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The Role of Copper in the Angiogenesis Process

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The Role of Copper in the Angiogenesis Process and Chelating Copper As A Nutritional Anti-angiogenic Strategy + Other Available Anti-angiogenic Agents Useful in the Control of Cancer

By Dwight L. McKee M.D.

Copper is believed to be the switch that turns on the angiogenesis process in tumor cells. It has been observed that abnormally high serum copper levels are found in patients with many types of progressive tumors.

According to the University of Michigan Oncology Journal, many studies have shown copper to be an obligatory cofactor in the process of angiogenesis. Growth factors in angiogenesis require binding to copper in order to function properly. As stated in Steven Brem's research at the Moffitt Cancer Center, "copper-binding molecules (ceruloplasmin, heparin, and the tripeptide glycyl-histadyl-lysine) are non-angiogenic when free of copper, but they become angiogenic when bound to copper." On January 21, 2000, the University of Michigan reported that researchers had successfully stopped the growth and spread of cancer by depriving the tumors of the copper supply they need to form new blood vessels. This study was done with a small group of patients with advanced cancer. A larger, 100 patient, Phase II trial is currently underway. Researchers are using an inexpensive compound called tetrathiomolybdate, a molecule combining 4 sulfur-hydrogen groups bound to an atom of the mineral molybdenum, to lower the ceruloplasmin (Cp) levels (the major copper binding protein in blood) in patients with cancer.

The goal of copper chelation with Tetrathiomolybdate (TM) as an antiangiogenic strategy is to lower ceruloplasmin levels to the target level, which is 15-20% percent of the baseline level, and remain at that level for at least 90 days, to see if the strategy will halt tumor growth. At this point, if any stabilization of tumor growth has occurred it should become apparent from scans taken at the 90 day point after reaching the target ceruloplasmin and compared to scans done after another 2-3 months (longer for tumors that have historically been slow growing). This is a long-term strategy, though, and these levels should remain low to prevent new blood vessels from growing. TM is currently available by a physician's prescription through a number of compounding pharmacies.

The serum copper levels in the body will lower with the ceruloplasmin levels, although in the first few weeks of TM therapy they may appear higher because TM chelates copper and then is bound to blood proteins and circulates before being eliminated from the body. Serum copper levels are useful to measure prior to starting chelation with TM and after at least a month on TM, after which point they will usually correlate with the ceruloplasmin level. When ceruloplasmin has been reduced to 20% of its baseline, serum copper will usually be below the lower limit of the range of normal. In contrast, zinc levels ideally should be at the high range of normal or even slightly above (though they are usually low when first measured in most cancer patients). A ratio of serum zinc levels approximately three times higher than copper levels appears to be optimal for immune function and angiogenesis blockade. The dose of TM used in the first phase of the University of Michigan study was one capsule (20mg of TM each) with meals and three capsules (60 mg) on an empty stomach. Taking the three "empty stomach" capsules in the middle of the night if one awakens to go to the bathroom seems to be the most effective in lowering ceruloplasmin levels. In a second phase of the U of M study the dose was increased to two capsules (40 mg TM) with meals and 3 capsules (60 mg) on an empty stomach. The higher dose was associated with more rapid drop in the ceruloplasmin level and showed no greater side effects (generally limited to sulfur smelling burps and occasional stomach upset, usually associated with taking the capsules on an empty stomach, and generally offset by eating a small amount of low copper food, such as rice crackers.

The capsules taken with meals block the copper from absorbing into the body from food or drink intake. The capsules taken on an empty stomach bind and excrete residual copper from the body. This is important to remember when titrating (adjusting) the dose of the TM as ceruloplasmin levels near the desired target.

