Cancer: Adjunct Therapies with Tamoxifen, Lupron and other Hormonal Drugs

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Breast and prostate cancers represent a large percentage of treatable cancers with long-term therapy to prevent recurrence or spread. Since most of these cancers are driven by hormonal stimulation, standard therapy involves long-term use of such drugs as Tamoxifen, Raloxifene (Evista), and Lupron. Unfortunately, these drugs present serious challenges to the overall health and welfare of the patients, which requires sound support therapies from Complementary and Integrative Medicine to counter side effects, support metabolic systems that will probably be damaged, and enhance the specific effects that we want to see from these drugs. To continue to ignore the problems with these therapies and fail to manage subsequent noncompliance is, in effect, failing our patients. Risk of uterine cancers, deep vein thrombosis, pulmonary embolism and stroke, and other serious consequences could be greatly reduced by a sensible integration of evidence-based Complementary Medicine as well. The pathophysiology and the drug mechanisms are complicated, and we must, as physicians, take a very active role in understanding the biology and keep current with research to present the best evidence-based approaches with Complementary and Integrative Medicine.

Not only decreased risks and enhanced effectiveness, but also quality of life considerations are increasingly important in discussions of options in the overall treatment protocol in cancer therapy, especially when utilizing hormonal therapies that have a large number of side effects that could seriously damage quality of life. This is especially important in the older patient. As we progress with research in Complementary and Integrative Medicine, and patients become more educated to this research, more and more oncologists are exploring an integrative treatment model to find more options in a patient centered approach. Flexibility in treatment protocol over the course of treatment is also becoming a consideration, as each patient presents a unique reaction to drug therapy, and the considerations of risks, benefit, and quality of life must fit the individual patient's reactions to drug therapy.

Breast cancer that is estrogen receptor positive

Early stage breast cancer that is estrogen receptor positive (ER2+) is a frequent diagnosis within the totality of breast cancers in the United States. Some studies suggest that 80% of breast cancer is hormone receptor positive, with a great majority ER2+. Tamoxifen is a drug that has been used for decades and is thought to work by blocking this type of estrogen receptor stimulation of cancer growth. Tamoxifen is only proven effective in treating estrogen receptor positive breast cancer. Although this drug has been used for decades we still do not know the ideal length of time that the drug should be administered. Since demographic studies show that recurrence of cancer is much less likely if the patient survives for 5 years without recurrence, Tamoxifen is currently prescribed for this length of time. For the postmenopausal patient, raloxifene (Evista), another selective estrogen receptor modulator (SERM) that is usually prescribed for osteoporosis, is also proven effective in long-term prevention of breast cancer recurrence. While both of these drugs are currently routinely prescribed for 5 years, harsh side effects and fear of serious health risks produce only a 37% compliance over time. A recent study in Great Britain found that 7% of patients prescribed tamoxifen stopped taking the medication entirely at an early stage of therapy, and of those remaining, only 49% continued therapy with no gaps longer than 3 months. The median length of therapy was 2.42 years, instead of the 5 years routinely prescribed. In 2003, a study of patients in the United States found only 87% of patients consistent in taking Tamoxifen in the first year, and a similar rate of overall noncompliance to the Great Britain study was seen over time. This data suggests that side effects and risks create a scenario where few patients are actually 100% compliant with prescribed use. Obviously, modern medicine needs to quit pretending, and come up with treatment options that match the patient needs and desires. Complementary and Integrative Medicine provides viable options and adjunct therapy.

The National Cancer Institute, a branch of the U.S. National Institutes of Health (NIH), states that there are only two studies that confirm the benefits of taking adjuvant tamoxifen daily for 5 years, and that the ideal length of treatment with tamoxifen is not known. Some studies have shown that there is little increased risk of ovarian and endometrial cancers with short-term use rather than long-term, while a more recent small study found that there may be small benefits in decreasing risk of use of tamoxifen for longer than 5 years in a subset of patients. These benefits versus risks considerations are complex, especially considering the alarming side effects and potential adverse effects of long-term therapy, as well as the significant percentage of patients who develop a resistance to the therapeutic effects of tamoxifen. In the past, oncologists had prescribed tamoxifen for a 6 month course. Ideally, the course of treatment should be determined by consultation between the oncologist and patient, and discussion of risk versus benefit in each individual case, with a full explanation of the treatment course choices presented to the patients. Of course, the ultimate decisions are made by the patient, and these decisions are usually difficult when cancer risk is involved. In making these decisions, new scientific study presents a variety of data that confirms the efficacy of various herbal and nutrient therapies that achieve a similar inhibition or modulation of estrogen receptor mediated estrogen driven cancer to tamoxifen. While these effects may not be supported by as vigorous of study with human trials, or may not have as specific or strong effects as the pharmaceutical therapy, the research support is sound, and a combination of these therapies may provide effective adjunct or replacement to long-term tamoxifen use, which would meet the desire of the patient for a decreased overall risk of side effects, endometrial cancer, and stroke. Some supporting data for this research, such as a 2009 study at UCSF confirming the efficacy of a Chinese herbal formula from Peking University, which was found to be significantly effective in estrogen receptor modulation and anticancer effects, will be mentioned later in this article. Nutrient medicines, such as DIM and NuLignan, have also been proven to modulate estrogen receptor activity, and will be discussed as well. Other considerations, such as use of other benign herbal and nutrient therapies that have proven anti-cancer activities specific to breast cancer, may also be considered in designing a comprehensive integrated course of therapy to reduce long-term risk of recurrence.

Since there is an acknowledged risk with tamoxifen in pregnancy, with teratogenicity (Cunha GR et al, 1987), genotoxicity (Poirier adn Schild, 2003), and reproductive toxicity (Taguchi, 1987) established, and association with ovarian follicular atrophy and degeneration (Branham et al 1996), consideration of the data supporting herbal and nutrient therapies may also be applicable to the patient that is pregnant, or wishes to become pregnant in the future.

Another consideration is the 2009 finding that women who took tamoxifen for at least 5 years had a 4.4-fold higher risk of estrogen receptor negative contralateral breast cancer than women not treated with synthetic hormone therapy (Cancer Research, Sept. 1, 2009). While long-term tamoxifen use lowered the risk of contalateral estrogen receptor positive cancer by 60 percent, it produced higher risk of other types of breast cancer. In discussion with the patient, this risk, as well as the other cancer risks, such as increased risk of uterine and ovarian cancers, is important. A serious consideration of reduction of risk with the use of Complementary and Integrative Medicine may be very much appreciated by a subset of patients. Integrating with a Licensed Acupuncturist knowledgeable in this area may expand the knowledge base and provide the patient with a reliable source of professional products to integrate into the overall treatment protocol, which of course should be overseen by the oncologist.

One scientific finding that complicates the 5 year prescription of tamoxifen is the significant percentage of patients on tamoxifen who become estrogen receptor negative. When this happens, prescription of tamoxifen is no longer appropriate, and may have negative consequences. Unfortunately, periodic testing requires biopsies and are not routinely performed. The prescribing physician and the patient are often unaware of changes in the metabolism where other chemicals, such as growth factors, become the stimulation of cancer growth, or anti-apoptosis, and the patient would need a different type of treatment to prevent recurrence of breast cancer. The most common type of growth factor studied with breast cancer is the Human Epidermal Growth Factor, whose receptor is one of the triad of basic hormonal markers in breast cancer, the HER2/neu (ErbB-2), or human epidermal growth factor receptor type 2, within the epidermal growth factor receptor family. Approximately 30 percent of breast cancers may have an amplification of the HER2 expression, which is associated with increased risk of recurrence and worse long-term prognosis. Both the estrogen receptor type 2 (ER2) and the human epithelial growth factor receptor type 2 (HER2) have been found to exist with a high degree of expression on breast cancer cells of the postmenopausal woman, while the premenopausal woman has a much lower incidence of these receptors driving the cancerous growth or initiation. Obviously, the hormonal changes and imbalances have much to do with the overexpression of these estradiol and growth factor cell receptors and the subsequent lack of proper control of cell apoptosis, or programmed cell death and growth. Adjunct treatment with Complementary Medicine may thus be a more important consideration for the younger breast cancer patients.

