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Life Extension Magazine November 2009
Reports

The “Unimportant” Molecule That May Help Cure Cancer

By Jonathan V. Wright, MD
The “Unimportant” Molecule That May Help Cure Cancer

Big Pharma is at it again. After decades of dismissing the molecule 2-methoxyestradiol as being inconsequential, they have recently reversed course and spent hundreds of millions of dollars trying to obtain FDA “approval” to rename and repackage it as Panzem®.

This aggressive move into bioidentical hormones marks a predictable change of heart by Big Pharma, which routinely dismisses natural therapies until they can find a way to patent them and rip off the consumer with inflated prices.

In the case of 2-methoxyestradiol, Big Pharma is in a virtual frenzy to amass research because it appears that it may be able to actually cure—or at least significantly slow—many types of cancer, including some of the most commonly feared forms, like prostate, breast, and ovarian cancers.

An “Inactive” Hormone Shows Its True Cancer-Fighting Potential

As usual with pharmaceutical research, the emphasis (and the rush) is on the “gold” that can be produced by selling an “approved” form of this entirely natural molecule (at an unnaturally high price), rather than learning how to work with nature as closely as possible, which would offer the most benefit at the least possible cost to patients everywhere.

Before turning the spotlight on 2-methoxyestradiol itself, it’s always important to have a little bit of general background. Estrogens and androgens are steroid hormones, that is, nature’s own original steroids, not the pumped-up-to-be-patentable, pseudo-steroids currently scandalizing professional athletics. These natural steroids are produced by the ovaries or testes, adrenal cortices, and other body tissues of both men and women.

An “Inactive” Hormone Shows Its True Cancer-Fighting Potential

But, as you have previously read in Life Extension®, too much estrogen, especially too much of the wrong kind of estrogen, increases the risk of new cancers and can promote the development of tumors if they are already present. This occurs primarily when two of the “major” forms of estrogen, estradiol and estrone, follow a pathway that metabolizes them into estrogen compounds that promote tumor formation. Other pathways produce estrogen metabolites that protect against tumors.

As it turns out, 2-methoxyestradiol isn’t inactive, as the “experts” once assumed.1 In fact, it’s one of the most potent anti-carcinogenic estrogen metabolites. This metabolite is formed from the hydroxy-lation of 17β-estradiol followed by O-methylation in the liver.2,3

Some recent studies have shown that 2-methoxyestradiol inhibits the growth of prostate cancer cells by inducing apoptosis (programmed cell death) and preventing tumor growth in rapidly growing cells.4 It showed similar benefits for both breast5 and prostate cancer cells6 when it was used in combination with other chemotherapeutic therapies. And speaking of its role among chemotherapy drugs, not only does 2-methoxyestradiol have potent effects against pancreatic and gastric cancer cells that have become resistant to other chemotherapeutic drugs,7 but it also reduced the amount of chemotherapeutic drugs needed to kill ovarian cancer cells by enhancing their anti-tumor effects.8

Researchers have seen similar results using 2-methoxyestradiol in many other kinds of cancer cells, including osteosarcoma,3,9 leukemia,10 and chondrosarcoma,11 a type of cancer affecting the cartilage.

Prostate cancer. Scanning electron micrograph
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Prostate cancer. Scanning electron micrograph
of cancer of the prostate gland. This is the inside of an acinus (glandular duct) lined with cancer cells.

Recent in vitro testing of 2-methoxyestradiol showed surprising effectiveness against one of the most aggressive breast cancers: triple-negative cells. Its efficacy was shown to be similar to that of the chemotherapy drug gemcitabine. This type of breast cancer (triple negative), which is negative for estrogen and progesterone receptors and Her2neu protein, may benefit from chemotherapy combined with 2-methoxyestradiol. Additional studies will be carried out to determine the synergistic effects of 2-methoxyestradiol in combination with other chemotherapy agents.12

For the past 30 years, cytotoxicity assays have been performed using a triple-negative breast cancer cell line13 (BOT-2 cell line) derived from an original breast tumor lesion. The cell line has been found to be an excellent indicator for the effectiveness of anti-cancer compounds. The efficacy of chemothera-peutic agents such as Taxotere® (docetaxel), gemcitabine, fluorouracil (5-FU), and others have been evaluated through this method.

