably by inhibiting the immunosuppressive function of histamine.18
Post-operative administration of cimetidine may also enhance the ability of cells known as peripheral lymphocytes to kill tumor cells, which is associated with enhanced disease-free survival.19 The presence of a lymphocyte response has been correlated with improved cancer survival.20 In a recent clinical study, cimetidine boosted peripheral blood lymphocytes and the tumor-infiltrating lymphocyte response. The authors concluded that administering cimetidine to gastrointestinal cancer patients several days before and after surgery may restore the diminished immune response often seen with cancer.21
A study from 2005 suggests cimetidine helps increase specific types of T-lymphocytes with protective attributes in the peripheral blood. Six healthy adults were given an 800-mg oral dose of cimetidine daily, and blood samples were collected at the study’s onset and one, three, five, and seven days later. Cimetidine treatment was associated with an increase in white blood cells, specifically neutrophils (cells that fight bacterial invaders) and T-lymphocytes (which are involved in cell-mediated immunity). These results further suggest that cimetidine modulates cellular immunity and may be useful as an activator of tumor-specific immune response.22
In sum, cimetidine appears to support cellular immunity via several mechanisms, including blocking the immunosuppressive effect of histamine, inhibiting suppressor T-cell activity, increasing the number of tumor-infiltrating lymphocytes, and boosting the activity of peripheral blood lymphocytes.