The subject of unresponsiveness to hormonal therapies, though, has become a heavily researched subject.

Tamoxifen citrate

Selective estrogen receptor modulators are a relatively new category of therapeutic agents that bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as estrogen antagonists in others. Tamoxifen, a triphenylethylene derivative, was the first clinically available selective estrogen receptor modulator. Research in 2000 revealed that tamoxifen metabolites induced caspase-dependant apoptosis, or programmed cell death, in breast cancer cells. By 2005, it was discovered that almost all tamoxifen-responsive breast cancer cell lines developed resistance to therapy, and that over time, tamoxifen produced estrogen-like effects in the endometrium that increased the incidence of endometrial cancer. Research into adjunct therapies to counter these problems has produced surprising results. Research has also found that SSRI anti-depresant medications may negatively affect tamoxifen by inhibiting CYP2D6 (P450 enzyme pathway of catabolism), reducing the formation of active metabolites and thus reducing the effect of the drug (2011 Univ of Catania, Italy; Caraci F et al).

Tamoxifen citrate is a nonsteroidal antiestrogenic antineoplastic whose exact biological and hormonal mechanisms are still unclear. Tamoxifen may exert cytotoxic action by blocking estrogen receptors within tumor cells, or on the surface membrane of the cells, and inhibit DNA synthesis that drives tumor growth, or it may stimulate hormone receptors in a modulatory manner that induces cancer cell death. No matter what the exact anticancer mechanism is, effects are not localized to breast cancer cells, and systemic distribution is still poorly understood, resulting in numerous unwanted effects. The drug is metabolized extensively in the liver into several metabolites, which may themselves be toxic, and primarily excrete in feces. Approximately 65% of the tamoxifen and 4 known metabolites are excreted in feces over 2 weeks, with more than 70% conjugated with other molecules. Standard dosage is 20mg daily, and it may take up to 2 months to attain a relative steady state serum concentration, which varies in patients from 67-183 ng/mL of tamoxifen, and 148-654 ng/mL of its most active metabolite, N-desmethyltamoxifen. This variation of circulating levels, the individual health of liver function, and the variation of elimination half-life from patient to patient, which ranges from 3-21 days in studies, could account for significant differences of effectiveness and adverse effects in the individual patient. (Information derived from AHFS Drug Information, American Society of Health-System Pharmacists, Bethesda, Maryland).

Common side effects of tamoxifen with long-term use include decreased platelet and white blood cell counts (thrombocytopenia and leukopenia), estrogen and progesterone imbalances with menopausal-like symptoms, reduced liver function with high triglycerides, transaminase enzymes, cholesterols, and other metabolic imbalances, such as high BUN (blood urea nitrogen, the endproduct of protein catabolism), endocrine effects of increased circulating thyroid hormone T4, increased serum calcium and deposition into tissues, and musculoskeletal pain, especially bone pain. These effects increase the risk of blood clots, strokes, cataracts, and chronic infections. In addition, headache, nausea, indigestion, diarrhea, constipation, weight loss, weight gain, fluid retention, skin changes, vaginal bleeding, irregular menstruation, amenorrhea, and irregular menstrual bleeding, are all commonly seen. The most significant side effect, though, is a double to quadrupling of the risk for uterine and ovarian cancers. There is more than a doubling of the risk of uterine sarcoma and endometrial cancers, with a higher chance of acquiring a life-threatening cancer. In addition, past studies (Williams et al, 1993; Styles et al, 1994) have shown significantly increased incidence of liver and lymphatic cancers from oral intake with study animals. More recent studies cite a high risk of developing hormone receptor negative cancer in the opposite breast with long term use (Cancer Research 2009; 69; 6865-70, Li Cl et al). Estrogen receptor negative cancer that is also HER2 negative is considered the most aggressive, and most difficult to treat effectively. The risk of blood clots attributed to long term tamoxifen use is similar to that from taking hormone replacement therapy. An extensive Danish study of over 16,000 patients found that the incidence of deep vein thrombosis and pulmonary emobolism with tamoxifen use for five years was 1.2 in every 100 women, with most of the incidence within the first 2 years of taking the drug. Of course, these thrombi and emboli are responsible for a large percentage of strokes and heart attacks.

Extensive long-term study of Tamoxifen side effects and risk include the STAR (Study of Tamoxiphen and Raloxiphene) trial, which follows over 19,000 women. This study found that there was a 45% incidence of hot flashes with Tamoxifen use, and over 85 significant side effects that affected quality of life. Women that took tamoxifen reported a high incidence of leg cramps, bladder problems, gynecological problems, hot flashes, night sweats, and symptoms related to blood pressure. The STAR trial points to a need for effective adjunct Complementary and Integrative Medicine to provide safe and effective therapies to counter these side effects and increase quality of life for a majority of the patients taking these medications long term.

Pathophysiology of estrogen receptor mediation of estrogen stimulation of cancer growth

Invasive breast cancers appear to evolve over long periods of time from premalignant breast lesions, which appear to evolve from normal epithelial cells in the ends of duct lobular tissue linings. Histological studies show that nearly all of the terminal duct lobular tissues in normal adult women contain ER-positive cells. On average, only about 30% of these cells are ER-positive at one point in time. Cells undergoing mitosis, or cell division, are almost always ER-negative, though. One key to prevention of estrogen positive tumors is improved regeneration of breast cells, with apoptosis of old cells encouraged, and anti-apoptotic mechanisms discouraged. Many researchers, conducting studies to justify more widespread use of so-called estrogen receptor inhibitors, emphasize theories that these estrogen receptors, found in more abundance on older cells, must be responsibe for mediation of estrogen stimulation of cancerous cell division. Other researchers have focused on the normal modulation of the two well known types of estrogen receptors, commonly called alpha and beta. Estrogen receptor beta seems to exert regulatory and pro-apoptotic effects on estrogen receptor alpha. Both of these lines of research are useful in producing more comprehensive treatment protocols to prevent breast cancer.

Early research on estrogen receptors in breast cancer cell lines largely ignored the role of estrogen receptor beta as a modulatory factor controlling normal regulation of cell apoptosis. Many more alpha estrogen receptors were found in cancer cell lines than beta. Like the alpha and beta testosterone, or DHT sensitive, receptors in prostate cancer cells, these two types of receptors are largely responsible for pro-apoptotic and anti-apoptotic cellular mechanisms that destroy aging cells before they acquire enough mutations to generate an active cancer growth. In breast cancer, stimulation of estrogen receptor beta, and stimulation of increase in estrogen receptor beta numbers, combined with inhibition of estrogen receptor alpha expression, will result in recreation of a healthy cellular environment and regulation of apoptotic mechanisms that protect the patient from recurrence of cancer growth stimulated by excess estrogen receptor alpha. The goal of overall holistic therapy is to recreate a normal physiological environment that insures a greater success in preventing cancer cell growth.

Hormonal cancer therapies, such as Tamoxifen, has been associated with higher incidence of cancer in other areas of the body, particularly the endometrium of the uterus. A 2011 study (cited below) by the University of Family Medicine in Romania found that tamoxifen-associated endometrial adenocarcinoma was characterized by a lower expression of ER alpha and more frequent expression of ER beta than endometrial spontaneous tumors (PMID: 22046795). Such studies as this demonstrate that the imbalance between the ER alpha and beta receptors appears to be a key factor in the driving of the cancerous growth. Even the occurrence of benign endometrial growth, in the form of polyps, an occurrence in a high percentage of postmenopausal women taking tamoxifen, has been associated with a higher than normal expression of ER beta. A number of factors appear to affect the balance of ER alpha and beta expression, and research has uncovered mechanisms that modulate these factors, especially the balance between estradiol, estrone and estiol in localized tissues. Estrone appears to have more affinity for the ER alpha, while estriol has more affinity for the ER beta. Research has found that 2-hydroxyestrone has an anti-proliferative effect, while 16alpha-hydroxyestrone has a pro-mitogenic effect on estrogen receptor positive breast cancer cells. Research by the Women's Health Initiative has also found that post-hysterectomy patients administered estrone (Premarin) rather than synthetic estradiol had a lower incidence of breast cancer. The subject of achieving a more homeostatic balance of the types of estrogens to counter the overexpression of one estrogen receptor type, and the subject of stimulating the ER beta to better regulate the ER alpha expression has been the subject of much study related to the use of herbal and nutrient medicine in adjunct breast cancer therapy.