In addition to promoting apoptosis in cancer cells and working with chemotherapy drugs to boost their effects with lower doses (which, hopefully, will help minimize the harsh effects of these drugs), 2-methoxyestradiol also works against cancers by inhibiting angiogenesis, the formation of new blood vessels that allows many cancers to nourish themselves.2,14 To top off this roster of benefits, 2-methoxyestradiol has also shown the ability to inhibit the metastatic spread of cancer.2

All of these various approaches to fighting cancer (and likely some that haven’t even been discovered yet), make 2-methoxyestradiol an extremely promising tool for treating the disease at many different stages.1,15

Giving Nature Its Cancer-fighting Due

The study results I listed above are really just the tip of the proverbial iceberg when it comes to the clinical trials being done on 2-methoxyestradiol. As a matter of fact, yet another 2-methoxyestradiol study was released—and made quite a splash in the media (probably because it was done at one of the most mainstream of mainstream institutions, the Mayo Clinic). The press report stated:

Metastatic cancer cells
Metastatic cancer cells

“A new study of an estrogen-derived drug shows promise as a treatment for breast cancer and breast cancer metastases to bone. A drug that has shown promise in treating sarcoma, lung and brain cancers, demonstrates that the drug may also be effective in treating breast cancer, in particular the spread of breast cancer.”16

I’m sure you’ve noticed the typical pharmaceutical company language “spin” in the previous quote right away. 2-methoxyestradiol is a natural estrogen, not a “drug,” but the word “drug” is used three times in the first two sentences. And the spin didn’t stop there.

“[Mayo Clinic researchers] studied the effect of 2-methoxyestradiol on the bone… In breast cancer, the cancer commonly lodges in the bone, destroying it in a debilitating painful process called osteo-lysis. Osteolysis can lead to bone fractures and causes patients to feel tired, or even to lose consciousness.”

According to one of the researchers, 2-methoxyestradiol is potentially very important in the treatment of breast cancer metastatic to bone because it has few of the unpleasant side effects of most chemotherapy drugs and targets both bone resorption and the cancerous tumor cells. According to another researcher, “We were expecting the ‘drug’ to have an effect, but we were not expecting to have as big of an effect as it did.”16

Getting the mainstream to credit nature instead of “drugs” is too much to hope for, but at least they haven’t tried twisting all-natural 2-methoxyestradiol into a patentable, foreign-to-the-body version—yet.

What You Need to Know: 2-Methoxyestradiol
  • While excessive amounts of certain types of estrogen may promote tumor formation or growth, 2-methoxyestradiol shows tremendous anticancer potential. Recently, the pharma-ceutical industry trademarked this naturally occurring estrogen metabolite under the trade name Panzem®.
  • Laboratory studies have shown that 2-methoxyestradiol inhibits cancer cell growth, both alone and in synergy with chemotherapeutic drugs.
  • In the laboratory, 2-methoxyestradiol shows promise against prostate, breast, pancreatic, gastric, and ovarian cancer cells, among others.
  • Scientists hope that 2-methoxyestradiol may one day be used in combination with chemotherapy drugs to boost their efficacy while allowing for the use of lower doses. 2-methoxyestradiol appears to work by inhibiting angiogenesis and metastasis.
  • Clinical research indicates that 2-methoxyestradiol holds promise in preventing the spread of breast cancer cells to bone and in preventing rising PSA levels in prostate cancer patients.
  • Oral 2-methoxyestradiol appears to be well-tolerated, but it may work better when administered by injection, which helps bypass metabolism by the liver.
  • Unfortunately, 2-methoxyestradiol is not yet available. For now, ensuring optimal intake of methyl groups (from healthy foods like green vegetables, citrus fruits, and nuts, and dietary supplements like SAMe, MSM, and B vitamins, especially the methylcobalamin form of B12, and the methylfolate form of folic acid) may help ensure that adequate methyl groups are available for the methylation of estrogens to 2-methoxyestradiol.

