Expert Opin Investig Drugs. 2009 Apr;18(4):541-8.
Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm.
Khan G,
Merajver S.
LINK
Source
University of Michigan, Ann Arbor, MI, USA.
gkhan@umich.edu
Abstract
BACKGROUND:
Tetrathiomolybdate (TM) is a novel anticancer and anti-angiogenic agent, which acts through copper chelation and NF-kappaB inhibition.
OBJECTIVE:
This review summarizes the scientific rationale for the use of TM as an anticancer agent in human studies.
METHODS:
A systematic review of the literature was conducted for the use of TM in cancer including preclinical, animal and human studies. The results of this search are summarized in this review.
RESULTS/CONCLUSIONS:
Copper chelation using TM has demonstrated efficacy in preclinical and animal models as an alternative and novel anti-angiogenic agent.
Phase I and II clinical trials conducted in solid tumors using TM have demonstrated efficacy with favorable toxicity profile. The use of copper lowering as an anti-angiogenic strategy in the cancer chemopreventative setting remains to be investigated.
- PMID:
- 19335282
- [PubMed - indexed for MEDLINE]
Tetrathiomolybdate
Not DCA, but well worth knowing about
http://www.thedcasite.com/Alternate_...treatment.html
Tetrathiomolybdate, or TM, is an incredibly effective copper chelating material. We first learned of it when searching for a treatment for close family friend.
Paul was diagnosed with malignant pleural mesothelioma (asbestos cancer) and given about 9 months to live. Doctors said they could do little to help him.
We focused on stopping vascularization of the tumor, known as antiangiogenesis. Green tea extract is an example. Paul started all these things but nothing worked and the tumor kept growing. We then discovered the work done by Doctor George Brewer of the University of Michigan.
Dr. Brewer found that tetrathiomolydate, a compound that binds up copper easily with essentially no side effects, worked remarkably well in stopping vascularization of tumors.
http://www.hg.med.umich.edu/faculty/brewer.php
http://www.medicineatmichigan.org/ma...on/06huron.asp
Previous to starting TM, we suggested that Paul get his serum zinc and copper levels determined. Normally these levels are about equal. But
many studies have shown that in aggressive tumors the ratio of copper to zinc is 5 to 1. And that was what Paul’s ratio was! By taking zinc supplements and TM, he changed his copper to zinc ratio to 1 to 5. The tumor stopped growing, and has not grown since. Paul lives a normal life, taking his zinc and TM, with no side effects. He is living with cancer and has now for nearly three years.
TM must be made by a 'compounding pharmacist'. TM is also not patentable, so no large company is pursuing it. I highly recommend you research TM.
http://george-eby-research.com/html/anti_ang.html is an excellent article on the topic.
Published in August, 2008:
A Phase II Trial of Tetrathiomolybdate After Surgery for Malignant Mesothelioma: Final Results.
(additional link) showed that mesothelioma responded well to TM.
A recent report shows that TM does not work against hormone-refractory prostate cancer.
Zinc supplementation lowers magnesium and potassium levels. I have a quick summary of this information on this
(click here) web page.
Additional information about TM
Paul takes four 20 mg tablets of TM daily, 2 in the morning and two at night, for a total of 80 mg/day.
He takes 200 mg of zinc daily.
Email, 22 February 2009
Jim: I have ordered the TM and will be starting my friend on it soon. [friend has mesothelioma]. He went to his doctor and intimidated her to order the tests for the CU and Zn.
When the tests came back, Zn was 60 and the Cu was 160, the doctor told my friend she could not give him anymore chemo until his zinc was up.
My friend asked, "If the zinc is so important, how come you have not tested for it before now?"
--end of email ---
I strongly encourage you to demand a serum copper and zinc test to be taken. Normal is 1:1.
Ann Thorac Surg. 2008 Aug;86(2):383-9; discussion 390.
A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results.
Pass HI,
Brewer GJ,
Dick R,
Carbone M,
Merajver S.
LINK
Source
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016, USA.
harvey.pass@med.nyu.edu
Abstract
BACKGROUND:
Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression.
METHODS:
Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.).
RESULTS:
The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49-81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 +/- 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 +/- 2 mg/dL) decreased from 2,086 +/- 390 pg/mL to 1,250 +/- 712 pg/mL (p < 0.002) at target ceruloplasmin (13 +/- 2 mg/dL; p < 0.0001 from baseline).
The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non-TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months).
CONCLUSIONS:
Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy.