Adjunct therapies that modulate estrogen receptors

Many women are interested in SERM protocol that is not synthetic, but derived from plant sources, such as estriol, as well as the 13C extracts from cruciferous vegetables and herbs, or the active metabolite DIM, and plant lignans that convert well to enterolactone, etc. An individualized and comprehensive treatment protocol insures greater success, and professional guidance is very important to avoid unwanted effects, as well as utilize therapeutic products of quality, and ones that are specific to your cnacer. The key therapeutic products are explained below. You do need to consult with a knowledgeable Complementary care physician, such as a Licensed Acupuncturist with this specialty, to insure that you follow a safe protocol.

Besides the use of bioidentical hormones, DIM, and NuLignan, there is a growing body of research uncovering selective estrogen receptor modulation activity in various Chinese herbs. Recent research at the University of California San Francisco, in collaboration with Peking University in Beijing, China, has confirmed that herbal formulas may be very effective in modulating estrogen receptors that are linked to breast cancer mutations. Initial findings showed that modulation of the estrogen receptors one and two by specific herbal formulas was more effective than the inhibition of estrogen receptor one, or alpha, with tamoxifen. Since the problem with estrogen stimulated tumors lies in the conversion of hormones in local tissues to estradiol, which is regulated by aromatase enzymes and other metabolic and hormonal controls, the dysfunction in the body is a little complicated. Allopathic medicine seeks to block just one step in the cancer causing process, but Complementary Medicine takes a holistic approach and utilizes scientific findings to restore healthy function throughout the entire sequence of steps. A knowledgeable Licensed Acupuncturist can explain this metabolic process and what needs to be accomplished.

An herbal formula proven to modulate estrogen receptors

In 2008, an historic agreement between California and China to share medical research in Complementary Medicine was accomplished with the help of Senator Diane Feinstein and Governor Arnold Swarzenegger. UCSF was a receipient of this collaborative scientific study and published a paper summarizing one of its first studies, a formula of Chinese herbs used to treat osteoporosis and breast cancer. Below is some of the findings of this research.

"Recent evidence suggests that selective activation of the estrogen receptor (ER)-beta subtype inhibits breast cancer cell proliferation. To establish whether ERbeta-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERbeta selective. MF101 promoted ERbeta, but not ERalpha activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERbeta. The ERbeta selectivity was not due to differential binding because MF101 binds equally to ERalpha and ERbeta. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ERalpha from ERbeta when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERbeta to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ER-regulated xenograft model. Our results demonstrate that herbal ERß-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes."

The findings of this research demonstrate that the Chinese herbal formula studied exerts estrogen receptor modulation in a manner that improves normal homeostatic mechanisms of estrogen receptor regulation. The effects were quite significant, as we shall see from study findings, but the way that the herbal formula exerted estrogen receptor modulation promoted the body's natural regulatory manner of controlling excess of estrogen receptor alpha, which drives breast cancer stimulation via anti-apoptotic mechanisms, by appropriate stimulation of estrogen receptor beta, and a cascade of coregulatory proteins that insured a balanced alpha/beta anti/pro-apoptotic regulation. The end result is that normal cell death was properly regulated and cancer was prevented. Also, unlike tamoxiphen or Evista, there was no unwanted estrogen effects from the herbs.

"Estrogens possess antiinflammatory properties by repressing the expression of inflammatory genes. The repression of the TNF or IL-6 genes might be an important mechanism by which estrogens prevent inflammatory conditions, such as osteoporosis. MF101 repressed the TNF activation of the TNF and IL-6 genes in the U2OS-ERbeta cells (a particular cell line), but not in the U2OS-ERalpha cells. These studies demonstrate that MF101 selectively triggers ERbeta-mediated transcriptional pathways. MF101 is an ERbeta-selective agonist in human cervical (HeLa), breast (MDA-MB-453), and endometrial (Ishikawa) cell lines. We investigated whether MF101 has growth- promoting properties in MCF-7 breast cancer cells, which express only ERalpha. Unlike estradiol, MF101 did not stimulate cell proliferation of MCF-7 cells. These data demonstrate that MF101 does not promote proliferation of MCF-7 cells or uterine growth and are consistent with the hypothesis that ER mediates the proliferative effects of estradiol. ("

"Phase 1 studies indicated that MF101 was well tolerated and provided a preliminary indication that hot flashes were reduced (data not shown). However, these uncontrolled studies await confirmation in a larger clinical trial. We demonstrated that despite containing many different herbs, the MF101 extract is ERß selective. Examining the effects of the crude MF101 on estrogenic activity advantages. First, it is important to study MF101 because it is currently being studied in clinical trials as a drug under an FDA investigational new drug. Second, MF101 might be more effective at preventing hot flashes and be a better drug than the individual compounds because of synergy among many compounds. Third, MF101 provides a starting point to isolate pure ERß-selective estrogens. Our studies have found that MF101 contains at least six different ERß-selectivecompounds by thin-layer chromatography, HPLC, and liquid chromatography/mass spectrometry (data not shown). Our results suggest thatMF101 or pure ERß-selective agonists from MF101 might be a safer approach to manage menopausal symptoms because, unlike estrogens used currently in HT, they do not cause the ER-mediated breast cancer cell proliferation or uterine growth. Our study also provides a scientific foundation to explore whether MF101 and other ERß-selective agonists from herbs prevent menopausal symptoms, breast cancer, and inflammatory diseases associated with menopause, such as osteoporosis and cardiovascular disease."

The herbal formula studied is a fairly standard formula in TCM. Scutellaria barbata (Ban zhi lian) 30g, was the principle herb, and has a number of proven anti-cancer chemicals of significance in it. Sophora root (shan dou gen) 15g, Anamarrhena (zhi mu) 12g (6g infused in alcohol for 72h), Glycine (black soy bean) 12g, Glycyrrhiza (gan cao) 8g, Rhei rhizome (da huang) 8g, Tritici (fu xiao mai) 15 g, Astragalus 12g, Rehmania (sheng di) 12g, Ligustri lucidi (nu zhen zi) 15g, Zyziphi (suan zao ren) 10g, Nelumbinis (lian zi xin) 10g, Poria (fu ling) 10g, Moutan (mu dan pi) 8g, Corni (shan zhu yu) 10g, Achyranthis (huai niu xi) 10g, Concho ostrea (mu li) 12g, Asparagi (tian men dong) 12g, Pueraria (ge gen) 10g, Atractylodis macrocephalia (bai zhu) 10g, Epimedi (yin yang huo) 8g. Since there were many herbs in the formula, there were many chemical activities that were anticancer and antitumor, as well as a number of significant chemical activities modulating hormonal production, blood production, and immune function, all of which relate to breast cancer prevention. This study demonstrates that herbal formulas in TCM are being studied as effective therapies, undergoing FDA human trials, and will be proven safe and effective in integrative standard therapy.

