An experimental drug called tetrathiomolybdate (referred to from here on as "TM") is currently undergoing clinical trials at the University of Michigan. TM is known to decrease copper levels in the body by a process called "chelation". In simple language, TM binds copper to a protein, forming a complex which can then be excreted from the body. Copper is used by many organs in the body, but the use which is of interest here is that it is essential to the growth of new blood vessels, a process called "angiogenesis". ("Angio" means blood vessel and "genesis" means new formation.) Whenever tumor cells "set up housekeeping" in the body, blood vessels are necessary to provide nourishment for their growth. Once a tumor reaches the size of two millimeters it needs a blood supply to maintain itself. Without an adequate level of copper in the blood, this new blood supply cannot form and thus the tumor cannot enlarge.
TM has previously been used safely and successfully at the University of Michigan for children and adults with Wilson's Disease, a condition in which copper accumulates in high levels in the tissues. A Phase I clinical research study (testing safety and dosage) has just been finished at the same institution in which TM was used in patients with a large variety of Stage IV cancers. (See attached.) Phase II studies on 100 patients (specifically testing efficacy) are currently underway. Five of six patients in the Phase I study who were able to achieve a target range of copper and maintain it there for 90-120 days achieved stable disease and remain stable a year later.
COMMONLY ASKED QUESTIONS:
How does TM work?
TM is a complex molecule of sulfur and molybdenum that forms a stable three-part complex with copper and protein. (Chelation). Taken with food, it binds to the copper in the food and keeps it from being absorbed. It also binds copper in the saliva and gastric juices and allows it to be excreted rather than absorbed. When TM is given on an empty stomach (2 hours away from any food), it is absorbed into the blood stream where it forms complexes with copper and serum albumin (a protein in your blood). This copper complex cannot be taken into the cells and is gradually excreted through the bile and the urine.
Does TM work for all types of cancers?
At present we cannot give a definitive answer because it has not been tried on all types, although a wide variety of cancers were used in the Michigan study. As a general rule, if the cancer depends on angiogenesis for growth, then TM should work. In addition to solid tumors, multiple myeloma, lymphoma, and leukemia are angiogenesis dependent.
Where is TM available?
TM is produced and distributed by several compounding pharmacies in this country. A physician's prescription is required to obtain it. It is very sensitive material that needs to be kept in an oxygen-free environment prior to compounding, and the compounding process is arduous. It is good to have an experienced pharmacist who does this on a regular basis and can answer all your questions accurately.
How do I get started?
First, you have to find a physician who is willing to write the prescription and follow you carefully while you are attaining target, as well as on an on-going basis. Since TM is not yet formally approved by the FDA for this indication, most oncologists will not write a prescription.
Both oncologists and family doctors are willing to participate once they understand the rationale and their responsibilities.
Second, you have to get baseline blood tests for serum copper, zinc, and ceruloplasmin (the protein that carries copper in the blood.) It is also necessary to get a CBC (complete blood count) because low copper levels can sometimes depress the bone marrow and this has to be watched closely. After this is done, you can start without waiting for the results to be reported. Only a few labs in the country do copper and zinc and so your lab will have to send them out. The process takes about a week. Many labs also send out the blood for ceruloplasmin, but the turn-around time for this should not be longer than 48 hours. If it is longer, you need to find a lab that will give you a faster turn-around time because ceruloplasmin levels are the ones we follow during the lowering of copper and results are often needed on a very timely basis.
At first you will get a ceruloplasmin level and CBC one month after starting TM and then every two weeks until the ceruloplasmin is down in the low teens, at which time you will have to have the blood test once a week until you are stable. The goal is to lower the ceruloplasmin to 20% of baseline. For example, if your initial ceruloplasmin is 40, your goal will be 8. This is the level at which stable scans were achieved in the University of Michigan Study. It takes a mean of 50-60 days to get to target. Once you have been at target for three months you can expect to see "stable scans" i.e. no further tumor growth.
Why does it take three months after reaching target to see stable scans?
The target level of ceruloplasmin reflects what is happening in the blood. Once the level of copper is low in the blood, we speculate that it then comes out of the tumor. Since tumors tend to collect a lot of copper, it may take time to make the tumor itself copper-deficient. When copper starts coming out of the tumor, the copper and ceruloplasmin levels in the blood may actually appear to increase. This is actually a good sign and the level will decrease over time. Once copper is chelated out of the tumor, which takes about three months, it is postulated that the tumor is no longer able to make new blood vessels to keep it going. The recommended procedure is to have scans three months after the target is reached and then repeat the scans at the six month mark. If the TM has been successful, the repeat scans should be stable, i.e. no evidence of tumor growth. (*Note: Tumors can continue to grow to some extent during the three months after achievement of the target.)
What is my dose of TM and how is this managed?
There are two "tracks" for starting on TM:
As your ceruloplasmin level decreases and you get close to target, the physician supervising you will adjust the dose accordingly. This can be a very delicate procedure and requires complete cooperation on your part, i.e. being compliant with exact doses and getting your blood work done in a timely fashion and reported to the physician. This process is called "titrating" your dose and means making fine adjustments up and down to find just the right amount that will keep you at target. This can vary widely with different people. We will give you a graph for keeping track of your progress at home. You are definitely a partner in this venture.
How should I store my TM?
