Copper-Reduction Therapy

Knowing that reducing copper can effect vascularization of tumor masses, Dr. George Brewer applied his copper-reduction techniques to cancer. New blood vessels appear to have a very strong dependence on copper for growth, but low copper levels are unlikely to affect existing vessels. By depriving cancer tumors of the copper they need to form new blood vessels, Dr. Brewer's research team at the University of Michigan stopped the growth and spread of the disease for over two years (as of December 2000) in a small group of patients with advanced cancer. The abstract of Brewer's Phase I trail results is shown in Appendix I, but the full ten page report released January 2000 is viewable on line, Treatment of Metastatic Cancer with Tetrathiomolybdate, an Anticopper, Antiangiogenic Agent: Phase I Study.(12) The (PDF version is available for printing if you have Adobe Acrobat Reader, and don't mind the few minutes it takes to load.)

The underlying hypothesis of antiangiogenesis using copper-reduction therapy is that the level of copper required for angiogenesis is higher than that required for essential copper-dependent cellular functions. The assumption is that there is "...a window of copper deficiency in which angiogenesis is impaired, but other copper-dependent cellular processes are not affected enough to cause clinical toxicity."

Dr. Brewer's clinical trial indicates that physicians might fight cancer by targeting copper as a "common denominator" of angiogenesis. Unlike other anti-cancer agents now being studied around the world, copper-reduction therapy is not limited to a single type of cancer. The relationship of copper to cancer is not causative but associative. Cancer cells in a high copper environment find it easy to proliferate into tumors. In an environment low in copper, cancer cells would remain dormant or very slow-growing, increasing survival time.(13)

For the cancer trials, Dr. Brewer teamed up with Sofia Merajver, Ph.D., M.D., a molecular genetics researcher and oncologist also at the University of Michigan Comprehensive Cancer Center. The promising results from the phase I trial prompted Merajver to state, "These initial results suggest that the tactic of preventing angiogenesis through copper deficiency holds significant promise. Through this and other therapies, we may one day be able to turn cancer into a chronic or controllable disease or to contribute to its eradication... We also believe that the earlier TM [copper-reduction therapy] is given in the progression of a patient's cancer, the better it should work [emphasis added]."(14)

Penicillamine and Trientine

There are a number of techniques that can be used to reduce copper stores. Most Wilson's disease patients use either penicillamine or trientine,(15) prescription drugs that act as chelating agents by binding to copper. Penicillamine (sold as Cuprimine or Depen) works by binding with copper and increasing renal excretion. It is effective in reducing copper levels, but up to 20 percent of penicillamine patients can suffer neurological symptoms. About half develop other adverse effects such as fever, rash, or joint pains. These people are usually changed to trientine (Syprine), another chelating compound which removes excess copper from the body. Unfortunately, trientine, like penicillamine, can also have significant side effects.(16)

In lieu of using either of the harsh drugs, penicillamine or trientine, Dr. George Brewer investigated zinc acetate to treat the presymptomatic or pregnant Wilson's disease patients. He also used a complex of molybdenum for the initial treatment of Wilson's disease patients with neurological symptoms who needed fast copper-reduction therapy, but this therapy required the patient to come to the University of Michigan.(17)

Molybdenum & Ammonium Tetrathiomolybdate

What is molybdenum? Molybdenum is an essential trace mineral that is needed for the proper function of certain enzyme-dependent processes, including the metabolism of iron. Some increased urinary excretion of copper will occur with daily molybdenum consumption of up to 10 - 15 mg (10,000 - 15,000 mcg) per day,(18) but intake of higher doses has produced clinical evidence of gout-like symptoms, such as joint pain and swelling.(19)(20) A combination of sulfur and molybdenum is required to form a metallothionein complex to effectively bind copper for excretion. This reaction does not occur naturally in the human body. Thus, molybdenum (as ammonium tetramolybdate) is not an effective copper chelator by itself.

What is TM? Ammonium tetrathiomolybdate (TM) is a complex of sulfur and molybdenum designed as a fast-acting compound to quickly lower copper levels by oral chelation.

