COMPLEMENTARY THERAPIES, continuedCimetidine (Tagamet)
Histamine (H2) receptor antagonists (such as cimetidine) became popular in the late 1970s to treat gastrointestinal ulcers and other benign conditions of the stomach, esophagus, and duodenum. In 1985, the Life Extension Foundation announced that cimetidine had merit as a cancer adjunct. Since then, many studies have been published encouraging the use of cimetidine as a means of disabling tumors and expanding survival rates (Tonnesen et al.1988; Yoshimatsuk et al. 2003).
Ways through which cimetidine impacts cancer involves a three-pronged mechanism including (1) inhibition of cancer cell proliferation, (2) stimulation of lymphocyte activity by inhibition of T-cell suppressor function, and (3) inhibition of histamine's activity as a growth factor (Siegers et al. 1999).
In a Japanese study, a total of 64 colorectal cancer patients (who had earlier undergone surgery) were evaluated for the effects of cimetidine on survival and disease recurrence. The cimetidine arm of the study received 800 mg a day of cimetidine along with 200 mg a day of the chemotherapy drug 5-fluorouracil (5-FU); the control group received only 5-FU. The treatment was initiated 2 weeks following surgery and terminated 1 year later. Strikingly beneficial effects were noted: The 10-year survival rate for patients treated with cimetidine/5-FU was 84.6%, whereas that of the control group (5-FU alone) was only 49.8% (Matsumoto et al. 2002).
The effect of cimetidine on a particularly aggressive form of colon cancer (Dukes grade C) was investigated. The cumulative 10-year survival rate of the cimetidine-treated group was consistently 84.6%, whereas that of the control group was only 23.1%. (Less virulent cancers (Dukes A or B) responded less well to cimetidine treatment) (Matsumoto et al. 2002).
Cimetidine treatment is particularly effective in patients whose tumors express higher levels of Lewis A and Lewis X antigens (i.e., breast and pancreatic cancers, as well as about 70% of colon cancers). Lewis A and Lewis X antigens are cell surface ligands that adhere to a molecule in the blood vessels called E-selectin. (Ligand comes from the Latin word ligare, meaning that which binds.)
The adhesion of the cancer cell to vascular endothelial cells expressing E-selectin is a key step in invasion and metastasis. Cimetidine improved patient outcome presumably by inhibiting the expression of E-selectin, thus abolishing the binding site for continued cancer growth and metastasis. The 10-year cumulative survival rate of the cimetidine group displaying Lewis antigens was 95.5%, whereas the control group was only 35.1% (Matsumoto et al. 2002). Comment: Patients are well-advised to undergo Lewis antigen determinations for optimal therapy and a more favorable outcome. Contact Impath Laboratories at 521 West 57 Street, New York, NY 10019, Telephone: (800) 447-8881, for information regarding testing.
Researchers recently unearthed another mechanism through which cimetidine offers cancer protection. Cimetidine enhanced cell-mediated immunity by improving suppressed dendritic cell function (Kubota et al. 2002). Dendritic cells capture foreign invaders and carry the antigen to lymph nodes and spleen. The "hand-delivered" antigen shows the immune system exactly what it has to fight. A more in-depth explanation regarding dendritic cells appears in a separate protocol entitled Cancer Vaccines.
The growth inhibitory effects of cimetidine were assessed on five cell lines derived from human brain tumors of different tissue types and grades of malignancy. Each cell line was treated with cimetidine 24 hours before analysis. Cimetidine significantly inhibited cell proliferation in three of five cell lines, which indicates the apparent dependence of these cells on histamine stimulation (Finn et al. 1996).
Because we do not wish the reader to interpret positive material as a universal ameliorant for all cancers, the following findings are noted:
- Fred Hutchinson Cancer Research Center researchers explored whether cimetidine exerted a cancer-preventive effect on prostate and breast cancers by tracking 48,512 individuals from 1977-1995. Unfortunately, the study concluded that cimetidine did not influence the risk of female breast cancers; in addition, the researchers concluded that there was little evidence to support the previously hypothesized preventive effect of cimetidine on the risk of prostate cancers (Rossing et al. 2000).