- PMID:
- 18640301
- [PubMed - indexed for MEDLINE]
lin Cancer Res. 2000 Jan;6(1):1-10.
Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.
Brewer GJ,
Dick RD,
Grover DK,
LeClaire V,
Tseng M,
Wicha M,
Pienta K,
Redman BG,
Jahan T,
Sondak VK,
Strawderman M,
LeCarpentier G,
Merajver SD.
Source
Department of Human Genetics, University of Michigan Health System, Ann Arbor 48109, USA.
FREE TEXT
Abstract
Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis.
Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in
18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals.
Serum ceruloplasmin (Cp) was used as a surrogate 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.
The level III dose of TM (120 mg/ day) was effective in reaching the target Cp without added toxicity. TM-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.
- PMID:
- 10656425
- [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2009 Dec 1;15(23):7441-6. Epub 2009 Nov 24.
Antiangiogenic tetrathiomolybdate protects against Her2/neu-induced breast carcinoma by hypoplastic remodeling of the mammary gland.
Pan Q,
Rosenthal DT,
Bao L,
Kleer CG,
Merajver SD.
FREE TEXT
Source
Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. Quintin.Pan
Abstract
PURPOSE:
The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent.
EXPERIMENTAL DESIGN:
Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice.
RESULTS:
At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and >460 days for TM-treated mice (P < 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 +/- 6.2% and 50.9 +/- 4.5% (P < 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase-positive mammary stem cells in Her2/neu and FVB mammary glands.
CONCLUSION:
Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment.
- PMID:
- 19934283
- [PubMed - indexed for MEDLINE]
Cancer Cell. 2010 Jun 15;17(6):574-83.
Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator.
Ishida S,
McCormick F,
Smith-McCune K,
Hanahan D.
FREE TEXT
Source
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract
Uptake of the anticancer drug cisplatin is mediated by the copper transporter CTR1 in cultured cells. Here we show
in human ovarian tumors that low levels of Ctr1 mRNA are associated with poor clinical response to platinum-based therapy. Using a mouse model of human cervical cancer, we demonstrate that combined treatment with a copper chelator and cisplatin increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis, and improves therapeutic efficacy. The copper chelator also enhances the killing of cultured human cervical and ovarian cancer cells with cisplatin. Our results identify the copper transporter as a therapeutic target, which can be manipulated with copper chelating drugs to selectively enhance the benefits of platinum-containing chemotherapeutic agents.
Copyright 2010 Elsevier Inc. All rights reserved.
- PMID:
- 20541702
- [PubMed - indexed for MEDLINE]
- PMCID: PMC2902369
Oncology. 2006;71(3-4):168-75. Epub 2007 Jul 18.
Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer.
Henry NL,
Dunn R,
Merjaver S,
Pan Q,
Pienta KJ,
Brewer G,
Smith DC.
LINK
Source
Department of Internal Medicine, Division of Hematology, University of Michigan School of Medicine, Ann Arbor, Mich., USA.
Abstract
OBJECTIVE:
Preclinical studies suggest antiangiogenesis strategies may be effective in the treatment of prostate cancer. In tumor models, the copper-chelating agent tetrathiomolybdate (TM) has been shown to be antiangiogenic. We evaluated the antitumor activity of TM in patients with hormone-refractory prostate cancer (HRPC).
METHODS:
Nineteen patients with asymptomatic HRPC enrolled. Copper depletion was monitored using serum ceruloplasmin levels.
Once the target ceruloplasmin level of 5-15 mg/dl was attained, patients underwent staging evaluation. Patients were reassessed every 12 weeks, and TM was continued until they developed evidence of disease progression or intolerable toxicity. Prostate-specific antigen and levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin (IL)-6 and IL-8 were measured at study entry, at the time of copper depletion, and monthly while on therapy. Results: Seventeen of 19 patients achieved copper deficiency on TM therapy.
Of the 16 evaluable patients, 14 developed progressive disease, 1 discontinued therapy because of toxicity and 1 patient opted to discontinue therapy because of rising prostate-specific antigen level without objective evidence of progressive disease. Levels of vascular endothelial growth factor, IL-6 and IL-8, but not basic fibroblast growth factor, were elevated when compared to normal controls prior to TM therapy, but there was no significant change during therapy. There was no correlation between prostate-specific antigen and levels of angiogenesis factors.
CONCLUSIONS:
Copper depletion with TM did not delay disease progression in patients with asymptomatic metastatic HRPC.
- PMID:
- 17641535
Mol Cancer. 2010 Aug 3;9:206.
Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis.
Kumar P,
Yadav A,
Patel SN,
Islam M,
Pan Q,
Merajver SD,
Teknos TN.
FREE TEXT
Source
Department of Otolaryngology-Head and Neck Surgery and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
pawan.kumar@osumc.edu
Abstract
BACKGROUND:
The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths.
Tumor metastasis is very complex and this process requires a tumor cell to acquire enhanced motility, invasiveness and anoikis resistance to successfully establish a tumor at a distal site. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. Copper is a mandatory cofactor for the function of many of these angiogenic mediators as well as other proteins that play an important role in tumor cell motility and invasiveness. We have previously shown that tetrathiomolybdate (TM) is a potent chelator of copper and it mediates its anti-tumor effects by suppressing tumor angiogenesis. However, very little is known about the effect of TM on tumor cell function and tumor metastasis. In this study,
we explored the mechanisms underlying TM-mediated inhibition of tumor metastasis.
RESULTS:
We used two in vivo models to examine the effects of TM on tumor metastasis. A
nimals treated with TM showed a significant decrease in lung metastasis in both in vivo models as compared to the control group. In addition, tumor cells from the lungs of TM treated animals developed significantly smaller colonies and these colonies had significantly fewer tumor cells. TM treatment significantly decreased tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX) activity, FAK activation and MMP2 levels. Furthermore, TM treatment significantly enhanced tumor cell anoikis by activating p38 MAPK cell death pathway and by downregulating XIAP survival protein expression.
CONCLUSIONS:
Taken together, these results suggest that TM is a potent suppressor of head and neck tumor metastasis by modulating key regulators of tumor cell motility, invasiveness and anoikis resistance.
- PMID:
- 20682068
- [PubMed - indexed for MEDLINE]
Diet and Tetrathiomolybdate
If you are undergoing treatment for cancer, your health care team will advise you about general dietary recommendations that are helpful. This may include instructions such as avoiding citrus food;spicy, acidic, or very hot food; salty items; alcohol;and tobacco.In addition to this, you may need totake some additional dietary precautions if you are taking Tetrathiomolybdate(TM) as part of y our cancer treatment.
Food and Tetrathiomolybdate (TM)
If you are taking a drug called Tetrathiomolybdate, which also is referred to as TM, your doctor may ask you to follow a low copper diet. Copper is a mineral that occurs naturally in many of the foods we eat. Copper can affect how TM, a cancer treatment medication, works in your body. If you have been told to follow a lowcopper diet, please keep the following in mind.
Following A Low Copper Diet
Some cancer treatments require that you avoid food that contains a lot of copper. The most common cancer medication that requires a lowcopper diet is called Tetrathiomolybdate or TM. If you are taking TM, you will need to follow a lowcopper diet to help your medication work properly.Your doctor can give you more information on howTM works and why you will be taking it.
Food to Avoid
Below is a list of food that contains large amounts of copper.Avoid these food items if you are taking TM.
HIGHCOPPER FOODS
- Organ meat, especially liver
- Sausage, hotdogs, bratwurst, and other smoked, processed, and mixedmeats
Shellfish (oysters, shrimp, clams, scallops, crab, lobster, crawfish, prawns)
Starchy beans (legumes)such as black-eyed peas, kidney beans, navy beans, lentils, chickpeas, great northern beans, white beans, soybeans and soybean products such as tofu, tempeh, andsoy milk
- Nuts & seeds
- Mushrooms
- Cocoa powder (a small amount of chocolate in candyand chocolate milk are ok)
The "germ" of grain products, such aswheat germ
The "bran" of grain products, such as what is found in high fiber, bran cereals
Dietary Supplements, Vitamins, Minerals, and Herbs
- Do notuse supplements, such as multivitamins, that contain copper. Most multivitaminand mineral supplements contain some copper. Even if the label does notsay so, these products can contain copper.
- Do take any herbs or other "natural products". Even if the label does not say so, these products can contain copper.
Liquid Nutritional Supplements
- Nutritional supplements such as Ensure and Boost do contain copper. If you need to use these products, please discuss it with your doctor,nurse,or dietitian first.
- It is ok to adda can of Ensure or Boost to your diet. If you want or need to use more of these products, please talk to your doctor, nurse,or dietitian.
- If you aregetting your nutrition through a tube (tube feedingor enteral nutrition)your doctor canwork with you to adjust your medication to account for the copper contained in your tube feeding formula.
This content was last reviewed August 15, 2010 by Dr. Reshma L. Mahtani.
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