Ceruloplasmin levels should be tested monthly to begin, then every two weeks as the target nears. Once the target is close, it should be tested weekly, continually, until the ceruloplasmin is successfully stabilized at the target. As the ceruloplasmin levels approach the target (15-20% of the baseline), in patients with a significant tumor burden (e.g. tumor masses visible on scans) the ceruloplasmin may begin to rise. This is thought to be the result of death of the most newly formed blood vessels feeding the tumors, with consequent death of the cancer cells dependent on this blood supply, and release of copper from these tumor cells (tumors concentrate copper from the body). In such patients, the copper chelation dose should not be reduced until the target has been achieved and maintained for several months. If the ceruloplasmin level goes too low, however (usually less than 5 mg/dl), the copper needed for normal bone marrow function may be inadequate and blood cell levels (red cells, white cells, and/or platelets) may fall. In patients being treated with chemotherapy or a lot of prior chemotherapy treatment, the bone marrow may be more sensitive to low copper levels, and low blood counts may occur with ceruloplasmin levels between 5 and 10. It is unusual for levels above 10 to affect bone marrow function. If TM is stopped or reduced for a week or so in patients with active tumor, copper levels generally rebound quickly. Red blood cell growth factor (procrit) often appears to compensate for low red blood cell levels (anemia) associated with low (i.e. anti-angiogenic) levels of ceruloplasmin, white blood cell growth factors (Neupogen, Leukine) nearly always raise low white counts, if they are seriously low. Although Leukine (GMCSF) is usually slower acting than Neupogen (GCSF) there are reasons to prefer it (Leukine) in this setting, as it has shown anti-angiogenic activity in several test systems, whereas Neupogen shows angiogenic activity. Some patients experience increased fatigue for a time after reaching target ceruloplasmin levels, but this generally resolves over a few weeks to months as the body adjusts. No other consistent side effects have been associated with lowering ceruloplasmin levels to this range, though some patients have reported nocturnal leg cramps and constipation, both of which appear to respond to increased magnesium supplementation. If surgery is required it may be prudent to allow ceruloplasmin levels to elevate to the low range of normal for 6 weeks to ensure adequate angiogenesis for wound healing, and then lower them again to the target range.

Another copper chelating compound, widely available in health food stores, and less expensive than TM is N-acetyl cysteine (NAC). Taken in amounts of 2-4 grams (2,000-4,000 mg), starting with 500 mg. daily and gradually increasing to 4 divided doses of 500-1000 mg. each, it can significantly lower copper levels in the body, though more slowly than TM. It too is quite non-toxic, and also can help to raise levels of glutathione in cells, one of the body's major anti-oxidant systems. It can be useful, along with zinc supplements in maintaining target ceruloplasmin levels after lowering them with TM, and may be used in place of TM in cases where developing angiogenesis blockade is not an urgent issue. Also available through health food stores and compounding pharmacies is the anti-oxidant alpha-lipoic acid (ALA-- also known as thioctic acid). This is another non-toxic sulfhydryl containing compound that will chelate copper, as well as some other heavy metals, in doses of 100-400 mg./day; it is best absorbed on an empty stomach. Larger doses are difficult to find as individual supplements, but can be compounded on prescription by a compounding pharmacy. In some cases ceruloplasmin comes down very slowly or not at all, despite doses of TM up to 200 mg. per day. This is possibly related to increased hepatic need for sulfur compounds which results in use of TM as a sulfur source, not allowing it to circulate and chelate copper. In such cases it is often useful to add other nutritional sources of sulfur, such as N-acetyl cysteine (NAC) and alpha-lipoic acid (ALA) as well as others, such as the amino acid l-taurine (500-1000 mg. per day) or MSM (methyl sulfonyl methane), 500 mg-2000mg daily in divided doses.

Serum copper and serum zinc levels should be tested monthly, until the zinc to copper ratio has been near 3 for several months. It is important to have blood drawn prior to taking any zinc supplements for the day, as oral intake of zinc prior to blood draw may falsely elevate the serum zinc level. The copper chelating strategy is a long-term strategy. An example of titration of one patient's ceruloplasmin levels with TM is as follows: (although Cp levels were monitored weekly in this example, intervals as noted above are generally adequate) baseline Cp 42.-target 8. Began TM 40 mg three times daily with meals, 60 mg. empty stomach.