- In multiple myeloma patients, cimetidine reduced by about 30% the bioavailability of melphalan (Alkeran), the standard treatment for the disease (Sviland et al. 1987).
- A total of 132 male rats were evaluated for immune status after ingesting cimetidine to forestall a diagnosis of gastric cancer. In the cimetidine-fed group, 19 of 48 developed cancer, versus 12 of 43 in the control group. The Norwegian researchers concluded that cimetidine had no significant immune-modulating effects on the development of gastric cancer in rodents (Hortemo et al. 1999).
While cimetidine is not efficacious in cancer prevention, it shows efficacy in treating certain cancers. A suggested cimetidine dosage for cancer patients is 800 mg (taken at night). Do not supplement with cimetidine without physician awareness; the drug can interact with several medications (such as digoxin, theophylline, phenytoin, warfarin, and lidocaine), increasing or decreasing drug potency.Clodronate
--is a bisphosphonate that inhibits cell proliferation and the threat of metastasis
Clodronate reduced the incidence and number of metastasis in bone and viscera (organs enclosed in the abdominal, thoracic, or pelvic cavity) in high-risk breast cancer patients by 50% (Diel et al. 1998; also see Journal Club on the Web).
Between 1990 and 1995, 302 patients (median age 51 years) with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastasis) were randomly assigned to receive 1600 mg a day of oral clodronate for 2 years or standard follow-up without clodronate supplementation (Diel et al. 1998).
At the conclusion of the trial, bone metastases were detected in 12 (8%) of the clodronate group versus 25 (17%) of the control group. The mean number of bony metastases per patient was 3.1 in the clodronate group versus 6.3 in the nontreated group. Visceral metastasis was observed in 13 (8%) versus 27 (19%) of controls; 6 patients (4%) died in the clodronate group, compared to 22 (15%) in the untreated group. Researchers concluded that clodronate opposed metastasis by altering the binding capacities of adhesion molecules on tumors and bone cells. Women with existing metastatic breast cancer (who added bisphosphonates to their regimen) reported less bone pain and fewer fractures with treatment.
The bisphosphonates (particularly zoledronic acid) appear to be effective against the skeletal complications of multiple myeloma, reducing vertebral fractures and pain. In the early phase of metastasis to bone, tumor cells activate osteoclasts, cells that break down and resorb bony tissue. This favors tumor growth, as growth factors are released when bone is degraded. Bisphosphonates inhibit the development of monocytes into osteoclasts (cells that digest and remove bone) and promote osteoclast death.
In addition, bisphosphonates restrain the production of bone-resorbing cytokines such as interleukin-6, an inflammatory marker for myeloma prognosis. Lastly, bisphosphonates directly affect myeloma by inducing apoptosis of malignant plasma cells. The biochemical effects of zoledronic acid continued for as long as 8 weeks after a single administration (Berenson 2001), but myeloma mortality was not decreased by bisphosphonates (Djulbegovic et al. 2001; Fromique et al. 2000). Typically, a synergism (a cooperative effort) exists between bisphosphonates and cytotoxic agents, increasing chemotherapy's effectiveness.
The standard dose for treating cancer is 800 mg of clodronate taken twice daily, although double this dosage has been used safely. Breast cancer patients may consider a 3- to 5-year regimen of clodronate or other bisphosphonate therapy. Blood tests to measure serum calcium levels and kidney function are required 10 days after beginning clodronate and every 1-2 months thereafter. Persons who are pregnant or who have severe renal insufficiency requiring dialysis should avoid clodronate.
Note: Newer bisphosphonate drugs such as Zometa, Actonel, Fosamax, and Aredia, more potent than clodronate, are now FDA approved and readily available in the United States and covered by most health insurance plans. Prophylactic bisphosphonate therapy is highly recommended for cancers with a propensity to metastasize to bone, such as prostate and breast cancers. Most cancer patients should be on bisphosphonate therapy since any amount of bone breakdown releases growth factors that fuel cancer cell growth. Refer to Cancer Treatment: The Critical Factors for more information about bisphosphonate drugs approved in the United States.Coenzyme Q10 and Statin Drugs
Statins, a class of cholesterol-lowering drugs, have been shown to inhibit the activity of ras oncogenes. ras oncogenes are involved in the regulation of cell growth, modulating the signals that govern the cancer cell cycle. Mutations in genes encoding Ras proteins have been closely associated with unregulated cell proliferation, a hallmark of cancer (refer to the protocol Cancer Treatment: The Critical Factors to read more about Ras oncogenes).