And these researchers did make one other bit of progress: They appear to be among the first to notice that swallowing steroids is not nature’s preferred route of administration. Of course, that should have made sense to any MD, PhD, or intelligent student of the human body. But nearly all other researchers have had their volunteers swallow 2-methoxyestradiol, which may be one of the reasons such enormous doses have been required in the research to date. According to the news report on the Mayo Clinic study:

“Clinical trials of 2-methoxyestradiol for breast cancer patients are in progress. These trials are based on an oral version of 2-methoxyestradiol to treat primary tumors, but this method has limitations as the oral version of 2-methoxyestradiol is poorly suited to getting into the blood system and reaching tumors. Researchers resolved this problem by delivering 2-methoxyestradiol by injection and found it was much more effective.”16

To put it simply, the Mayo Clinic study found that 2-methoxyestradiol can:

  • Effectively target breast cancer cells
  • Prevent the spread of breast cancer cells to bone
  • Protect bone from osteolysis, which is a type of bone metastasis in which the bone is eaten away by cancer cells
  • Is much more effective in smaller quantities when not swallowed, but (in this case) injected17

Safety in Numbers—and Larger-than-normal Doses

The Mayo Clinic study may be the most recent—and accurately conducted—research on 2-methoxyestradiol so far, but there are lots of other studies on this estrogen metabolite as well that show just as much promise, even with some wrinkles in the methodology.

In a Phase 1 clinical trial of 2-methoxyestradiol in 15 women with metastatic breast cancer, 10 patients stabilized in their disease progression and two reported reductions in bone pain and the use of painkillers. And there were no adverse effects from daily oral doses of 200, 400, 600, or 800 mg, although at 1,000 mg per day, all patients reported hot flashes.14

Another Phase 1 study of 2-methoxyestradiol examined its effects when combined with the cancer drug, docetaxel, in 15 patients with metastatic breast cancer. This time, no adverse effects were observed when oral 2-methoxyestradiol was administered in concentrations between 200-1,000 mg per day for 28 days following 4-6 weeks of docetaxel therapy.18,19

The next clinical trial on 2-methoxyestradiol’s resumé involved 11 men and nine women who were given oral doses of the hormone to find the maximum-tolerated dose and determine any level of toxicity. To be enrolled in the study, patients had to have malignant, metastatic, inoperable solid tumors and to have exhausted standard treatment options. Prostate and ovarian cancers were the most commonly represented tumors in the study group. Patients were initially given a specific oral dose of 2-methoxyestradiol over the course of 28 days. When a treatment cycle was completed without adverse effects or progression of disease, doses were escalated to the next highest dose. Results of the study determined that 2-methoxyestradiol was well tolerated orally at dose levels ranging from 400 mg to 3,000 mg twice daily, though side effects typical of estrogenic compounds, such as hot flashes and thrombosis, did occur in some participants.20

A Phase 2 study indicated that 2-methyoxyestradiol may be beneficial for men. In one randomized, double-blind study specifically on PSA levels and prostate cancer, 33 patients were given either 400 or 1,200 mg per day of oral 2-methoxyestradiol over the course of 16 weeks. PSA numbers either stabilized or declined by as much as 40% in many of the patients receiving the 1,200 mg dose. Three patients did develop minor abnormalities in liver function that resolved when 2-methoxyestradiol was discontinued, but other than those few instances, the 2-methoxyestradiol was well tolerated in the study participants.21

Once again, no matter how the media—or the pharmaceutical industry—tries to spin it, 2-methoxyestradiol is a naturally occurring estrogen metabolite, not a “drug.” And this natural substance has enormous potential as an anticancer agent for a wide variety of cancers, particularly when it’s administered properly (into the bloodstream first, before the liver gets a chance to change it and destroy it, which is actually the liver’s job with steroid hormones).

But even the studies that used the wrong method of administration demonstrated that 2-methoxyestradiol has few adverse effects and little toxicity.

The Good News and Bad News about this Revolutionary Cancer Therapy

The good news we can take away from the 2-methoxyestradiol research to date is that a much safer and effective form of cancer treatment is coming. Now for the bad news: given the “approval” process, it may still be years away. And, unfortunately, like all other newly introduced “approved drugs” it will be enormously expensive (although more likely to be covered by insurance than non-“approved” natural treatments).

The Good News and Bad News about this Revolutionary Cancer Therapy

But by now you might be wondering why you need to wait around for approval at all. Since 2-methoxyestradiol is a naturally occurring estrogen, doctors, especially ones skilled and knowledgeable in the safe and effective use of bioidentical hormones, should be able to order it through their compounding pharmacies, and prescribe it for you just like the other estrogens used in an overall bioidentical hormone replacement therapy (BHRT) program. Not to mention the fact that even though they’ve been proven safe, it’s also very likely that you wouldn’t need doses as large as the ones used in the research studies: there’s every reason to believe that much lower doses of 2-methoxyestradiol-topical “crème” (applied transmucosally) will be just as effective if they’re used as part of an overall, natural anticancer approach, in combination with excellent diet, detoxification, immune support and stimulation, and many other safe and natural anticancer compounds. So why not just talk to your doctor about adding this safe and all-natural hormone to your current BHRT regimen now?