Endocrinology, doi:10.1210/en.2006-0803 Endocrinology Vol. 148, No. 2 538-547 Copyright © 2007 by The Endocrine Society Selective Activation of Estrogen Receptor-ß Transcriptional Pathways by an Herbal Extract. Aleksandra Cvoro, Sreenivasan Paruthiyil, Jeremy O. Jones, Christina Tzagarakis-Foster, Nicola J. Clegg, Deirdre Tatomer, Roanna T. Medina, Mary Tagliaferri, Fred Schaufele, Thomas S. Scanlan, Marc I. Diamond, Isaac Cohen and Dale C. Leitman. Departments of Obstetrics, Gynecology, and Reproductive Sciences and Center for Reproductive Sciences (A.C., S.P., C.T.-F., D.T., R.T.M., D.C.L.), and Departments of Cellular and Molecular Pharmacology (A.C., S.P., J.O.J., C.T.-F., N.J.C., D.T., R.T.M., T.S.S., M.I.D., D.C.L.), Neurology (J.O.J., M.I.D.), Pharmaceutical Chemistry (N.J.C., T.S.S.), and Medicine (F.S.), University of California, San Francisco, San Francisco, California 94143; and Bionovo Inc. (I.C., M.T.), Emeryville, California 94608

Adjunct therapies that potentiate tamoxifen anticancer effects

A study at Tulane University School of Medicine (Yatrik M. Shah, Brian G. Rowan et al) found that the organic selenium compound methyseleninic acid (MSA) can potentiate growth inhibition of 4-hydroxytamoxifen in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Also, in tamoxifen-resistant breast cancer cell lines MCF-7-LCC2 and MCF7-H2delta16, as well as endometrial and lymphatic cancer cell lines stimulated by tamoxifen, this selenium was found to produce inhibition of cancer cell growth as well when combined with tamoxifen. The effects of selenium included decreases in estrogen receptor alpha mRNA and protein without an effect on estrogen receptor beta, showing a positive modulatory effect. Methylselenocysteine may be the most effective form of selenium for this purpose.

Tamoxifen is a caspase dependant drug. Caspases are a group of enzymes derived from the amino acid cysteine. Cysteine and methionine appear to be tightly controlled amino acids via circulating homocysteine bioavailability. High circulating homocysteine levels have been revealed as a marker for a variety of diseases, and probably represent a dysfunction in the ability of the body to convert homocysteine to cysteine and methionine as needed, but also may be linked to dysfunctions in digestive enzyme metabolism, with poor betaine conversion, and to dysfunction in the glutathione metabolism. Even though this metabolic cycle and the regulation of the metabolism is complex and poorly understood, it is evident that problems with the homocysteine transamination are linked to many alarming disease processes. Caspase deficiency may be a significant aspect to this quantum metabolic imbalance.

Caspases are important to the apoptotic mechanisms that trigger cell death when our cells become vulnerable to excess mutation and cancer. Activated caspases control rates of destruction of essential cellular proteins, and triggers to this caspase activation are both intrinsic and extrinsic to the cell. This apoptotic mechanism acts in a similar way to the immune complement cascade, with a variety of enzymes activated in an expanding cascade to carry out apoptosis. Unless a balanced environment is maintained apoptotic mechanisms that protect us from cancer are difficult to effect. Even an allopathic drug like tamoxifen depends upon this controlled environment. For this reason, holistic approaches to improve this environment, and increase the function of the caspase cascade may be very important to the ultimate effects of tamoxifen in prevention of the return of cancer. Certainly, supplementation with N-acetylcysteine, SamE or zinc monomethionine, Vitamins B12, B9 (folic acid, or the active form 5MTHF), B6 (or active P5P), and betaine, could have significant benefit for the cysteine bioavailability and function of the caspase cascade. Some of all of these nutrient molecules may be added to the protocol with methylselenocysteine to amplify the effectiveness of a tamoxifen therapy.

Increased study around the world to find effective herbal chemicals to aid therapy in breast cancer treatment have focused on these specific pathways as well. For instance, a study at the National Yang-Ming University School of Medicine in Taipei, Taiwan (cited below in additional information) showed that a chemical in the Chinese herb Evodiae fructus (Wu zhu yu) induced apoptosis in estrogen-receptor positive breast cancer cell lines via up-regulation of caspase-7 activation, PARP cleavage, and down-regulation of estrogen receptors alpha and beta, in a dose-dependent manner (PLoS One 2013 June26;8(6): e67297). Research at various University Medical Schools has found that curcumin, a widely touted polyphenol extract from a few Chinese herbs, also aids apoptosis of breast cancer cells via activation of caspase pathways, inhibition of STAT3, and various other anti-cancer and antioxidant effects. Novel methods to increase the effective absorption of and circulating concentration of curcumin via optimization have been found. Research at the National Cancer Research Institute in Tokyo, Japan has also shown that curcumin may enhance the effects of PARP inhibiting drugs, shown to perhaps be the most effective pharmaceuticals to treat BRCA 1 and 2 related breast cancers. As research is funded to explore specific effects of herbal chemicals, the potential for improved integrative therapies with herbal medicines in breast cancer are evident. The reluctance of standard medical journals to publish such study is perhaps the biggest stumbling block to this progression. Other current studies have shown that artemisinin, a constituent of the Chinese herb Artemesia qinghao, now famous as an antimalarial, exerts inhibition of expression of BRCA2, as established by research at the University of Mainz in Germany. Of course, the semisynthetic version of this herbal chemical, artesunate, is promoted as an adjunct cancer therapy in BRCA2 cancers rather than simple use of the herb Qing hao, which has no side effects. A 2008 study by the National Cancer Institute, Bethesda, Maryland, found in a broad survey that 51.8 percent of women diagnosed with a BRCA1 or BRCA2 cancer reported use of a biological-based herbal or nutrient medicine in therapy, but little professional guidance was noted. Given the increasing demand for integration of Complementary Medicine, it would behoove medical doctors to provide integrated referral with trusted professional herbalists, such as Licensed Acupuncturists, who have knowledge of this cancer research and treatment protocol.

Aromatase, I3C, DIM, lignans, and regulation of hormone receptors

In the study of estrogen receptor activation and modulation much research has uncovered a metabolic cascade of chemicals that are responsible for hormonal stimulation of cancerous growth. Circulating estrogens may not be the most important drivers of estrogen receptor positive cancer cells. In fact, reduced circulating estrogens, in post-menopausal women, may be the driving factor for excess creation of estrogen receptors, and locally produced estradiol (E2) may be responsible for most estrogen receptor driven cancers. Aromatase is a protein enzyme that, when overexpressed, converts C19 steroids to estradiol. Aromatase activity is stimulated by a number of chemicals, including prostaglandin E2 (PGE2), and exces cyclooxygenase, or COX2, may promote excess PGE2. Certainly, for this reason, a diet with much less red meat and acid creating foods, and more fresh vegetables and whole grains, which results in less unhealthy prostaglandins and fatty acids, has been consistently shown to decrease incidence and recurrence of breast cancers. This same aromatase stimulation of conversion of other steroid hormones to estradiol locally has been found to drive endometrial cancers, which occur more readily when tamoxifen is taken long term.

Endocrine disorders are associated with inappropriately high aromatase expression. Aromatase production has been found to be highest in tissues surrounding cancer cells. There appears to be a feed-back loop that stimulates excess aromatase activity, or perhaps fails to modulate it in a health manner. All of these findings point to the need to restore a normal physiological environment in order to successfully prevent excess aromatase production. Hormonal balance, decrease in PGE2, immune health, and other factors, must be examined to effectively inhibit the imbalances that drive local aromatase production around cancer cells.

