A World Without Cancer

ForzaVitale, Inc.

800-571-6241

www.forzavitalehealth.com

© Copyright 2012 ForzaVitale, Inc.

The Prevention of Cancer by eliminating step one Imagine a world where the word “cancer” is considered archaic. A world where your grandchildren and their children share only stories of this deadly disease. A world where cancer is brought up in the past tense, like polio, smallpox and the plague. Imagine a world where cancer is not treated, but prevented. That world might seem like nothing more than a pipe dream, but it’s closer to reality than you realize—thanks to two simple words. Estrogen metabolism. Estrogens—more commonly known as the primary female sex hormones—are responsible for causing many types of cancer.1,2 Estrogens become carcinogenic when our body’s natural protective mechanisms fail to do their job. Many factors, including diet, the environment, lifestyle and genetics, can modify the natural metabolism of estrogens and spark the onset of cancer. Surprised? You’re not alone. So are many of the world’s leading cancer researchers. It sounds unlikely that the many faces of cancer—a disease with hundreds of forms—could often have a common origin, but it’s worth a second look. Want to know what these researchers are just learning? Keep reading.

Contents Introduction Cancer: Step by Step

2

How Cancer Spreads

3

Prevention versus Treatment: Beating Cancer to the Punch

4

The Story Behind Estrogen and HRT

6

Eliminating Step One

8

The Major Action

9

The Research

11

A World Without Cancer

12

Frequently Asked Questions

13

The formation of cancer cells is a multi-step process, like changing a tire or cooking a meal. Scientists and medical researchers have discovered that normal cells become cancerous due to mutations in critical genes that control how a cell functions.1-3 When certain specific mutations occur, a process begins that transforms a normal, healthy cell into a cancer cell.

Cancer Step by Step

Decades of research studying cancer at the molecular level have revealed that estrogens, compounds found in both men and women, are likely culprits for the initiation of this first step in many prevalent cancers. These include breast cancer and prostate cancer. Normally, healthy cells divide only sparingly and at a slow rate or to replace old cells. Cancer cells miss these regular checkpoints and continually multiply and divide, even when they’re not supposed to. When these excessive cells invade normal tissues, the important features of cancer emerge. When a body’s estrogen metabolism is unbalanced, estrogen metabolites react with and damage DNA. The mutations that result can lead to cancer.2-5

The good news is we believe the tools exist to ward off cancer, thanks to a combination of two antioxidants that help reduce the amount of damage done to DNA by estrogens. More on that in a bit. 2

How Cancer Spreads

Two particular types of genes—oncogenes and tumor suppressor genes—play key roles in cell proliferation. Oncogenes are normal genes, but if they mutate they drive cells to continually divide. Tumor suppressor genes, sometimes called antioncogenes, help prevent cells from dividing but lose that ability when they become mutated. A helpful analogy is to picture a mutated oncogene being like a stuck gas pedal in your car, and therefore you can’t stop. In the case of tumor suppressor genes, imagine your brakes failing. In either example, you’re operating a runaway vehicle. The same is true in cancer; the end result is the unwanted division of cells.

Eventually, cancerous cells begin to break off in clumps and travel through the bloodstream and lymph system. These cells eventually stop somewhere else in the body, often in a small capillary, and that’s how cancer spreads. The process is known as metastasis. It’s important to know that in most cases, people who die from cancer don’t die from primary cancer, unless it’s in a vital organ such as the lung. In the case of two prominent cancers such as breast cancer and prostate cancer, people succumb to the cancer when the malignant cells metastasize and seek out a vital organ in the body, such as the brain, lung or liver. The breast is not a vital organ, but cancer that begins in the breast should still be treated because it can spread. The perilous diagnoses that usually accompany the spread of cancer to one of the vital organs are the main reason why it’s important to catch cancer as soon as possible. If you can prevent the spread of cancer, you increase your chances of leading a longer, happier life. But what if there was a way to beat cancer to the punch and increase your body’s chances of avoiding the disease before it ever gets started?

Good news. There is.

It can’t be treated with bandages and hydrogen peroxide, and it doesn’t heal in a few days. Cancers are deadly. They spread. They invade. They kill.