A number of studies have shown the value of statin drugs in a cancer regimen, and the benefit escalates when a statin is combined with a nonsteroidal anti-inflammatory drug (NSAID). People who regularly used NSAIDs lowered their risk of colon cancer by as much as 50%; when lovastatin was added to a cyclo-oxygenase 2 (COX-2) inhibitor, the rate of cell death of three colon cancer cell lines increased up to five-fold (Agarwal et al. 1999).
The statin’s mode of operation, however, raises concern. Statin drugs reduce cholesterol synthesis in the liver by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is required for the conversion of HMG-CoA to mevalonic acid, a step in cholesterol synthesis (Folkers et al. 1990). Inhibiting HMG-CoA reductase results in lower amounts of cholesterol being produced. Disruption of the cascade also interferes with the synthesis of coenzyme Q10 (CoQ10), creating a potential tradeoff regarding advantages and disadvantages gathered from statin usage (Folkers et al 1990; Hattersley 1994).
The impact upon CoQ10 levels when taking statin drugs can be significant. For example, patients taking CoQ10, who later started lovastatin, lowered their CoQ10 levels by 44-75%. The problems associated with drug-related suppression of CoQ10 escalate when age-associated decline in serum CoQ10 levels are also present. A CoQ10 deficiency of 25% is linked with illness in animals and a deficit of 75% with death (Hattersley 1996; Bliznakov et al. 1988). Administering adequate amounts of CoQ10 with a statin drug allows the cancer patient the value of the drug without the risks imposed by depletion of the coenzyme.
In 1997 the Life Extension Foundation suggested that cancer patients ask their oncologist to consider lovastatin (80 mg a day) as adjunct therapy. The recommendation was based on scientific studies indicating lovastatin interfered with the cancer cell cycle and appeared to encourage cell death (apoptosis) (Dimitroulakos et al. 2001). Lovastatin, sold under the name Mevacor, is a fat-soluble statin drug, as are Zocor and Lipitor. Water-soluble statin drugs such as Pravachol may not work as effectively against cancer as the fat-soluble varieties, although one study showed Pravachol induced significant benefits to a group of primary liver cancer patients (Wang et al. 2000).
One of the concerns associated with low levels of CoQ10 is an increased risk of developing cancer. CoQ10 has been reported to be effective in inhibiting the progression of cancers and metastasis, even in patients for whom all conventional treatment failed (Folkers et al. 1993; Lockwood et al. 1995). CoQ10, acting as a nonspecific stimulant to the immune system, increases blood levels of T-lymphocytes and improves the T4-T8 lymphocyte ratio (Folkers et al. 1991). Contrast this with the energy loss and immune suppression associated with conventional cancer therapies.
Dr. Karl Folkers, a pioneer in CoQ10 exploration, reported that in a study of blood levels of CoQ10 in 116 breast cancer patients, 23.1% had blood levels of CoQ10 below 0.5 mcg/mL. The incidence of breast cancer cases with levels below 0.6 mcg/mL was 38.5%, higher percentages than observed in healthy women. A subsequent study reported in the Journal of Clinical Pharmacology and Therapeutics showed a statistically significant relationship between the level of CoQ10 deficiency and breast cancer prognosis (Folkers et al. 1997; Joliet et al. 1998).