Local estradiol production, via excess local aromatase production, appears to be the important driving force in breast cancer. Systemic and circulating estradiol may have much less significance, especially when we see estrogen driven breast cancers in patients with various levels, and increased breast cancer incidence in patients with perimenopausal to postmenopausal hormone deficiencies. Most estradiol in the body is either produced from the ovaries in reproductive age women or by conversion of androstenedione to estrone and then to estradiol in peripheral tissues. Even breast cancer cell growth attributed to HER2 (human epidermal growth factor) is linked to the estrogen receptor imbalance acquired by poor regulation of local estrogen production and conversion. Cell growth is regulated by hormonal receptors on the surface and within the cells that control the rate of apoptosis, or normal programmed cell death and replacement. Hormonal and metabolic imbalances create excess surface estrogen receptors, which drives anti-apoptosis. A number of chemicals besides the local estradiol have been found that stimulate these receptors, and when the receptor imbalance occurs, inflammatory mediators such as COX2 (cyclooxygenase enzyme), epithelial growth factors, insulin-like growth factors, and other chemicals, may stimulate the cancer mechanisms. Herbal chemicals, such as resveratrol, from the Chinese herb Hu zhang, have been found to inhibit these growth factors.

Synthetic aromatase inhibitors decrease aromatase throughout the body drastically, and effectively eliminate systemic estradiol production. This has been shown to successfully treat estrogen receptor breast cancers, but not endometrial and ovarian cancers, and in fact, may have negative consequences. These findings have introduced many doubts and questions concerning our understanding of aromatase inhibition. Research has found that aromatase plays an important role in the brain, especially in hypothalamic function, and strong chemical inhibition may have a variety of negative effects in neuroendocrine function over time. In response to the side effects and negative consequences of long term prescription of aromatase inhibitors, much research has revealed effective aromatase inhibitors derived from foods and herbs that may be used, and in fact, have a modulatory effect that maintains physiologically normal aromatase levels. DIM and NuLignan are two such products. Promotion of aromatase homeostasis would seem to be the safe and effective course compared to synthetic aromatase inhibition. Of course, if a particular patient needs this more intensive drug therapy to survive, this is the course to take, but always with the aid of adjunct therapies to enhance effectiveness and counter the ill effects.

Indole-3-carbinol (I3C), and the active metabolite DIM (diindolemethane), are a derived from a nutrient found in many vegetables, especially cruciferous vegetables containing glucobrassicin. Digestion and assimilation of these nutrients produces DIM, which is used by the body to modulate aromatase activity. Since I3C needs to be transformed in the gut to DIM, DIM is the preferred supplement to insure effect. Many studies have confirmed that I3C significantly inhibits aromatase and acts as an anticancer agent. Given to study animals along with a carcinogen, oral I3C was found to inhibit estrogen driven cancer cells in the breast, uterus, stomach, colon, lung, and liver. Further studies, designed to discount I3C use, gave unnaturally high dosage to animals and found that extreme dosage could promote cancers in some animals (fish were used, which is suspect, since fish are not as close to human metabolism as rats). Further studies (Carcinogenesis 2006, Yu X et al, Oregon University) found that inclusion of I3C in the dietary supplementation with pregnant subjects provided chemoprotection against a common carcinogenic pollutant that also causes birth defects, dibenzopyrene aromatic hydrocarbon, and was safe for the mother and fetus. A study by Wake Forest University in 2009 also found that glutathione is protective against this strong carcinogen. Glutathione metabolism may be enhanced by supplementation with various nutrients and Chinese herbs, including L-cysteine, P5P, zinc methionine, betaine, active folates, Vitamin B12.

I3C has thus passed numerous hurdles in the complete sequence of studies confirming efficacy in aromatase inhibition. DIM, the active metabolite, and not dependent on the particular gut acidic environment of the individual patient, is further back in this sequence, but already has demonstated efficacy. A recent 2009 study by Carmel Medical Center in Haifa, Israel, (PMID:20010430, European Journal of Cancer Prevention), found that DIM was not toxic and has an in-vivo preventive effect against development of prostate cancer in a mouse model. A 2009 study at Wayne State University School of Medicine in Detroit, Michigan (PMID: 19693769) found that DIM down-regulates an intermediate step in aromatase conversion and stimulatio of estrogen receptors, as well as an estrogen independent cancer stimulator, the urokinase plasminogen activator receptor, which is seen overexpressed in aggressive breast cancers. The study also found that DIM, in the abscence of these receptors, directly inhibited growth factors VEGF and MMP-9, that are implicated in estrogen receptor negative tumors. Not only has DIM now been demonstrated to inhibit aromatase conversion of local hormones to estradiol and estradiol metabolites, but also to protect in a variety of ways by inhibition of various growth factors that overexpress and drive breast cancers, and it is proven in vivo to do this in a modulatory manner. Once again, Mother Nature and eons of evolution have created an apparently superior chemical that is already integrated into our biology. The numerous positive studies emerging on DIM show that it has a significant role to play as an integrative therapy to enhance cancer prevention and recurrence, whether the patient decides to take tamoxifen or a synthetic aromatase inhibitor or not.

As far back as 1997, researchers at the Strang Cancer Research laboratory at Rockefeller University discovered that DIM changes so-called strong estradiol to weak estradiol, altering metabolites of estradiol that drive cancer. This inhibits cancer cell growth and stimulates apoptosis. Subsequent study at the University of California at Berkeley found that DIM inhibits some human breast cancer cells from growing by as much as 90% in cultures. Other studies have shown that DIM promotes higher levels of estriol, an estrogen that does not drive cancer, and also promotes increases in a biologically inactive metabolite of estrone, 2-hydroxyestyrone. These findings show that chemicals like DIM, that evolved in the body over great periods of time, exert beneficial modulatory effects in a number of ways. The benefits of DIM are great, and the only question is bioavailability. Quality products are now concerned with absorption enhancement, and thus, in the unregulated supplement industry, it is sensible to obtain the DIM from a professional that purchases the highest quality researched product.

Lignans are beneficial chemicals that are also commonly found in food and herbs. Lignans in flax seed helped propel this ancient grain seed to popularity, along with healthy essential fatty acids. The common thread between these two classes of super nutrients are that they are fat based, and the common diet in the United States was slowly depleted of healthy fats by commercial food production and marketing. Hormones are generally fat based, and plants contain many beneficial hormones that are bioidentical to animal hormones, because hormones are simple molecules with much potential to stimulate lipoprotein receptors, which are found in both animals and plants. Lignans are one of the major classes of phytoestrogens, which not only help our bodies with hormone bioavailability and regulation, but also serve as potent antioxidants. This information leads us to the conclusion that specific lignans must be effective in estrogen receptor modulation and cancer prevention.

NuLignan is a product based on current European research into the use of specific plant lignans in hormonal therapy. It is a patented extract of 7-hydroxymataireinol extracted from Norway Spruce Trees (Picea abies). This lignan extract has been found to promote the body's own production of enterolactone, which protects the body against tumor formation. Enterolactone reduces excess circulating estrogen, blocks excess aromatase, binds to estrogen receptors, and selectively blocks estrogen activity in specific peripheral tissues, inhibiting cell growth and the signaling cascade that drives estrogen receptor positive cancer cells. Like tamoxifen, enterolactone may also mimic the effects of estrogens, or block estrogen receptors. Unlike tamoxifen, this chemical that evolved in our bodies also evolved modulatory effects that work with other chemicals in our bodies in a quantum, or holistic, manner. If such chemicals evolved in our bodies with effects that promoted cancers or had deliterious effects, natural selection would eliminate those animals with harmful versions of such chemicals.