Ammonium tetrathiomolybdate (TM) is a complex of sulfur and molybdenum designed as a fast-acting compound to quickly lower copper levels by oral chelation. This compound may be the world's safest and most potent anti-copper agent. It is extremely well tolerated, with few side effects, and TM is particularly useful to patients who wish to avoid the potential adverse reactions to the standard chelating agents, penicillamine and trientine.(21)

How does TM work? In his trials, Dr. Brewer wants to determine if copper deficiency is a feasible modality to stop cancer's growth by inhibiting tumor neovascularization. Dr. Brewer found that TM could be safely administered to his copper-reduction therapy patients in daily doses of 120 mg (six capsules of 20 mg each), at least ten times the maximum safe dosage of molybdenum alone. TM lowers the body's copper level by chelating (binding to) the copper and protein, making a stable compound that cannot be used by the tumor cells or any part of the body. Taken at mealtime, TM prevents the body from processing and absorbing the copper in food as well as the copper normally found in saliva and gastric secretions. When taken between meals separated from any food by at least two hours, TM is even more effective. (Capsules taken in the middle of the night if one awakens to go to the bathroom seems to be the most effective in lowering copper levels.) On a relatively empty stomach, TM is absorbed into the blood and binds copper to serum albumin, a protein in blood. The TM-protein-copper complex does not interact with other biological molecules and is excreted.(22)

How can TM be obtained? TM has been registered under the FDA's Orphan Drug Act (23) since 1994. The University of Michigan claims to be filing a new-use patent for TM in the treatment of cancer and other diseases that rely on angiogenesis.(24) The University of Michigan states that full-scale toxicity studies are required before TM can be made available to large numbers of people, and this would be a necessary step for the FDA to approve TM as a drug suitable for any therapy. According to the University of Michigan, the National Cancer Institute has accepted them into a program designed to speed access to new medications. Verification is impossible as the FDA considers all pending applications as confidential.

At the University of Michigan, TM is currently available only through their clinical research programs.(25) Dr. Brewer's source for TM is Sigma-Aldrich, Inc., in Milwaukee where they specifically refine the product for human consumption. Dr. Brewer further tests the product for freshness by spectrum analyses and biological assays. Apparently, any pharmaceutical TM purchased from Sigma-Aldrich outside of the University of Michigan's control with Dr. Brewer must be initiated by the patient's doctor, approved as patient specific through FDA, purchased in bulk, and encapsulated at a compounding pharmacy.(26) After a lot of customer prescreening, Sigma-Aldrich has sold their technical grade of TM in powder form which is guaranteed pure only up to 99.97%. Technical grades are not always pure enough for human ingestion as they can possibly contain toxic contaminants. However, there are other sources available for obtaining TM.

The FDA Modernization Act of 1997 (27) changed availability of many drugs which have not been approved. TM is not a common substance, and Sigma-Aldrich is not the only source. Several compounding pharmacists (28) have found other companies to provide it. Only a doctor's prescription is required, and there is no requirement for patient specific FDA approval.

Every day more compounding pharmacists are becoming familiar with TM as they start supplying it to their customers, usually by mail order prescription. We have listed known suppliers in Appendix VI

What is the physician's liability for prescribing TM or any other drug not approved for a specific medical indication? It is not legal to promote TM as a treatment for cancer since it lacks FDA approval for anything other than experimental use. A physician can order prescriptions for a drug if he thinks it is medically justified even if there is no specific approval for the specific condition he is treating. In general, there are two things a doctor might be worried about. One is having administrative sanctions imposed on him (the main one being losing his license), and the other is being sued by a patient for damages suffered because of inappropriate treatment that was not up to the generally recognized standard of care. This is a major reason doctors are reluctant to try drugs not officially approved. In relation to treating cancer patients, the only human data on the effect of TM in this group is from Brewer's limited Phase 1 trial. If something goes wrong, the doctor could be judged according to whether his judgment in prescribing the medication was professionally reasonable. TM is an unproven experimental treatment for cancer which requires caution.

The Mineral Zinc

Zinc compounds

Zinc is a trace metal needed for more than 300 enzymes used by the body. It is not a copper chelator, zinc acts to block dietary copper in the intestines by preventing additional absorption of copper. It induces cells of the intestinal tract to produce a metallothionein protein (MT) which has a very high affinity for copper and is excreted in the stool. This means that any newly ingested copper does not reach the blood circulation system.(30)(31) Zinc is an alternative to older copper chelating agents, and Wilson's disease patients frequently use it in their maintenance programs.