Despite decades of fabulous advances in the treatment of cancer, the sad reality is that many treatment options end unfavorably.

Prevention versus Treatment: Beating Cancer to the Punch When a young child falls off a swing set and scrapes her knee, conventional wisdom dictates that you clean the wound with hydrogen peroxide and cover the scrape with a bandage. Usually the wound heals within a few days, and the child resumes her normal play routine. That treatment regimen is sufficient in the case of schoolyard scratches and scrapes. Preventing these kinds of minor injuries is nearly impossible. After all, exercise is an important part of every child’s lifestyle, and restricting playtime would be an unnecessary reaction to a small scrape.



Cancer is different.

We live in a society consumed by cures. You have a headache? Just take a pill. Stressed out? Take a vacation. Overweight? Try joining the latest diet craze. Cancer is no different. Only after discovering that we’re stricken with cancer do we take the first step towards fixing it. All too often, by the time that cancer is discovered, it’s too late. The cancer cells have spread, and they’re taking hold. Prospects for a comprehensive cure are grim. Doctors and patients alike describe cancers according to their level of aggressiveness. They’ll say things like, “Cancer, my gosh, how fast it grew.” Other cancers, they find, progress more slowly and respond to treatment. They believe that a cancer’s aggressiveness corresponds to the different mechanisms that initiated the cancer, and they have a difficult time subscribing to the theory that many types of cancer have one common origin. The causes of cancer start working long before the cancer gets discovered. A cigarette smoker, for example, doesn’t get cancer overnight. It takes 15 or 20 years before symptoms are prevalent. There’s a well-accepted progression here. What we’re looking at is called initiation. Once a cell undergoes its first few mutations, it then goes through a process called promotion. During this phase, it tends to divide more often and without boundaries. Over the course of these generations of cells, tumors change so radically that they no longer

look homogeneous. By the time a physician gets a look at the tumor, it seems impossible—given its heterogeneous appearance—that it could have had a single origin.

If given the choice, most rational individuals would take any necessary step to prevent cancer. Then why don’t we? Until recently, we didn’t think it was possible to prevent cancer. It seemed hard to imagine preventive medicine being used to ward off cancer. Dental care is perhaps the best example of preventive medicine. The best way to cure cavities is to prevent them from developing, which is why dentists advise patients to brush their teeth regularly, floss, use mouthwash and avoid sugary foods. If dentists didn’t advise their patients to take these preventive measures, their chairs would be full of people waiting to have cavities filled. Floss and mouthwash would be afterthoughts because they’d be too busy plugging holes. The dentists might make more money, but the overall health and well being of their patients would suffer. Consider another example of preventive medicine. For many surgeons, their longtime bread and butter operation was ulcer surgery. That all changed with the introduction of antacids. Suddenly ulcer sufferers had a pill that could solve their problem. It may have taken a few operations away from surgeons, but in the long run it saved their patients countless dollars in medical bills. Plus, the cost of prevention stands to be reasonably less than the cost of “cures.” A daily antacid comes much cheaper than a threenight stay in the hospital.

5

The Story Behind Estrogen and HRT

You may recall a strong estrogentaking movement that began in the 1980s. Women indulged themselves with hopes of staying younger. They were told—and believed— that estrogen was equivalent to the fountain of youth. They were making a big mistake.

Exposure to estrogens has been linked with increased risk of breast cancer, including evidence of a dose-response relationship.6 Estrogens are also found in certain contraceptives and hormone replacement therapy (HRT) used frequently by postmenopausal women. In recent years, the use of HRT has dropped dramatically. Studies found that incidence of Parkinson’s disease, heart attack, stroke and breast cancer were higher in women who took HRT than women who took a placebo.7 Many clinical oncologists continue to be shocked to learn that estrogens, which are naturally part of our bodies, cause cancer. On the whole, women today only use HRT if they experience extreme hormonal or menopausal symptoms. Doctors are prescribing these therapies only at the lowest dose and for the shortest period of time to help women recover from extreme hormonal side effects. There also exists a subset of women—so-called Hollywood types or fashion slaves—who feel using estrogen makes them look young. But they’re a small group.