How are lignan effects beneficial in our bodies? Plant lignans are composed of aromatic carbon benzene rings called phenols. Aromatic molecules have free electrons and are able to stimulate physiological activity more freely. The lignan aromatic rings are composed of monolignols, and the most potent of these lignols is coniferyl alcohol, of which the lignan and lignins in Norway Spruce are almost completely composed. Because these monolignols are produced in plant cells as glucosides, they are somewhat water soluble, alkaline, and transport to the inner part of our cells easily. The chemical reactions that create lignans is catalyzed by oxidative enzymes and proteins that dictate steriochemistry, as occurs with steroid hormones. This makes lignans inherently potent as modulators of oxidative reactions and steroid isomers in our bodies. They are also of a class of medicinal herbal chemicals called terpenes, which are highly reactive. Essential oils are composed of terpenes, and even the aromatic benzene rings of essential oils that escape into the air and are taken in by our breath have potent medicinal activities. Brassica vegetables, from which research derived I3C and DIM, also contain potent lignans. Of all the lignans studied, pinoresinol and matairesinol are the most beneficial, and these are found in abundance in sesame seeds, rye bran, and wheat bran, as well as spruce resin. Of course these most beneficial lignans are provided in concentrated dosage in NuLignan. These lignans create beneficial enterolactones. Entero- refers to chemicals created in the intestines, and lactones are chemicals that work inside molecules (intramolecular), and are carbon based oxides, meaning that they are useful as oxidizing chemicals that clear cells of harmful debris and prevent degeneration and cancerous mutation. To make the most use of NuLignan, it would be wise to promote health in the intestines as well as to provide antioxidants concurrent with use. A prescription of herbal formulas to clear unhealthy microbes and restore gastrointestinal function, if needed for the individual patient, then a quality probiotic and perhaps bovine colostrum, followed by NuLignan, and then effective antioxidants, would insure the most success with therapy.

Research into these matairesinol lignans has uncovered much evidence of medicinal effects in recent years. Some of these studies are accessible below in additional information. 7-hydroxymatairesinol has been found to have potent chemopreventive effects, immunomodulatory activity, antioxidant properties, and mild proestrogenic effects (stimulating increased estriol), as well as selective estrogen receptor modulation, and inibition of aromatase. Our bodies obviously have evolved to utilize these chemicals in many ways to prevent cancer. The extract NuLignan did not show estrogenic or antiestrogenic activity at either estrogen receptor alpha or beta in vitro, or antiandrogenic responses that would drive prostate cancers, but did decrease the number of growing breast cancer tumors, and regressed and stabilized tumors in animal studies in 2000 at the University of Turku, Finland. Conversion of NuLignan to enterolactone was almost 100% in animal studies. The course of therapy was 51 days. The anticancer effects were specific to well-differentiated adenocarcinoma, which was reduced significantly in animal studies. Combining NuLignan with other anticancer herbs which would affect estrogen receptor negative and undifferentiated tumors would be advisable in a comprehensive package of care./p>

As time progresses, we see no research with negative findings on NuLignan, and a series of progressive studies that confirm that NuLignan blocks estrogen receptors by substituting as a stereoisomer, acts in a modulatory manner, and has a reduced effect in the presence of tamoxifen. Studies have also revealed that NuLignan exerts an anti-tumor effect on liver cancer, which may be stimulated by the use of tamoxifen. NuLignan and enterolactone also were found to exert pro-apoptotic effects and tumor suppression of human colon cancer cells both in vitor and in vivo (Anticancer Research.2005 May-June;25(3B):2269-76). All of these findings support the inclusion of NuLignan in a preventative course of integrative therapy for estrogen receptor positive breast cancer patients.

Some of the research on aromatase overexpression has been misleading. One study, examining whether red wine consumption would increase aromatase and local estradiol production, fed wistar laboratory rats only red wine as a fluid for a prolonged time, which significantly raised aromatase and local estradiol in tissues. It was postulated that moderate or minimal red wine consumption was a risk factor. This seems to be a stretch of logic, and does not examine the effects of small amounts of red wine on aromatase production. With the widespread and complex patterns of fraud and misleading study design found by the Senate committee investigations headed by Senator Charles Grassley, all medical professionals need to take a closer look at the details of health studies to arrive at workable clinical treatment protocols, and not rely on study summaries and journal articles, which are often manipulated.

Supporting blood deficiencies, thrombocytopenia and leukopenia

One of the primary concerns with tamoifen therapy is the subsequent thrombocytopenia and leukopenia that results from toxic therapy. The ability of your marrow to produce new blood cells may be severely hampered by the damage caused by either chemotherapy or radiation therapy, as well as the tamoxifen, if these therapies are also part of the anticancer protocol. Damage from these therapies is not limited to the site of the cancer. Standard treatment has included the use of EPO, or synthetic erythropoetin, a hormonal analog that stimulates marrow production of blood cells. A report in the Journal of the American Medical Association (JAMA), published in February of 2008, concluded that "Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of venous thromboembolism and mortality. Our findings, in conjuction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer." Complementary Medicine does offer safe and effective therapy to stimulate healthy bone marrow production of blood cell lines without the risks and side effects of synthetic hormonal therapy.

Lupron

The use of Lupron in prostate and ovarian cancer therapy also presents severe side effects and risks, limited benefit, and the need for a more comprehensive therapeutic approach to achieve maximum results. Lupron, and other drugs in this class, work by inhibiting hormone production throughout the body, and effect the entire endocrine system. The theory behind this treatment is that chemical androgen ablation (similar to physical castration), will decrease the stimulation of androgen receptors that are responsible for the uncontrolled growth of cancerous tumors. Recent research on hormonal receptors reveal that a gradual imbalance of hormonal cell receptors in local tissues tilts the balance of maintaining older cells with replacing these cells. This process is called apoptosis, or programmed cell death, and is utilized by your body to remove older cells and replace them with new healthier cells to avoid the cell mutations that result in cancerous growth. When the body faces hormonal imbalance, such as in menopause, andropause, or even with premenstrual syndromes, this hormonal imbalance may stimulate an increase of the receptors that prevent normal cell death, or apoptosis. This is because the deficiency in certain local hormones prompts increased creation of the receptors for these hormones. In testosterone driven cancers, such as prostate, it is now known that the deficiency of testosterone drives this process. While active testosterone metabolites, such as DHT and estradiol, do stimulate cancer growth, restoration and maintenance of physiological normal levels of hormones has been proven to reverse this process. The scientific understanding of last year is being overturned by the increased scientific understanding of the present year. Balance of homoestatic mechanisms and a quantum biochemical perspective are proving effective in the treatment of prostate cancer. Complementary Medicine is not tied to the need to promote expensive drugs based on old evidence, but is able to utilize current research to deliver a host of natural products that are not tied to the patent system. Integrating complementary medicine would allow the M.D. to address a number of variables that create environments that drive the stages of prostate cancer, as well as decrease side effects of standard therapy and provide for improve quality of life. Thinking outside of the allopathic box provides increased potential in therapeutic outcome.

An alternative to lupron, Casodex (Bicalutamide), acts as an anti-androgen in early stages of prostate cancer and acts by specifically binding to membrane androgen receptors, accelerating the mAR degradation. This is an option in therapy adopted by a number of oncologists.

If the androgen blockade or ablation, utilizing lupron, and perhaps other androgen blockers, such as the chemotherapies carboplatinum, Taxotere, Emcyt, is given for 13 months, upon completion of this blockade, the patient can expect rather rapid increases in PSA and testosterone after stopping therapy. On average, the PSA increases to 9, and the testosterone to 80, within the next 11 months. Use of adjunct therapies is important in this scenario as well.

New Paradigms of treatment strategy for Prostate Cancers

Research at a number of prestigious medical Universities, including Harvard, University of Chicago, UCLA, Boston University School of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, Martiniclinic Prostate Cancer Center of Hamburg-Eppendorf, University of Brussels, McMaster University in Ontario, and others have supported a series of research studies that have entered into phase 1 and 2 of human clinical trials, that demonstrate that standard medicine has been dead wrong on prostate cancer stimulation. Prostate cancer is driven by an imbalance of hormonal stimulation that promotes anti-apoptotic mechanisms over physiologically normal pro-apoptotic mechanisms. Research has revealed that this is driven by DHT (dehydroepiandosterone), a metabolite of testosterone that is converted from hormones locally. The belief that pathologic prostate growth, benign or malignant, is stimulated by circulating androgens has been a commonly held belief without scientific basis, and has driven a false zeal to inhibit testosterone production in prostate cancer patients, most of whom are aging and have been afflicted with andropausal decreases in testosterone prior to the development of cancer. Years of castration therapy proved statistically fruitless, yet the continued push of lupron prescription to effectively achieve chemical castration, or ablation of testosterone, continues with almost religious zeal. Medical doctors who dared to challenge this pharmaceutical imperative, and patients who questioned the therapy, were ridiculed as promoters of a dangerous philosophy.

