Tetrathiomolybdate (TM)

My opinion:

Clear science – Accessible (cost and source) – Clinical trials with positive results – Can be added in parallel to other treatments – Needs constant blood tests to follow Cu levels
Conclusion: Good addition to most anticancer treatment strategies and, alone, TM can be a good anti cancer treatment.

What is impressive to me is to see that this drug has been in the news, as an anti-cancer element with serious potential, since 2000. And today remains in the news:
2015: Drug Creates €˜Inhospitable€™ Environment for Breast Cancer Progression
2014 in Nature: Copper is required for oncogenic BRAF signalling and tumorigenesis
2014 in Nature: Inhibiting oncogenic BRAF signalling by copper depletion

Update September 27th, 2015: This is a very interesting paper I found today indicating that tetrathiomolybdate protects against liver injury from acetaminophen in Mice http://jrnlappliedresearch.com/articles/Vol4Iss3/Brewer.pdf I like this article a lot because paracetamol/acetaminophen is needed during pro oxidant therapies such as 3BP or other chemotherapies to inhibit glutathione production (a resistance mechanism of cancer cells against pro-oxidant therapies). One main drawback of using paracetamol/acetaminophen is the liver toxicity and co-administration of tetrathiomolybdate seems to protect against that. This is a great bonus from TM next to its anti-angiogenesis properties.

Note: Do not take the angio-inhibitors while healing (e.g. from surgery or fracture) or while pregnant.  Do not give to a child.

Summary

Angiogenesis is the physiological process through which new blood vessels form. In cancer, this is a vital mechanism that helps the tumors get their oxygen and the other nutrients all cells need to survive and continue growing.  Like healthy cells, cancer cells cannot live without oxygen and nutrients. So they send out signals, called angiogenic factors, that encourage new blood vessels to grow into the tumor. Without a blood supply, a tumor can’t grow much bigger than a pin head. (Ref)

As a result, angiogenesis was recognized as a therapeutic target for blocking cancer growth.

Copper has an important role in the angiogenesis process and copper chelation is recognized as a potential anti-cancer treatment targeting the inhibition of the angiogenesis process (Ref).

TM (tetrathiomolybdate) is a copper chelator and thus works against tumors by removing copper from the body. It is a drug already approved for human use, for the treatment of Wilson’s disease. In cancer treatment in humans, TM is used to reduce copper by 80%: €œDecreasing copper by 80% turns out to be fine to maintain the normal, housekeeping functions of normal cells,€ Merajver told Cancer Network. €œBut this level is not enough for very active angiogenesis required by tumors. The new blood vessel growth required for tumor progression is inhibited when copper is within this low level. This is the window of opportunity that this copper chelation affords.€ (Ref)

Case reports and Clinical studies

Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study. M-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.

Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer Four patients (31%) had stable disease for at least 6 months during copper depletion (median, 34.5 weeks). TM was well tolerated, with dose reductions most commonly occurring for grade 3-4 granulocytopenia of short duration not associated with febrile episodes.

Mechanism

TM is a copper chelator, while copper seems to be required for the development of new blood vessels needed to support the the tumor growth.
Its mechanism may involve inhibition of NF-κB and downstream cytokines.

Safety/Toxicity

“TM has been used in humans to treat a disease of copper excess known as Wilson€™s disease, and found to have some mild side effects. TM is likely safe to use in cancer patients, based on preliminary human research (noted above), provided it is used under close medical supervision. TM can cause the body€™s copper level to go too low resulting in low white and red cell counts (temporary). This can cause fatigue, dizziness, and susceptibility to infection. Low cell counts can be rapidly corrected by adjusting the dose of TM. Other known side effects include bad breath, diarrhea, and rash. In our experience, mild drops in cell counts are common, and most patients have little or no side effects from the drug itself. Patients who receive TM must be closely monitored for drug side effects with routine check-ups and comprehensive lab tests.” (Ref.)

“Two adverse effects predominate. One is overtreatment bone marrow suppression. Since the bone marrow requires copper for cellular proliferation, higher doses of tetrathiomolybdate causing bone marrow depletion of copper result in bone marrow cellular suppression. The other adverse effect is elevation of serum aminotransferase enzymes, possibly due to hepatic mobilization of copper in livers already loaded with copper. Both adverse effects are dose related and occur much less frequently if the daily dose of tetrathiomolybdate does not exceed 120 mg. Since there does not appear to be an efficacy advantage of higher tetrathiomolybdate doses, we recommend 120 mg/d for initial therapy in Wilson’s disease, to minimize adverse effects. Both adverse effects, if they do occur, are quickly responsive to drug holiday and/or dose reduction.” (Ref.)

“Dr. Vahdat: Well, everything has risk. I would say the two side effects that we’ve seen is that if we over copper deplete patients there is a risk of them having a low white blood count, we do that three percent of the time, and the other thing that patients can get is a sulfur burp. Sulfur burps actually smell like rotten eggs. My patients will always tell me that it bothers other people more than it bothers the patient, but we give them what we call a PPI, a proton pump inhibitor, to decrease the acid level in their stomach and it gets rid of the sulfur burp. So, really the only risk that we’ve seen so far, and we have patients who are on trial for more than six years, is that if we over copper deplete them their white blood count can be lowered.” (Ref.)
Based on the above, PPIs such as Omeprazole or Lanzoprazole should solve the issue of sulfur burps.