Molecular Aspects of Medicine reported the results of an 18-month study conducted in Denmark involving 32 breast cancer patients (Lockwood et al. 1994). The patients had complicated medical profiles, that is, some had involvement in axillary lymph nodes and others had distant metastasis. The patients all received antioxidant therapy, consisting of vitamins C, E, and beta-carotene, select minerals and trace minerals, along with essential fatty acids, and 90 mg of CoQ10 a day. Their treatment was an integrated approach that also included surgery, radiation therapy, and chemotherapy. The survival rate during the 18-month study was 100%; a follow-up evaluation at the 24-month interval indicated all participants were still alive, although the expected deaths were four at 18 months and six at 24 months. All 32 of the enrollees in the study reported improvement in quality of life, stabilization of weight, a withdrawal from pain medications, and no signs of further distant metastases; six of the 32 patients showed apparent partial remissions.
Patients (n = 15) with myeloma showed a mean CoQ10 blood level of 0.67 ± 0.17 mcg/mL. The incidence of a CoQ10 blood level below 0.7 mcg/dL was 53.3%, which is higher than the 24.5% found among a group of nonmyeloma patients (Folkers et al. 1997). Individuals with bloodborne tumors are often saddened with the scarcity of nutritional material relevant to their type of cancer. When links are found, patients and physicians should take special note. The full clinical implication of this finding remains to be explored.
Patients, with and without cancer, report a decrease in the incidence of infection while taking CoQ10 (Bliznakov et al. 1970). This is particularly important to the cancer patient, who often faces additional challenges because of a suppressed immune system. Another extremely important characteristic of CoQ10 is its antioxidant potential, stabilizing cell membranes and preserving cellular integrity (Ernster et al. 1993).
One of the most potent chemicals used in cancer chemotherapy treatment is Adriamycin (doxorubicin). A significant consequence of this drug is cardiac damage, especially in older patients with established heart disease. Italian researcher Dr. Mario Ghione discovered a depletion of CoQ10 in the diseased hearts of animals after long-term Adriamycin administration. When CoQ10 was given to a group of mice before Adriamycin therapy, 80-86% survived; a control group (receiving Adriamycin but without CoQ10) had only a 36-42% survival rate (Bertazzaoli et al. 1977; Cortes et al. 1978).
Dosage suggestions are 90-390 mg a day of CoQ10, taken with some fat to enhance absorption. The American Journal of Health-System Pharmacy reported that liver enzymes could become elevated when taking 300 mg of CoQ10 a day for extended periods of time (Pepping 1999). Also, Folia Microbiologica reported that mice injected with human small cell lung cancer cells and then given high doses of CoQ10 had a diminished response to radiation therapy compared to the non-supplemented group (Lund et al. 1998). Note: Refer to the Cancer Chemotherapy and/or Cancer Radiation protocols along with Cancer: Should Patients Take Dietary Supplements to read about the appropriateness of supplementing with CoQ10 during chemotherapy or radiation therapy.Food sources of CoQ10 include mackerel, salmon, and sardines along with beef, peanuts, and spinach.Conjugated Linoleic Acid (CLA)
--is a trace fatty acid that inhibits tumor formation and metastasis, suppresses arachidonic acid, and encourages apoptosis
Researchers at the Roswell Park Cancer Institute (Buffalo, NY) showed that CLA, derived mainly from dairy products, reduced the incidence of breast cancer (Ip et al. 1999). Animal experiments showed that only 50% of rats feeding on CLA butter developed mammary tumors when exposed to high doses of known carcinogens, compared to 93% of the rats deprived CLA. This research demonstrated for the first time that CLA in foods is biologically active and that a food can offer significant protection against cancer (Cornell News 1999).
Anticancer Research published supporting data that CLA (in both test tube and animal models) demonstrates strong antitumor activity. Particularly gratifying effects were observed regarding inhibition of growth and metastatic spread of transplantable mammary tumors in severely immune deficient mice. The mice were fed CLA for 2 weeks prior to inoculation with human breast adenocarcinoma cells (107 MDA-MB468) and throughout the trial. CLA completely abolished the spread of breast cancer cells to the lungs, blood, and bone marrow. These results indicate that CLA blocks the local growth and spread of human breast cancer via mechanisms independent of the immune system (Visonneau et al. 1997; Banni et al. 1999; Ipet al. 1999).