Edward Friedman of the University of Chicago provided a mathematician's analysis of conflicting data in 2005 to explain how prostate cancer is initiated and driven. Professor Friedman was dismayed at the long-standing argument over prostate cancer mechanisms that created diametrically opposed groups, one advocating that high levels of androgens are responsible, and the other proposing that high levels of androgens should be effective in the prevention and treatment of prostate cancer. While almost all prostate cancers initiated with deficient levels of androgens, which would seem to contradict the first group, small studies that correlated increased incidence of prostate cancer with higher levels of free testosterone3, seemed to contradict the second group. What was discovered with analysis is that increased free testosterone in an androgen deficient patient stimulates increased cancer growth to a point, but as testosterone levels continue to increase there is no further increase in prostate cancer growth, and in fact testosterone at physiological normal or above both exerts mechanisms of cellular maintenance and inhibits estradiol dominant initiation of new cancer cells.

The Friedman data also revealed that prostate cancer is stimulated at different stages with different mechanisms. In the initiation stage, prostate cancer seems to be stimulated by a process similar to estrogen receptor breast cancers, namely that estrogen receptor alpha stimulation is not modulated by estrogen receptor beta, and that estradiol dominance is necessary for initiation, perhaps accelerated in the androgen deficient environment. One model proposed by Friedman to explain estradiol dominance as a cancer initiator would be the excess creation of telomeres, the repetitive DNA at the ends of chromosomes that protect them from programmed cell death, which would increase the lifespan of aging cells undergoing excess mutation. In the next phase of cancer growth, activity of 5-alphadihyrotestosterone (5alphaDHT) is essential for further growth by excess stimulation of membrane androgen receptor over intracellular androgen receptor, creating an anti-apoptotic effect that protects the early cancer cells from normal destruction. Once again, both the local hormonal imbalances as well as the abnormal hormone receptor balance created in the disease environment is key to cancer progress. In the third phase of the cancer growth, testosterone appears to bind to membrane androgen receptors to upregulate proteins that promote apoptosis and kill the cancer cells. Once again, aromatase activity was found in prostate cancer cells, but not in normal cells, linking conversion of hormones locally into estradiol, as well as an excess creation of estrogen receptor alpha, as part of the cancer process, just as in breast cancer. Since DHT drives the cancer and the imbalance between pro-apoptotic mechanisms and anti-apoptotic mechanisms, and since testosterone may be converted to either estradiol or DHT in the local tissues under various conditions, it appears logical that we must seek to restore a homeostatic environment to stimulate remission and proper apoptotic balance, and treat each patient individually according to stage of disease and hormonal assessment.

Abraham Morgentaler at Harvard Medical School co-authored a 2009 study entitled Testoserone and Prostate Cancer: Revisiting Old Paradigms, which concluded: "the available literature strongly suggests that testosterone therapy neither increases the risk of prostate cancer diagnosis in normal men nor causes recurrence of cancer in men who were successfully treated for prostate cancer. " Although ablation of testosterone has demonstrated a short window of remission of metastatic prostate cancer, long term outcomes are still very poor with this treatment, and the evidence does not support the long term testosterone ablation as a cure. The Morgantaler and Traish saturation model presents hard facts that while cessation of testosterone will temporarily affect DHT driven cancer cells, increases in testosterone above deficient levels does not increase DHT and cancer growth. In fact, testosterone is well known as vital for health maintenance of the prostate cells, and restoration of a physiologically normal health maintenance environment is proving to be clinically successful in the treatment of prostate cancer. Friedman states that "The evidence is overwhelming that testosterone is capable of inducing apoptosis in prostate cancer." This model has driven extensive research that confirms that high dose, or restoration of physiological normal testosterone, with testosterone patches or inserted time-released pellets in the gluteal muscle, may help restore the cellular environment that the patient needs to reverse metastatic prostate cancer growth. The challenge to medical doctors is how to help the capability of testosterone to induce apoptosis in prostate cancer, and here Complementary Medicine may play a large role in used research evidence to create the correct physiological environment for high dose testosterone to induce apoptosis.

In 2009, Robert Gardiner et al, from the Universities of Queenland and Adelaide, and the Royal Adelaide Hospital Cancer Center, wrote in the Journal of the European Association of Urology: "Following submission of Morris et al's manuscript to the journal, an electronic publication of another study by Szmulewitz et al from the University of Chicago has become available. Their participants, who were at an earlier phase of castration resistance than those enrolled into Morris et al's study, also used topically administered testosterone. Both studies were designed to assess the safety of the exogenous testosterone administration strategy. Only 1 of 15 patients from Szmulewitz et al's cohorts was withdrawn due to grade 4 cardiac toxicity; the Morris et al trial withdrew one man who had a prior history of epidural disease and developed spinal compression but without neurological symptoms. Because there was a tumor effect in both studies (with a fall in prostate-specific antigen in 7 of 12 patients in the Morris et al trial and 3 of 15 patients in the Szmulewitz et alt trial), these findings pave the way fo further studies to examine potential therapeutic benefits from exogenous testosterone therapy in select castrate-resistant prostate cancer patients. A notable finding from Morris et al's manuscript is that despite administering three times the usual replacement dose of testosterone, serum levels did not, on average, exceed normal levels. Szmuliwitz et al experience similar findings. This may partially explain the fact that none of the 12 patients in Morris et al's study exhibited an objective response. As pointed out by these authors, prostate cancer growth is stimulated by lower doses of androgens than those that result in growth repression. Thus, while failure to reach supraphysiological testosterone serum levels may have adversely affected tumor responses in both of these trials, it may have inadvertently served to test the prime objective of safety." The outcomes presented in these initial trials shows that topical or intramuscular pellet testosterone at high dose is safe, and will probably not raise free testosterone levels above physiologic normal. This also indicates that other therapies need to be added to this testosterone therapy to achieve higher rates of success to reverse tumor growth. Complementary and Integrative Medicine strategies presented above, and below in this article offer safe protocols that are proven to be effective.

Abscence of calreticulum on membrane androgen receptors is suspected as the main cause of apoptosis during hormonal blockade. Apoptotic proteins promote apoptosis, and some medical doctors have used novel approaches, including RU486, and Arimidex to increase apoptotic proteins at the membrane androgen receptors. Unfortunately, these strategies also increase bcl-2, which prevent apoptosis. Arimidex blocks estrogen receptor alpha, and use of various Chinese herbs, DIM, and NuLignan may present an effective alternative to this drug. RU486 blocks the effects of progesterone on progesterone receptor alpha. In patients with progesterone receptor alpha dominance, RU486 is used to block PGa selectively. Studies have shown, by monitoring elevation of alkaline phosphatase in response to treatment, that combining RU486 with topical progesterone stimulating cream may have positive effects, since increased progesterone eliminates estradiol dominance and aids healthy cell maintenance. Studies have shown that combining progesterone stimulating cream with RU486 more effectively downregulates estrogen receptor alpha as well. Various herbs also potentiate RU486 in this regard, but not nearly as effectively as progesterone stimulating cream. These herbs in order of effectiveness are Viscum alba, nutmeg, and yucca. Monitoring of hormonal levels with inexpensive laboratory analysis of saliva metabolites is recommended. Use of low dose topical progesterone stimulating cream at 5-10mg per 12 hours is used. Use of concurrent RU486 with this low dose progesterone stimulating cream topically is shown to be effective in increasing calreticulum and apoptotic proteins as well (Dr. Paul Savage).

Of course, these studies are designed for the patients that have shown progression of the cancer despite the use of lupron, but that still have no evidence of metastases. When the patient fails lupron therapy and metastatic cancer is detected, especially when the cytology of distal tumors shows undifferentiated and primitive cell line, neither lupron or testosterone therapy is applicable. In these cases, there is little to offer in standard therapy, and even more reason to aggressively pursue remission with Complementary and Integrative protocols. To offer no therapy despite the growing body of evidence that the patient may benefit from a variety of complementary protocols seems cruel.