With a normal concentration of stomach acids, most forms of digestible zinc will break down and be absorbed into the bloodstream through the intestinal walls. Because zinc acetate undisputedly releases all of its zinc as zinc ions,(33) it is bioavailable. Before the advent of Galzin®, Dr. Brewer used zinc gluconate for his patients. Although easily absorbable, high doses of either zinc acetate or gluconate can cause stomach upset in sensitive patients. Zinc as amino acid chelates avoids nausea and naturally facilitates absorption as long as sufficient stomach acids are present.(34)(35) Another suggestion has been zinc citrate as a consideration of the best tolerated non-prescription form of zinc. Successful zinc therapy requires absorbing the proper amount of the mineral in the blood, but once in the bloodstream, it does not matter what form of zinc was ingested. Zinc serum level in the bloodstream may be easily measured by a common lab test.

Zinc Metabolism

Excessive supplemental zinc is not stored. The human body is extremely efficient in removing surplus zinc in fecal matter, urine, and sweat. Gram doses might be tolerated very well for a few days in some very ill people in need of zinc, but not likely for longer periods of time.

Some people do not absorb zinc well and live their entire lives in a state of poor health. Others absorb zinc very well and rarely are sick.(36) Zinc deficiency should be taken seriously as there is a direct correlation between cancer and zinc deficiency(37) Advanced cancer appears invariably associated with zinc deficiency.(38)

Zinc deficiency, low zinc serum levels below the normal range of 60 to 150 mcg/dL, is common in cancer and causes immune suppression since zinc is a key component of many enzyme systems necessary for T-cell function and regulation.

Studies such as Chrandra's (42) back in 1984 have claimed that zinc serum concentrations significantly above the optimal high-normal range of 140 to 160 mcg/dL can cause immune suppression. Other studies have concurred with Chrandra that the optimal zinc serum range of 140 to 160 mcg/dL is best for maximizing (doubling) T-cell function (43), (44), and (45). Back in 1997, Dr. Brewer did his own study on the effects of high dose zinc on Wilson's disease patients. He found no compromise in T-cell / lymphocyte function and stated, "We have seen no indications of immune suppression or increased susceptibility to infections in our patients, who have now been treated with zinc for up to 15 years. We conclude that any side effects from compromised lymphocyte function caused by administration of zinc are not of concern to patients of Wilson's disease."(46)

Zinc has been scientifically researched and is well documented as safe, and even the effects of gram doses of zinc given over many months was shown to be non-lethal. An interesting story of chronic zinc intoxication has been reported of a psychotic twenty-year-old woman who took an average of 2300 mg elemental zinc per day, in doses ranging from 400 mg to 5700 mg, for four months. She presented herself for a routine examination. The most striking laboratory findings were a serum zinc level of 1160 mcg/dL, a copper serum of 8 mcg/dL, and an undetectable serum ceruloplasmin level. The patient was severely anemic and exhibited macrocytosis (excessively large red blood cells) and neutropenia. (Neutropenia is an adverse condition where white blood cells known as neutrophils have dropped so low that there is a much greater risk of developing infections, particularly in the mouth, throat, sinuses, lungs and skin.) Her only intolerance appeared to be some vomiting. Oral copper therapy and the cessation of excess zinc consumption produced a remarkable reversal of all parameters. Her rapid recovery from long-term zinc toxicity was essentially complete in one month, and an examination one and a half years later confirmed that there was no apparent permanent damage.(50)

Data indicates that as much as one-half of the world's population is at risk of zinc deficiency, but zinc toxicity is a rare phenomenon. High dose zinc supplementation has been used to treat patients with Wilson's disease to deplete copper for up to 15 years. Dr. Brewer saw no indications of immune suppression or increased susceptibility to infections in his patients.(51)

There are over 1800 MedLine citations about "zinc deficiency" and only about 15 on "zinc toxicity." Zinc can stimulate the immune system to increase the number of circulating effector T-lymphocytes and natural killer (NK) cells which kill cancer. Zinc deficiency is related to immunosuppression, which allows cancer cells to grow freely.(52)

Therapeutic Use of Zinc

History of Zinc Treatment in Cancer

In the early 1950s, discovery of abnormal zinc metabolism in chronic adult leukemia patients suggested use of zinc as a therapeutic drug in its treatment. Zinc may act by stimulating cell mediated immunity.

When in 1979 a child's acute T-cell lymphocytic leukemia (ALL) was put into permanent remission within two weeks of initiation of chemotherapy in conjunction with therapeutic doses of adult doses of vitamins and minerals, her oncologist questioned whether one of the supplements might have enhanced her therapy.(53) It was the child's father, George Eby, who researched to identify zinc as the element saving his daughter's life.(54) He found that raising zinc concentration in the serum to 140 mcg/dL resulted in numerous immunological and adjuvant to chemotherapy effects which had the effect of rapidly eliminating all detectable leukemic blasts in bone marrow and blood. The high normal zinc serum concentration was maintained according to blood test each two weeks during the three year chemotherapy program. The young woman remains without relapse to this date.