The effects of CLA and beta-carotene were assessed on white blood cell (lymphocyte) and macrophage function. CLA alone increased lymphocyte numbers and their cell killing ability. Conversely, CLA inhibited interleukin-2 production (a desirable cytokine) and suppressed the ability of macrophages to destroy foreign material. When given together, CLA and beta-carotene interacted in an additive manner to increase lymphocyte production and their cytotoxicity. In addition, beta-carotene was able to overcome the inhibitory action of CLA on the phagocytic activity of macrophages (Chew et al. 1997).
Note: The Melanoma Center at the University of Pittsburgh Cancer Institute showed a potential role for histamine in cancer immunotherapy. A Phase II trial of IL-2 versus IL-2 and histamine in patients with metastatic melanoma demonstrated a trend toward a superior survival benefit from IL-2 and histamine for all patients enrolled and a statistically significant survival benefit for patients with hepatic metastasis (Agarwala et al. 2001).
The effect of three different diets on the local growth and metastatic potential of human prostatic carcinoma cells (DU-145) in severely immune-deficient mice was studied. Animals were fed either a standard diet or diets supplemented with 1% linoleic acid (LA) or 1% CLA for 2 weeks prior to inoculation with cancer cells and throughout the 14-week study. Mice receiving the LA-supplemented diet displayed significantly higher body weight, lower food intake, and increased local tumor load as compared to the other two groups of mice. Mice fed the CLA-supplemented diet exhibited not only smaller local tumors, but also a significant reduction in lung metastasis (Cesano et al. 1998). It was estimated that CLA inhibited the formation of premalignant lesions by approximately 50%, while increasing apoptosis in diseased cells (Ip et al. 2000).
CLA, in a dose-related fashion, has an ability to suppress arachidonic acid (AA). Since AA produces inflammatory mediators that can promote cancer at initiation and progression, CLA's ability to stifle AA elevates its status as a chemopreventive (Miller et al. 2001; Urquhart et al. 2002).
In 1996, the Life Extension Foundation was in the forefront, recommendingCLA; after evaluating the results of numerous studies, the Foundation presented the promising anticarcinogenic nature of CLA to members. Relatively small doses (3-4 grams of CLA) are effective. For example, young female rats (still maturing) fed 0.8% of their diet from CLA achieved long-term protection against breast cancer. The dose of 0.8% correlates positively to the recommended daily dosage of 3-4 grams endorsed by the Foundation. A dose of six 1000-mg CLA capsules (76%) each day is suggested for cancer patients, pregnant and lactating women should avoid CLA.Cyclooxygenase-2 (COX-2) Inhibitors (Naturally Occurring)
Note: The following compendium drawn (in part) from Beyond Aspirin (Newmark et al. 2000) underscores herbs that inhibit COX-2, an enzyme intricately involved in the cancer process. Natural compounds usually have many mechanisms of action; thus, the protective mechanisms common to the herb often extend beyond enzyme inhibition and are described herein. Because of the synergism of herbs, combinations are often of greater value than a single herb. The COX-2-cancer connection is thoroughly discussed in the protocol Cancer Treatment: The Critical Factors.Berberine-Containing Herbs
(Goldenseal, Barberry, Goldthread, and Oregon Grape)
Berberine, strong and bitter in taste and found in various herbs, delivers anti-inflammatory properties via COX-2 inhibition (Fukuda et al. 1999). Kaempferol, a constituent of berberine, is a strikingly active inhibitor of COX-2 activity (Chen et al. 1999; Newmark et al. 2000). Berberine is unique, having the ability to inhibit COX-2 activity without involving the beneficial COX-1 enzyme. Berberine, perhaps by impacting the production of cyclooxygenase, influences the development of cancers at various sites:
- Berberine is effective against bladder cancers (Chung et al. 1999).
- Berberine suppressed colon carcinogenesis and inhibited COX-2 without COX-1 inhibition. The COX-2 enzyme is abundantly expressed in colon cancer cells and plays a role in tumorigenesis. The berberine-COX-2 connection appears to best explain the mechanism of berberine's anti-inflammatory and antitumor-promoting effects (Fukuda et al. 1999, Newmark et al. 2000).
- Berberine-induced apoptosis in human leukemia cells (Kuo et al. 1995).