6

Eliminating Step One

We know the first step in the initiation of cancer by estrogens. Certain estrogen metabolites, when reacting with DNA, interrupt our body’s natural damage control process and spark genetic mutations that result in cancer.8,9 So how do we eliminate these cancers?

The Major Action

By eliminating the initiating step. It’s the same philosophy you’re already using in your own dental care to eliminate cavities. Stop them before they ever get started. In relation to initiating cancer, estrogens should be treated as chemicals, not hormones. Organic chemistry can be divided into three major classes of compounds: aliphatic, aromatic and heteroaromatic. Aromatic molecules are rarely present in the human body, and estrogen is among them. Also included among the aromatic molecules in our bodies is dopamine, whose large decrease is most notable in sufferers of Parkinson’s disease. The parent of aromatic compounds is the benzene, which has been found to produce the cancers leukemia and non-Hodgkin’s lymphoma. It seems strange that nature would intend for us to have these hazardous aromatic compounds in our bodies if they can result in such horrific diseases. Nature, in order to afford us these two molecules (estrogen and dopamine), uses protective mechanisms that ensure our survival. When these protective mechanisms break down, cancer can form. Research has shown that it’s now possible by imitating nature in a less sophisticated way, to impede the process by which estrogens become carcinogenic and initiate cancer. By using specific antioxidants such as N-acetylcysteine and resveratrol as controllers of balanced

estrogen metabolism, either inhibiting some of the activating enzymes or inducing higher levels of protective enzymes, the initial steps of cancer may be preventable.2,10

The value of antioxidants has been a subject of controversy for some time. When you’re talking about antioxidants, you have to ask the question, “Antioxidants with respect to what?” The two compounds N-acetylcysteine and resveratrol that we’re calling antioxidants act to control estrogen metabolism.10-12 The best way to explain this relationship is to say they help balance estrogen metabolism. They either inhibit activating enzymes13 or induce higher levels of protective enzymes2. That’s the major action that takes place to eliminate this first step.

Antioxidants have been touted for their benefits in the fight against aging. That stems from the free radical theory of aging, which states that our bodies have oxygen atoms reacting with various molecules inside our bodies, doing a little damage here and a little damage there. It’s very random, but over time these small damages compound, and that’s why we end up aging. Antioxidants have been found to inhibit this damage to some degree. Proponents of antioxidants extrapolate these benefits to conclude that antioxidants must have similar benefits in the fight against diseases such as cancer. We respectfully disagree with that line of reasoning. The attacks purported by these reactive oxygen radicals, called free radicals, are random. Cancer, on the other hand, results from specific mutations. It stands to reason that in general antioxidants are fairly powerless in the fight against cancer because it doesn’t result from the same sort of random attacks that induce aging. The attacks on DNA that result from imbalanced reactions with estrogen metabolites affect very specific sites of DNA. If these attacks were random, then the only consequence would be the destruction of DNA. You wouldn’t get cancer. In order for cancer to develop, mutations have to be produced that cause a cell to lose control.

Remember, cancer is a multi-step process. By eliminating the first step, you can prevent the other steps that follow. Recall the earlier example of changing a tire. You won’t have much luck removing the flat if you don’t first jack up the car.

9

the research

Rest assured, the information you’re reading is the product of years of intense research and experimentation. While most people at low risk for developing cancer mostly convert estrogens to metabolites that do not react with DNA, those at higher risk for cancer form larger amounts of estrogen metabolites that do react with DNA.2,14-16 These metabolites form estrogen-DNA adducts that place them at higher risk of genetic mutations which can ultimately lead to cancer. Studies have been conducted in women to investigate the role of estrogenDNA adducts in breast cancer. Results obtained from these studies indicate that the level of estrogen-DNA adducts in urine from healthy women is low. Conversely, urine of women with breast cancer or women at high risk of developing the disease reveals higher levels of estrogen-DNA adducts.2,15,16 To explain this a step further, it’s important to understand the term “adducts”. It’s helpful to think of adducts as links formed when estrogen metabolites chemically link to DNA. The adducts that lead to cancer fall out of the DNA and leave gaps in the genetic code where cancer-causing mutations can be formed. One of the natural ways to get rid of the reactive estrogen metabolites is for them to react with the cellular scavenger glutathione (GSH), thus protecting against the formation of estrogen-DNA adducts. Keep in mind that cancer initiation is based on an imbalance in estrogen metabolism. A variety of external factors such as diet, environment, lifestyle and genetics can disrupt balanced estrogen metabolism.