About a dozen other families with leukemic children and one with lymphoma followed Eby's protocol of zinc plus chemotherapy between 1985 and 1987. They were all successful in putting their child's cancer into a very strong remission (zero blasts in bone marrow and blood) within about two weeks. When publicity ran out on the Eby case, no one followed up with human trials to supplement the diet with zinc in treating childhood leukemia.(55)

George Eby changed his career to biomedical research and published years of research in one of the largest zinc sites on the Internet starting in 1996.(56) He developed zinc cold lozenges which were proven effective in many trials, with the most recent clinical trial (57) in 2000 led by an expert in zinc studies, Ananda S. Prasad, M.D., Ph.D., a well-known research oncologist at Wayne State University in Detroit, Michigan.

Zinc's Role in Wilson's Disease

In 1987, doctors Brewer and Prasad, experts in copper and zinc metabolism, both joined together on a research project which developed the following standard zinc maintenance protocol used today for Wilson's disease, a genetic disorder in which the body is unable to excrete excess copper.(58) This therapy received approval by the Food and Drug Administration (FDA) early in 1997, and it is used as standard protocol today.(59)

1. Dose: 50 mg zinc three times a day (zinc acetate / Galzin®). Separate from food and beverages (other than water) by one hour.

2. Food: avoid liver, limit shellfish.

3. Check drinking water. Restrict intake if copper more than 0.1 ppm (0.1 mcg/L).

4. Monitor copper and zinc in 24-hour urine collection tests every six months. Good control in preventing copper loading is less than 125 mcg/24 h. Good compliance in zinc supplementation is more than 2 mg/24 h.

High urine copper levels indicate excessive amounts of toxic unbound copper in Wilson's disease patients. Ceruloplasmin (Cp) is a protein used to transport copper, and Wilson's disease patients typically present with low Cp levels. Despite excessive copper storage levels, the liver of a Wilson's disease patient is not able to produce sufficient Cp to bind the free copper in the blood.

Dr. Brewer found that zinc is less effective when taken with meals. He advised separating each zinc dose from any food or beverage other than water by at least one hour before and two to three hours after eating. Since there is no known testing of combinations of vitamins or mineral supplements with zinc, it is best to take the zinc apart from any other substance.(60) Further, single daily doses of zinc are relatively ineffective in maintaining the blockade of intestinal copper absorption that is necessary to preclude significant copper reduction.(61) Some patients have found that 50 mg zinc is too upsetting on an empty stomach. One possible alternative might be to take a small piece of meat with the zinc which may inhibit any vomiting or nausea. Meat interferes with zinc absorption less than other foods.(62)(63)

Initial Copper Reduction and Maintenance in Wilson's Disease

The initial therapy for Wilson's disease patients was to use either penicillamine or trientine, prescription chelating agents that bind to copper. By the 1990s, Brewer had made a major advancement in copper reduction therapy when he started protocols with TM which the University of Michigan registered under the FDA's Orphan Drug Act in 1994. TM is very effective and quick-acting, and its method of excretion does not cause temporary increases in brain copper levels like penicillamine or trientine.

Zinc is not recommended as an initial treatment because it is slow-acting and produces little effect in the first few weeks. Its use as initial therapy for Wilson's disease patients is usually limited to those who are pregnant or without symptoms of copper toxicity.(64)

After initial therapy normalizes copper levels, the patient must be maintained to prevent further toxic copper accumulations. Zinc has been used by Dr. Brewer for Wilson's disease maintenance therapy for up to 15 years, and he has seen no indications of undesirable afflictions, immune suppression, increased susceptibility to infections, or other side effects in Wilson's disease patients treated with zinc.(65)

From Wilson's Disease to Cancer

Dr. Brewer noted several minor adverse effects from copper depletion in his Wilson's disease patients. These effects were easily controlled with treatment modifications, but the incidents drew Dr. Brewer's attention to other possible therapeutic uses for zinc.(66)

At the University of Michigan in 1999, Dr. Brewer applied his Wilson's disease protocol of copper reduction to cancer trial patients substituting TM during the actual copper-reduction therapy.(67) TM usually takes one and a half to two months to reach therapeutic levels of copper deficiency for cancer patients. Dr. Brewer stated that the main advantage of TM over zinc supplementation in reducing copper levels is speed of therapy. Although Dr. Brewer's original plan was to change the cancer trial patient's protocol from TM to zinc at the maintenance stage, his initial six successful trials patients were thriving so well on TM that they have continued to be maintained on it.