Week 1 Cp 33
Week 2 Cp 25
Week 3 Cp 16
Week 4 Cp 14
Week 5 Cp 9 -TM lowered to 20 mg with meals and 40 mg. on empty stomach.
Week 6 Cp 7.3- TM stopped
Week 7 Cp 13.9 TM restarted at 20 mg with one meal, and 20 mg. on empty stomach.
Week 8 Cp 16.3
Week 9 Cp 17.2 TM increased to 20 mg. with two meals and 20 mg on empty stomach.
Week 10 Cp 21.4 TM increased to 20 mg. with three meals and 40 mg on empty stomach.
Week 11 Cp 18.1
Week 12 Cp 12.6
Week 13 Cp 7.9
Week 14 Cp 6.6 TM decreased to 20 mg. with three meals and 20 mg. on empty stomach.
Week 16 Cp 5.7 TM decreased to 20mg with 2 meals and 20 mg on empty stomach.
Week 17 Cp 6.7 TM changed to 20 mg with each meal.
Week 18 Cp 5.2
Week 19 Cp 5.4 TM decreased to 20 mg. with two meals only.
Week 20 Cp 16 TM increased to 20 mg. with two meals and 20 mg on empty stomach.

After this point, Cp remained between 5 and 8, with no dose adjustments necessary for the next two months.

During the above time period, the patient's hemoglobin dropped from 14.8 gm at baseline to 10.1 gm at week 6. Procrit was started and hemoglobin increased to 12.9 by week 16. WBC was 4.4 at baseline, dropped to1.9 at week 6 and recovered to 4.1 by week 17 without growth factor support. Platelets were 100,000 at baseline, dropped to 80 by week 4, and recovered to 137 by week 17 without support. CT scans (stage 4 lung cancers with lung, bone, and brain metastases) showed no progression between baseline and week 14, with no other treatment. This patient was also taking Celebrex 400 mg. twice daily, and Anvirzel 2cc. daily (an extract of the oleander plant thought to have anti-angiogenic activity, as well as other possible mechanisms, currently in Phase I trials at the Cleveland Clinic and clinically available in Turkey, China, Ireland, and Honduras). Tumors had shown 60% increase in size between the end of chemotherapy (given to point of maximal response) and start of TM (16 week interval), despite Celebrex and Anvirzel.

In addition to the TM supplement, it is also important to refrain from consuming high-copper foods and water, especially if TM is ultimately discontinued. The only foods high enough in copper to overwhelm the chelating capacity of TM are liver and other organ meats, and some shellfish, particularly lobster (though scallops are often low in copper). Food tables listing copper content of foods are not necessarily highly reliable however, as copper content may vary widely depending on the area of the country, seed strain, growing conditions, types of fertilizer used, etc. (For example, copper compounds are frequently used in organic agriculture for their anti-fungal effects, which may significantly elevate the copper content of the produce). The bottom line is monitoring the blood levels, and using copper binding agents such as TM and/or NAC/ALA/zinc (citrate or acetate (the latter available as a prescription called Galzinā) in the diet to maintain the target level.

Regarding diet, here are some examples of some foods which often are high in copper: whole grains, particularly buckwheat and whole wheat; shellfish, such as shrimp and other seafoods; liver and other organ meats; most dried peas and beans; and nuts, such as Brazil nuts, almonds, hazelnuts, walnuts, and pecans. Oysters have high amounts, about five times as much as other foods. Soybeans supply copper, as do dark leafy greens and some dried fruits, such as prunes; cocoa, black pepper, and yeast are also sources. In addition to food sources, copper can come from water pipes and cookware. A recent book published in paperback (Feb 2000) entitled Why Am I Always So Tired?: Discover How Correcting Your Body's Copper Imbalance Can Keep Your Body from Giving Out Before Your Mind Does by Ann Louise Gittleman and Melissa Diane Smith, although not addressing the issue of copper and angiogenesis, does give a thorough coverage of nutritional issues and how to maintain a healthy diet with a low dietary copper intake, as well as discussing other nutrients beneficial in preventing build up of copper in the body.