The ideal balance (considered less likely to initiate cancer) provides low levels of estrogen-DNA adducts. The reverse— high levels of adducts—results in higher risk for developing cancer. We’re now able to minimize the formation of adducts by using specific antioxidant compounds to improve the balance of estrogen metabolism.10-12 Several antioxidants have been examined during in vitro studies for their effectiveness achieving a balanced estrogen metabolism, including cysteine, N-acetylcysteine (NAcCys), GSH, melatonin, resveratrol (Resv) and reduced lipoic acid. Resveratrol, a natural compound present in grapes, and N-acetylcysteine, an antioxidant and a building block for GSH, proved most effective at blocking the formation of depurinating estrogen-DNA adducts. In fact, resveratrol and N-acetylcysteine block the cancer-initiating steps in cultured human breast cells. A mixture of these natural compounds has been found to imitate nature and block the reaction of specific estrogen metabolites with DNA.10 Besides N-acetylcysteine and resveratrol, another dietary supplement can be used to prevent cancer, vitamin D.17 People who have low levels of vitamin D tend to be more likely to develop cancer. In addition to its main function of regulating calcium to make healthy bones and teeth, vitamin D can work in several ways to reduce the risk of cancer at all stages. This happens because high levels of vitamin D generate two vitamin D metabolites that protect against cancer.

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A World Without Cancer

We again invite you to imagine a world without cancer. Imagine a population not dependent on hope for a miracle cure but a population confident and reassured that the necessary preventive measures have been taken. After decades of intensely studying cancer, we now know how it begins. Better yet, we know how to disrupt the initiating step and stop the disease before it ever gets started.

Let’s review five key ideas we’ve covered: 1 Estrogens—more commonly known as the primary female sex hormones—are likely culprits of many prevalent types of  cancer. Estrogens become carcinogenic when our body’s natural protection mechanisms fail to do their job. 2 Cancer results from attacks on very specific places in DNA, not random occurrences. 3 Specific antioxidants such as N-acetylcysteine and resveratrol, used as controllers of estrogen metabolism, can either  inhibit some of the activating enzymes or induce higher levels of protective enzymes, making them a valuable tool in blocking the initial steps of cancer. 4 Preventive medicine can save lives and money over the long haul. The more expensive and sometimes less-successful  alternative is trying to “cure” diseases such as cancer. 5 The ideal balance (considered less likely to initiate cancer) of estrogen metabolism includes low levels of estrogen-DNA  adducts. The reverse—high levels of adducts—results in higher risk for developing cancer.

Frequently Asked Questions

Literature Cited

Q: Wait, men have estrogens?

1. C  avalieri E, Rogan E.(Eds.) Estrogens as Endogenous Carcinogens in the Breast and Prostate. J. Natl. Cancer Inst. Monographs. 27: 1-159, 2000

A: Yes, actually they do. Most of us learn that men have androgens and women have estrogens, but each sex has both androgens and estrogens. However, women do possess estrogens in larger quantities than men.

2. C  avalieri EL, Rogan EG. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J. Steroid Biochem. Mol. Biol. 125: 169-80, 2011.

Q: If women have more estrogens than men, does that make them more likely to develop cancer?

4. Chakravarti D, Mailander P, Li K-M, Higginbotham S, Zhang H, Gross ML, Cavalieri E. Rogan E. Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and form mutations in the H-ras gene. Oncogene. 20: 7945-7953, 2001.

A: No. What’s important is how well balanced your estrogen metabolism is, not the amount of estrogens in your body.

Q: Are estrogens considered carcinogenic? A: No, estrogens are not naturally carcinogenic. They only produce cancer when their metabolism is unbalanced.