Copper Control in Cancer

Even with consistent, good compliance of 150 mg daily zinc and reaching the optimal zinc serum range of 140 to 160 mcg/dL, copper reduction with zinc therapy is extremely slow. Current estimates are that zinc therapy will lower Cu approximately 25 mcg/dL and Cp approximately 5-7 mg/dL over a 70-90 day period. High levels of zinc may be slow to reduce copper, but zinc is still a healthy supplement to enhance immune function and form an angiogenesis blockade to retard cancer's growth.

According to Dr. Brewer, even when the target Cp baseline is reached, it can take an additional four months to see tumor reduction because tumors sequester copper and will only reduce in size as the formation of new blood vessels is blocked. Given approximately two years, long-term oral zinc treatment can be a safe and effective alternative to copper chelating agents. Assuming the more urgent necessity of control for a patient's cancer condition, more aggressive therapy with copper chelators is usually indicated.(68)

Dr. Brewer choose TM for the cancer trials because speed was needed to control the patient's disease, but once at baseline, zinc should be easy to substitute for TM in maintaining low copper levels. The dose would need to be individually tailored to maintain the patient's Cp within Brewer's copper deficiency window.

There has been speculation that since TM and zinc function differently in the body, a protocol could be used combining them both in copper reduction. Several anecdotal reports from patients who tried such combinations were negative. They found that their rapidly declining Cp was accompanied by bone marrow toxicity exhibited by platelets, neutrophils, WBC, and RCB counts dropping to unsafe levels. The problem could well have been dosage in that daily amounts of 120 mg TM combined with 150 mg zinc is too high. Alternate protocols such as 60 mg TM and 150 mg zinc are now being tested.

Although not yet standard protocol, new treatments of low-dose chemotherapy are being are being tried where the patient is administered continuous low doses of standard anticancer drugs that target the tumor vasculature. Since there are no standard or well tested protocols, most oncologists are not participating in writing such therapies for their patients. A number of anecdotal reports have been heard of patients responding well to a combination of copper-reduction therapy with TM and low-dose chemotherapy. When these treatments are combined, extreme care must be taken by weekly monitoring of CBC counts because the combination of chemotherapy and TM can be more likely to produce bone marrow depression. Procrit or epogen may be needed to increase low RBC counts. In order to keep up your WBC, it may be necessary to take Leukine, also referred to as granulocyte macrophage colony stimulating factor (GM-CSF), a man-made form of a protein called a growth factor. Be sure to choose GM-CSF and not neupogen known as granulocyte colony stimulating factor (G-CSF). Neupogen is known as an angiogeneic agent where as leukine is mostly antiangiogenic.(68.1)

Captopril

The drug captopril is another copper chelator. It is an angiotensin I-converting enzyme (ACE) inhibitor that is approved and widely used for hypertension and congestive heart failure. Side effects may include anemia, rash, eosiniphila, low blood pressure and peripheral or facial edema (swelling). Although its positive effects on heart disease have been known for some time, only recently has its copper chelating and antiangiogenic properties been investigated. It appears that captopril inhibits angiogensis via three distinct pathways: conversion of plasminogen to angiostatin, copper chelation, and MMP inhibition.(69) Any use of captopril would require a doctor's supervision, probably a cardiologist since it is a potent heart medication. Since this drug chelates both copper and zinc, the advisability of supplementing with zinc during captopril therapy should be discussed with the administrating physician. Cancer patients who also have hypertension or a heart condition for which an ACE inhibitor is indicated may wish to contact their doctor to discuss the possibility of using captopril. Clinical trials of this drug for cancer are now underway at Northwestern University, but only as an agent to prevent lung injury in patients receiving a bone-marrow or stem cell transplant.

EDTA Chelation

Although chelation therapy has been used since the 1940's for a wide variety of ailments, it is still considered "alternative medicine" for anything other than heavy metal poisoning.(70) Chelation therapy usually consists of an intravenous solution containing a synthetic amino acid called ethylene diamine-tetraacetic acid (EDTA). When administered properly, it is a safe and effective way to deplete heavy metals and other toxins from the bloodstream. Although the authors could not locate any study results using EDTA chelation for copper-reduction therapy, one lymphoma patient known to them did make the attempt. He used standard EDTA chelation for five treatments, but he abandoned the therapy when test results indicated it was ineffective in lowering copper levels.