Other available prescription medications have anti-angiogenic activity as well, and may increase the effectiveness of lowered copper as an anti-angiogenesis strategy. These include the new anti-inflammatory medications referred to as COX-2 inhibitors, Celebrex and Vioxx. For most people without a history of ulcers or kidney problems these medications can be safely used long term at up to twice the maximum labeled dosage (i.e. 400 mg twice daily with food for Celebrex and 50 mg twice daily with food for Vioxx). People with a history of sensitivity to sulfa anti-biotics (like Septra/Bactrim) and high blood pressure should choose Vioxx over Celebrex. There are also a number of botanical sources of COX-2 inhibitors that do not cause GI irritation, such as turmeric, reseveratrol (from grape skins), rosemary extract, boswellia, and meadowsweet. Thalidomide also may be useful, and generally has few side effects up to doses of 200 mg. taken at bedtime. Older patients tend to tolerate it less well. Alfa interferon that may be injected subcutaneously or taken sublingually, in low doses, such as one-half million units daily, may also add to effectiveness of angiogenesis blockade. Laboratory studies and anecdotal clinical evidence also suggest that conventional radiation therapy is more effective when used along with lowered copper +/- these other anti-angiogenic agents.

In addition, low doses of certain chemotherapy agents taken on a weekly basis appear in many cases to have potent anti-angiogenic effects. Some of these include cyclophosphamide (Cytoxan*,) 400 mg/M2, which may be used orally or IV; 6-mercaptopurine, 60 mg/M2. by mouth; 5FU 400 mg/M2 IV or Xeloda* (oral form of 5 FU) 1000 mg. by mouth; taxol*, 80 mg/M2 or taxotere* 30 mg/M2 IV; etoposide (VP-16) 50 mg/M2 orally or IV, and gemcitibine, 400 mg/M2 IV. Anecdotal clinical experience and laboratory studies in animal models suggests that changing chemotherapy agents every 2-3 weeks may be most effective in attacking tumors' blood supply. Recent anecdotal clinical experience with drug resistant tumors have shown stabilization using Cytoxan 400 mg/M2 weekly for 3 weeks, followed by taxol 80-90 mg/M2 weekly for 3 weeks, followed by oral etoposide 50 mg. orally daily for 3 weeks (or dose adjusting to titrate the WBC to between 2and 3,000.), then repeating the cycle. If tumor sensitivities are known or likely, based on tumor type, it would make sense to use 3-5 of these agents sequentially which also may share tumor cell cytotoxicity for 3 weeks each, then repeating the cycle. (Note: etoposide is the only of these agents used more often than every 6-7 days).

When anti-angiogenic chemotherapy is applied in patients who have already depleted copper levels below the angiogenic threshold, but have not yet achieved tumor stabilization, their bone marrow shows greater sensitivity to these chemotherapeutic agents. In such situations it is best to use the above doses of these agents as total dose, rather than as a per meter squared dose, and check the CBC prior to each repeat dose of chemotherapy. Copper depleted patients will not likely tolerate etoposide (oral or IV) more often than every 6 days. If red cell growth factor support is needed, give Procrit 40,000 units the day after chemotherapy on a weekly basis. If WBC support is needed, give GMCSF (Leukine) 500 mcg. daily starting the day after chemotherapy and stopping 48 hrs. before the next dose of chemotherapy (i.e. for 3 or 4 days between doses, depending if the interval between chemotherapy doses is 6 or 7 days. Chemotherapy doses should also be attenuated as needed to maintain blood counts. If cytopenias are severe, it is better to give a very small dose of chemotherapy followed by growth factor support, than to skip doses, as endothelial cell damage from chemotherapy agents repairs very quickly.

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