Originally we were told to store it in the freezer, but now know that this is not necessary. Actually, if you do not have a frost-free freezer it may cause the TM to collect moisture. The most important thing is that the TM not be exposed to air or moisture insofar as this is possible. Always keep it in the container in a cool, dry place. Don't take capsules out far ahead of when you will use them. We have asked the pharmacist to stuff the bottle with cotton to keep down the air space as you use the capsules. The TM is stored under a special gas until it is put into capsules. When you receive your capsules, they have a 90% shelf-life of 8 weeks. This means that in two months they will not have degraded more than 10%. To be on the safe side, we ask you to order only one month's supply at a time.
What side effects might I expect from the TM?
Although the Michigan study reported no side effects, we have seen a few. None are especially serious unless you are on chemotherapy at the same time. (To be discussed later.)
Can I take TM if I am on chemotherapy?
Yes, however, this has to be carefully coordinated with your oncologist because the combination of chemotherapy and TM is more likely to produce bone marrow depression. You will need to have weekly CBC's and may need to take leukine (GMCFS) to increase your white blood cell count and/or procrit or epogen to increase your red blood cell count. Be sure that you take leukine rather than neupogen for the white cells because neupogen is an angiogenic agent whereas leukine is mostly anti-angiogenic. Let us know if you need literature references regarding this.
What if I have to have surgery while I am taking TM?
There is no hard evidence that low copper interferes with wound healing, but theoretically it could. When TM is discontinued, copper levels rebound quickly. Notify your physician, who will cut your dose of TM to bring you to a low normal level for approximately six weeks postoperative.
How does TM affect radiation therapy?
Actually, conventional radiation therapy is more effective when the copper level is low.
What if I neglect to take my TM or decide to stop it once my copper level is lowered?
In the Michigan study they found that when TM is discontinued, the copper level reverts to normal in a few days and tumor growth seems to spurt. DO NOT UNDER ANY CIRCUMSTANCES STOP TM ONCE YOU ARE CLOSE TO TARGET WITHOUT CHECKING WITH YOUR PHYSICIAN.
What is the role of zinc in my TM treatment?
Studies at the University of Michigan showed that maintaining zinc at 140-150 micrograms in the blood helped to decrease copper. The ideal copper to zinc ratio is 1:3, i.e. your zinc level should be three times your copper level. A direct correlation between cancer and zinc deficiency has been shown. On the other hand, too much or too little zinc can be immunosuppressive. The Copper Reduction Protocol uses zinc at 50 mg with 30 mg of vitamin B6 per capsule (three per day) that helps assimilate the zinc. We usually recommend that you take 60 mg of zinc specifically in the form of zinc citrate at night before you go to bed on an empty stomach. Since zinc can sometimes cause gastric irritation, you may take it with a couple of rice crackers if that is the case. NOTE THAT RAISING ZINC LEVELS MAY SOMETIMES GIVE A FALSE HIGH PSA (prostate specific antigen) READING.
What if I am totally compliant with taking my TM and my ceruloplasmin will not go down?
We postulate that when the liver is not functioning properly it has a need for extra sulfur. In this situation it uses sulfur from the TM, leaving TM unavailable to chelate copper. In that case we give extra supplements such as MSM, etc to supply sulfur to the liver and allow TM to do its job. Your physician will discuss this with you.
Do I need to stay on a low copper diet while I am taking TM?
Patients in the Michigan study were not put on low copper diets. We have found that it is best (and faster) if you stay away from high copper foods. Two foods that you should definitely not have are organ meats and shellfish which are very high in copper (except for scallops). So far we have not found a very reliable table of copper content of foods since a lot of the content depends on the area of the country in which the food is grown. Generally, whole grains, especially buckwheat and wheat, nuts, chocolate, molasses, dried beans, tofu, black pepper, yeast, and dark leafy greens are known to be high in copper. Be sure if you do eat these foods you are taking your TM with the meal so the ingested copper can be chelated out. Generally, the TM taken at the conclusion of a meal will chelate copper out of the food ingested.
Do I need to fast before getting my blood tests?-the lab says that I should.
The tests done in the Michigan study were not done fasting. It is probably a good idea not to take zinc for 24 hours before you do a zinc test. (You will only need to do copper and zinc levels once a month. The rest of the time we will be following only the ceruloplasmin.)
What supplements do I need to take to support the copper-lowering process?
How does low-dose chemotherapy fit into this picture?
Fairly new on the oncology scene is the concept of low-dose anti-angiogenic chemotherapy. Used in small weekly doses, many chemo agents act to inhibit growth of blood vessels to tumors rather than killing the tumor directly. A number of our patients with Stage IV disease have responded well to a combination of TM and low-dose chemotherapy. Everything is anecdotal at this point so most oncologists are not participating. Some are, however. We are writing a separate information sheet on low-dose chemo so if you are interested, just request it.
What about copper in my drinking water?
This can be a significant source of copper ingestion, especially if you have copper pipes. The best thing to do is to get your water tested (look under Water Systems in your yellow pages for a lab near you.) Your water should have less than 0.1 mg of copper. DO NOT UNDER ANY CIRCUMSTANCES USE DISTILLED WATER - it is energetically "dead" and can leach minerals out of your body. The best filter to install in your home is a reverse osmosis filter. Some patients have found that the Multi-Pure filter removes an adequate amount of copper. It is best not to get most of your drinking water from plastic bottles, since carcinogens are leached from many types of plastic.
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