Well, unfortunately, it’s not that easy. One compounding pharmacist said that chemical supply sources advertising 2-methoxyestradiol for sale online refused to sell to compounding pharmacies, giving various excuses. Another compounding pharmacist actually was able to purchase a very small amount, which arrived in a package emblazoned with a skull and crossbones, accompanied by a “safety sheet” that cautioned about potentially toxic effects of 2-methoxyestradiol! Either these sources don’t have a clue what they’re selling, or they’re already in the pocket of Big Pharma.

Since 2-methoxyestradiol is in fact a relatively harmless natural hormone metabolite with great potential for good, the hope is that it becomes available through the same sources as other bioidentical hormones at a reasonable price sometime in the near future. Otherwise, it’ll be the same old story: if you develop cancer, don’t call your doctor, call your travel agent!

In the meantime, though, there are some things you can do to increase your body’s own 2-methoxyestradiol levels.

Stockpiling Your Own Internal Reserves

2-methoxyestradiol is one of the metabolites monitored in the 24-hour urine evaluation. Even though it’s present in very tiny quantities, don’t be fooled by the research studies using huge doses given by unnatural means (oral administration). As I mentioned above, even tiny quantities can be pivotal as “signaling molecules” when they occur naturally in your body.

For example, one research study found that an exceptionally tiny amount of 2-methoxyestradiol has anti-proliferative, anti-angiogenic, and apoptotic effects on uterine fibroid cells.22 Although there’s no concrete proof, it’s very likely that one function of the very tiny quantities of 2-methoxyestradiol in our bodies is to avert both benign hormone-related tumors such as fibroids as well as hormone-related cancers before they get started.

So how can you increase your own level of 2-methoxyestradiol? Remember the term “methyl-ation” from the beginning of this article? It’s the process that produces 2-methoxyestradiol from other forms of estrogen. Methylation relies on certain enzymes and molecules called “methyl donors” to function properly. Making sure you’re supplying your body with enough of these methyl donor molecules may be key to ensuring that these methylation processes can proceed normally, which may support healthy 2-methyoxyestradiol levels.

The list of foods that contain the necessary methyl donor molecules will probably look familiar: green leafy vegetables, legumes, citrus, berries, and nuts. Although in this particular case, it’s very important that the foods have been processed as little as possible before you eat them—and that includes heating and freezing. Keeping these foods as fresh and “raw” as possible helps preserve the methyl donor molecules they contain.

There are also a few supplements that supply methyl groups, including particularly S-adenosylmethionine (SAMe), followed by methylsulfonylmethane (MSM), betaine (including the betaine from betaine hydrochloride), 5-methyltetrahydrofolate (a “new-in-the-stores” and more natural form of folic acid), and methylcobalamin (a form of vitamin B12).

If your 24-hour urine test reveals that your levels of 2-methoxyestradiol are low, increase your consumption of the foods listed above, and check with your physician skilled and knowledgeable in bioidentical hormone replacement therapy about which and how much of these supplements to take.

And on a non-supplemental note: stress, especially prolonged stress, could reduce the methylation of estrogens, if the required methyl groups get used by the body to make adrenaline instead. Meditation, biofeedback, and other stress and “adrenaline reducing” techniques might make more methyl groups available to support the optimal conditions for making 2-methoxyestradiol, thus reducing your risk of cancer at the same time.23-25

Summary

While the estrogen metabolite 2-methoxyestradiol has shown excellent anti-cancer fighting potential and is naturally occurring, Big Pharma has recently trademarked it under the name Panzem®. Studies have shown that 2-methoxyestradiol slows cancer cell growth, both alone and with chemotherapeutic drugs, while the most potential benefit may be against prostate, gastric, breast, pancreatic and ovarian cancer cells. 2-methoxyestradiol may work better when administered by injection, but at this time, it is not available. Eating the proper amount of citrus fruits, nuts and green vegetables may help ensure the optimal intake of methyl groups for the methylation of estrogens to 2-methoxyestradiol.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Thanks to Lauren Russel, ND for her organization and summary of the data collected for this article.

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