Preparation & Administration

Serum ceruloplasmin (Cp) was used as a marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15€“20% of baseline. (Ref)

TM (120 mg/day) was effective in reaching the target Cp without added toxicity. (Ref)

In order to determine if TM is effective in treating cancer, it is recommend at least 3 months of treatment. If a patient responds to the drug, their therapy may continue indefinitely.

Here is the Treatment Schema: Doses and Escalation from the Phase 1 clinical trial:

Three dose regimens were evaluated. All dose levels consisted of 20 mg of TM given three times daily with meals plus escalating (levels I, II, and III) in-between meals dose given three times daily for a total of six doses/day. Loading dose levels I, II, and III provided TM at 10, 15, and 20 mg, three times daily between meals, respectively, in addition to the three doses of 20 mg each given with meals at all dose levels.

Baseline Cp was taken as the nearest Cp measurement to day 1 of treatment (including day 1) because blood was drawn before TM treatment from all patients. The target Cp reduction was defined as 20% of baseline Cp (so the goal is to reduce Cp to 20% of the inital value measured). Due to Cp assay variability of approximately 2% at this institution, a change of Cp to 22% of baseline was considered as achieving the desired reduction of copper. In addition, if the absolute Cp was less than 5 mg/dl, then the patient was considered as having reached the target Cp. No patient reached the 5 mg/dl target without also being at least 78% reduced from baseline. After reaching the target copper-deficient state, TM doses were individually tailored to maintain Cp within a target window of 70€“90% reduction from baseline.

If the above is not clear you could also read this webpage where the treatment is described in a more simple way.

In one of the case reports from Medicor there is a reference to a patient who developed crampy pains in her leg muscles. After administration of oral magnesium tablets that was resolved.

Update September 25th, 2015: 58 capsules of 20mg tetrathiomolybdate (see pic below):

Tetrathiomolybdate

Source & Cost

CAS number: 15060-55-6

Once source can be chemical companies such as Sigma where 10g would cost about 200euro and would be enough for about 3 months.

Another example of a source is Flora Apotheke in Hanover, Germany where the one month supply would cost about 250 euro.

Patents

Tetrapropylammonium tetrathiomolybdate and related compounds for anti-angiogenic therapies Disclosed are copper-binding compounds with improved properties and methods of using such compounds in the prevention and treatment of angiogenic diseases, such as cancer. Advantages of the invention include the enhanced stability of the compounds, which is achieved without reduction in efficacy. Pharmaceutical compositions, therapeutic kits and combination treatment methods and uses are also provided.

Literature

COPPER AND ANGIOGENESIS: UNRAVELLING A RELATIONSHIP KEY TO CANCER PROGRESSION

The promise of copper lowering therapy with tetrathiomolybdate in the cure of cancer and in the treatment of inflammatory disease.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer. In a phase 1/2 clinical trial of advanced and metastatic cancers, freedom from progression averaged 11 months, and some individual results were quite dramatic. Eight phase 2 studies of specific cancers have been launched. TM’s hypothesized mechanism of action is inhibition of angiogenic cytokines. Unlike other current approaches to antiangiogenic therapy which target single agents, we hypothesize that TM inhibits multiple angiogenic cytokines. Part of this effect appears to stem from inhibition of nuclear factor kappa B (NF(K)B), which in turn controls transcription of many angiogenic and other cytokines. However, there are probably multiple mechanisms, in that some angiogenic cytokines appear to have separate mechanisms of copper dependence. The inhibition of multiple angiogenic cytokines gives TM the potential to be a more global inhibitor of angiogenesis.

Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer.

Bad penny: Cancer’s thirst for copper can be targeted

Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer.

Synergists & Antagonists

Low gastrointestinal acidity may require less TM (Ref)

Clinics Treating Patients with Tetrathiomolybdate

Canada: Medicor

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Related Articles


Leave a Reply

17 Comments on "Tetrathiomolybdate (TM)"

avatar
  Subscribe  
Notify of
Vipul Agarwal
Guest

How long one should take this Treatment

David S
Guest
My girlfriend started taking TM in late 2001 after her oncologist threatened to cut her off if she didn’t have mastectomies and a hysterectomy. She had several lumpectomies, cervical surgery and one ovary removed at that point, spread out from age 19 to age 30. I connected her with nurse Jan at the University of Michigan that was dispensing TM to the group of 30 + people with advanced cancer, and she benevolently supplied us with contact information of the supplier and the Tennessee pharmacist that made the caps and aided in communication between the staff at U of M,… Read more »
Chuck
Guest

David, you are a good person for helping her through a difficult period in her life… I believe in Karma, your life will be filled with a lot of happiness

Rachel Coleman
Guest

Hi. What is a reputable high quality source of tm without a prescription.

Alfredo
Guest

what about other copper chelators D-Penicillamine, trientine hydrochloride, zinc etc? Tetrathiomolybdate is not the only copper depletor.

what are your thoughts on vitamin b6 for this?

Douglas Edwards
Guest

Do you know of a specific clinic or doctor in the US that would prescribe this to prevent breast cancer recurrence?

Shanti
Member
Having a status of no evidence of disease (NED) or low tumor burden may be key for TM success Of interest, I recently attended the American College of Nutrition 2017 conference in Alexandria, VA. Dr. Linda Vahdat presented her research on TM and breast cancer and Dr. GJ Brewer was also present at the conference. Dr. Brewer has done some extensive work with TM in various capacities, including cancer and you can find his name attached to several human clinical trials using TM in cancer patients. Dr. Vahdat’s work was quite impressive, showing increased survival and long term remission in… Read more »