Q: What about other so-called cancer-causing agents such as tobacco, asbestos or pesticides? A: For many years it was commonly believed that environmental carcinogens were largely to blame for causing cancer. In decades of research since that time, many of those supposed cancer-causing agents have been eliminated. Today, they represent only a small part of cancer inducers. Unless you are in direct contact with these compounds, you won’t develop cancer. External factors such as diet, polluted environments and lifestyle can be thought of as the triggers of unbalanced estrogen metabolism.

Q: How safe are resveratrol and N-acetylcysteine? A: In a word, these antioxidants are safe. Neither N-acetylcysteine or resveratrol have caused problems in people, even at doses much higher than those recommended in dietary supplements.

3. C  avalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, R ogan E, Russo J, Santen R, Sutter T. Catechol estrogen quinones as initiators of breast and other human cancers. Implications for biomarkers of susceptibility and cancer prevention. BBA-Reviews on Cancer. 766: 63-78, 2006.

5. Yue W, Wang JP, Li Y, Fan P, Liu G, Zhang N, Conaway M, Wang H, Korach KS, Bocchinfuso W, Santen R. Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms. Int. J. Cancer. 137: 1748-57, 2010. 6. K aaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, Bingham S, Boeing H, Bueno de Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A, van Gils CH, Gonzalez CA, Gurrea AB, Critselis E, Khaw KT, Krogh V, Lahmann PH, Nagel G, Olsen A, Onland-Moret NC, Overvad K, Palli D, Panico S, Peeters P, Quirós JR, Roddam A, Thiebaut A, Tjønneland A, Chirlaque MD, Trichopoulou A, Trichopoulos D, Tumino R, Vineis P, Norat T, Ferrari P, Slimani N, Riboli E. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J. Natl. Cancer Inst. 97: 755-65, 2005. 7. H  eiss G, Wallace R, Anderson L, Aragaki A, Beresford SAA, Brzyski R., Chlebowski RT, Gass M, LaCroix M, Manson JE, Prentice RL, Rossouw J, Stefanick ML, for the WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299: 1036-45, 2008. 8. Zahid M, Kohli E, Saeed M, Rogan E, Cavalieri E. The greater reactivity of estradiol-3,4-quinone versus estradiol-2,3-quinone with DNA in the formation of depurinating adducts. Implications for tumor-initiating activity. Chem. Res. Toxicol. 19: 164-172, 2006. 9. R usso J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM,Garber J, Russo IH. 17 -Estradiol induces transformations and tumorigenesis in human breast epithelial cells. FASEB J. 20: 1622-34, 2006. 10. Z ahid M, Saeed M, Beseler C, Rogan EG, Cavalieri EL. Resveratrol and N-acetylcysteine block the cancer-initiating step in MCF-10F cells. Free Radic. Biol. Med. 50: 78-85, 2011. 11. Venugopal D, Zahid M, Mailander PC, Meza JL, Rogan EG, Cavalieri EL, Chakravarti D. Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine. J. Steroid Biochem. Mol. Biol. 109: 22-30, 2008. 12. L u F, Zahid M, Wang C, Saeed M, Cavalieri EL, Rogan EG. Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev. Res. 1: 135-45, 2008. 13. H  ayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR. 17β-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc. Natl. Acad. Sci. USA. 93: 9776-81, 1996. 14. R ogan EG, Badawi AF, Devanesan PD, Meza JL, Edney JA, West WW, Higginbotham SM Cavalieri EL. Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: Potential biomarkers of susceptibility to cancer. Carcinogenesis. 24: 697-702, 2003. 15. G  aikwad NK, Muti P, Meza J, Yang L, Pruthi S, Ingle J, Rogan EG, Cavalieri EL. The molecular etiology of breast cancer: Evidence from biomarkers of risk. Int. J. Cancer. 122: 1949-57, 2008. 16. G  aikwad NW, Yang L, Pruthi S, Ingle JN, Sandhu N, Rogan E, Cavalieri E. Urine biomarkers of risk in the molecular etiology of breast cancer. Breast Cancer: Basic & Clinical Research. 3: 1-8, 2009. 17. Fleet JC. Molecular actions of vitamin D contributing to cancer prevention. Mol. Aspects Med. 29: 388-96, 2008.