- Berberine inhibited the development of skin tumors (Kitagawa et al. 1986).
- Berberine has potent antitumor activity against human and rat malignant brain tumors (Zhang et al. 1990). Studies using goldenseal, which contains the alkaloid berberine, showed average cancer kill rate of 91% in rats, over twice that seen in BCNU (a standard chemotherapy agent for brain tumors). Rat studies used 10 mg/kg of berberine.
A suggested dose is three 250-mg capsules of goldenseal each day. The preparation should be standardized to provide 5% hydrastine. Various respected herbalists suggest that goldenseal should be cycled (rotated with other herbals) rather than routinely administered. Goldenseal contains the alkaloids berberine, hydrastine, and canadine.Feverfew
The anti-inflammatory traits of Feverfew have an ability to inhibit the COX-2 enzyme (Hwang et al. 1996). According to Newmark et al. (2000), feverfew contains a lactone, or chemical compound called parthenolide. Parthenolide, in turn, contains a variant of methylene-gamma-lactone (MGL) that interacts with macrophages. The white blood cell-lactone interaction suppresses a critical protein process, a repression that ultimately inhibits the COX-2 enzyme. In addition, feverfew contains apigenin (a flavonoid) and melatonin, both COX-2 inhibitors (Murch et al. 1997).
Researchers at Children's Hospital Medical Center (Cincinnati, Ohio) explained another of parthenolide's anti-inflammatory traits: its ability to inhibit NF-kB, the predecessor of a number of potentially damaging cytokines (Sheehan et al. 2002). Recall that as inflammation is reduced the risks of many degenerative diseases decrease as well (turn to the protocol entitled Cancer Treatment: The Critical Factors to read about the cytokine/cancer connection).
In addition, feverfew inhibits 5-lipoxygenase, an enzyme that metabolizes AA. A byproduct of this metabolism (hydroxy-eicosatetraenoic acid or HETE) feeds cancer cells and promotes angiogenesis, the development of new blood vessels. Agents that inhibit the production of lipoxygenase should be of particular interest to individuals taking COX-2 inhibitors; as the COX-2 enzyme is inhibited, 5-lipoxygenase enzymes become activated (Pizzorno 2001).
A suggested dosage is 1-2 capsules of feverfew a day, standardized to contain 600 mcg of parthenolide. Pregnant and lactating women should avoid feverfew, as well as those showing allergic sensitivities.Ginger
From the scores of biologically active components contained in ginger, some are specific for inhibiting COX-2 and others for inhibiting 5-lipoxygenase, enzymes responsible for the formation of pro-inflammatory agents (prostaglandin E2 and leukotriene B4) from AA. Ginger safely modulates COX-2 activity but also brings balance to COX-1 (an enzyme responsible for gastric mucosal integrity) in a manner vastly superior to synthetic NSAIDs (Newmark et al. 2000; Reiter et al. 2001).
As COX-2 and 5-lipoxygenase are repressed, two distinct metabolic pathways are inhibited, one leading to the synthesis of prostaglandins and the other leading to the production of HETEs. Prostaglandin E2 (PGE2) (produced from COX-2-arachidonic acid interactions) promotes cellular proliferation, and 5-HETE is considered indispensable fuel for tumor growth (prostate in particular).
It has been speculated that therapeutic dosages of ginger inhibit PGE2 by up to 56%. As ginger slows down 5-lipoxygenase and 5-HETE production, cell death is stimulated in both hormone responsive and nonresponsive human prostate cancer cells (Suekawa et al. 1986; Ghosh et al. 1998). Leukotrienes, produced by lipoxygenase, are considered 1000 times more reactive than histamine. Ginger has more 5-lipoxygenase inhibitors than any other botanical source (Newmark et al. 2000).
Ginger may also be useful in overcoming nausea that accompanies chemotherapy and toxicity associated with the breakdown products of cancerous tissue. James Duke, Ph.D., distinguished botanist and author, has high regard for ginger, adding that it has a major advantage over other antiemetics because of its safety profile. Ginger's antioxidant activity adds another plus to a booming list of anticancer credits. A suggested dosage is 2 grams of ginger a day.Continued
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