This treatment strategy has yet to be confirmed with long term stage 3 clinical human trials, but is being quickly accepted by a number of cancer experts, especially those not interested in practicing pure defensive medicine, but doing what seems most efficacious for their patients. Use of this therapeutic approach is especially applicable for those patients that have failed testosterone ablation or chemical castration with lupron, or patients that experience castrate resistant prostate cancer. While acute high-risk prostate cancer will still be treated with radiation therapy and lupron, management of the long-term therapy with hormone modulation and selective therapeutic protocols, utilizing Complementary and Integrative Medicine, will be demanded by a public that increasingly does its own research.

For these medical doctors, a comprehensive package of therapy, utilizing Integrative and Complementary Medicine, maty be essential for success. A number of strategies suggested to identify patients who are resistant to lupron have been identified. 40% of castrate-resistant prostate cancer patients have androgen receptor amplification noted in circulating tumor cells. Fluorinated dihydrotestosterone positron emission tomography tracers are suggested to identify patient with upregulation of androgen receptors. Biopsy with evaluation of androgen receptor gene amplification, or evaluation of circulating castrate-resistant prostate cancer cells, are other suggestions.

Specific biological mechanisms in prostate cancer and the role of Complementary Medicine to control them

DHT, or 5alpha-dihydrotestosterone, is a biologiclly active androgen metabolite that drives prostate cancer within an altered cellular environment. DHT interacts with intracellular androgen receptors (iAR) to suppress the pro-apoptotic proteins that are produced by the proliferation of membrane androgen receptors (mAR). Lowering the DHT alone, rather than the beneficial testosterone, removes this iAR suppression, and allows mAR to express the pro-apoptotic proteins that remove cancer cells. DHT is primarily formed in a normal environment via rate control of conversion of inactive testosterone to DHT by the enzyme 5alpha-reductase. While free testosterone may be converted to estradiol in local tissues via the enzyme aromtase, diminishing the level of DHT, DHT cannot be converted by aromatase to estradiol. To holistically control abnormalities in hormone conversions that drive prostate cancer, we must utilize chemicals that modulate aromatase and 5alpha-reductase, as well as 17-alpha-hydroylase/C17,20 lyase. These chemicals can be found in nature, in forms that the animal organism has long adapted to through evolution, and that are without side effects.

To prevent new cancer growth, hormonal balance, correction of estrogen dominance and androgen deficiency, as well as regulation of, or inhibition of aromatase, would prevent excess estradiol from initiating cancer growth, under the Friedman model. In aging adults, testosterone falls with andropause, inducing increased DHT, estradiol dominance in relation to progesterone drops, and deficient D3 prohormone cholecalciferol, all contribute to abnormal prostate cells, and as these abnormal prostate cells avoid apoptosis and continue to mutate further. Increases in membrane androgen receptors, estrogen receptor alpha, and progesterone receptor alpha, over their counterparts, pushes anti-apoptosis over pro-apoptotic mechansisms. Including progesterone stimulating topical bioidentical hormone cream, cholecalciferol, DIM, NuLignan, saw palmetto, pumpkin seed oil, and various herbs in formula, to counter this common aging process may dramatically help to prevent early stages of development of prostate cancer.

In the later stages of prostate cancer, regulation of, or inhibition of 5alpha-reductase would decrease the excess conversion of testosterone to DHT. Since studies demonstrate that there are rate-limiting mechanisms preventing excess testosterone conversion to DHT once physiological normal levels of free testosterone are reached, even in a cancer state, use of herbal and nutrient therapy that provides the body with the tools to modulate these enzyme activities is both effective and safe.

The main reason for use of various natural 5-alpha-reductase inhibitors in long-term therapy in prostate cancer is the large percentage of cases that are shown to be resistant to chemical castration, or ablation of testosterone. Robert Gardiner et al, from the University of Queenland, Royal Adelaide Hospital Cancer Center, and University of Adelaide Hanson Institute wrote in journal of the European Association of Urology in 2009: "It has been documented recently that intrtumoural androgen levels in castrate-resistant prostate cancer are sufficient to stimulate tumor growth, indicating that local synthesis of androgens is another mechanism for maintaining androgen receptor signalling in the castrate environment." Clearly, whether utilizing lupron or not, additioinal therapies to inhibit enzyme rate control of hormone conversion in local tissues needs to be added to provide thorough treatment protocol.

A number of herbal and nutrient chemicals have been proven effective to inhibit 5-alpha-reductase, including saw palmetto fruit, black cohosh and red clover in alcohol extracts. Krill oil is also useful as a source. As usual, conflicting studies have been presented, but benefits in reducing prostate cancer risk as well as lowering PSA by 50% over 12 months have been demonstrated. Negative studies using synthetic 5-alpha-recuctase inhibitors, finesteride et al, show that treatment with thise chemicals increased incidence of high-grade prostate cancers, but this could be attributed to chemical adverse effects. Natural 5-alpah-reductase inhibitors in foods and herbs have shown no adverse effects. These include the foods, brussel sprouts, soybean, cashew, pineapple, peanut, asparagus, black mustard greens, collards, kale, kohlrabi stem, papaya, mandarin orange, chili, paprika and chicory root, many nuts and seeds, especially pumpkin and flax, wlanuts, and legumes.

The chemicals curcumin, linoleic acid, alpha-linolenic acid, oleic acid, palmitic acid, alizarin, and biochanin-a have been confirmed as herbal 5-alpha-reductase inhibitors. Chinese herbal formulas to treat cancer commonly include herbs with these chemicals, incorporating, e zhu (curcuma), da huang (rheum), ge gen, hong hua, nu zhen zi, xuan shen, and others. Quality professional Chinese herbal formulas are based in part on scientific studies current with research. Specific herbs containing these chemicals include: curcumin: curcuma longa (yu jin), curcuma zedoaria (e zhu), turmeric (jiang huang); alizarin: mulberry wood (sang bai pi, sang zhi, noni), wild rhubarb root rheum (da huang), rubia cordifolia madder (qian cao gen), quinine red cinchona bark; biochanin-a: Noni wood morinda citrifolia, peuria kudzu (ge gen), Sophora japonica (huai hua), red clover; inoleic acid: honghua, xuanshen, digupi, cheqianzi, yinchenhao, gouqizi, sangshen, nuzhenzi; linolenic acid: xuanshen, digupi, cheqianzi, chaihu, congbai, duhuo; oleic acid: xuanshen, chiqianzi, yinchenhao. The essential fatty acids may also be found in passionflower, vitex, ashwaganda, walnut oil, pumpkin seed oil, and safflower seed oil. Krill oil (EPAq from Health Concerns) is high in these essential oils, as is Evening Primrose oil. Negative press concerning herbal and nutrient 5-alpha-reductase inhibitors is limited to a warning that these herbs and nutrients may mask diagnosis by lowering PSA! Medical doctors that take such warnings seriously need to think harder.

PSA velocity more accurately detects prostate cancer than total PSA. National Comprehensive Cancer Network clinical practice guidelines in oncology published in 2005, and Carter et al, JAMA, 1992;267;2215-20, show that rates of increase in PSA over a year are better determinants in detection of prostate cancer than PSA, which has been shown to produce many false positives. Prostate cancer needs to be evaluated with more than total PSA. Prostate cancers proceed through 4 stages, and it is important to adopt a diverse integrative strategy before the cancer reaches stage 4, where there are nearby metastases, spread to regional lymph nodes. In prostate cancers, tumor tissues closely resemble normal tissue in a great number of cases, making evaluation of the spread to lymph nodes and evaluation of metastases important in evaluation. Prostate cancers are heterogenous masses of various abnormal prostate cells with variable degrees of receptor expressions, gravitating toward high membrane androgen receptors relative to internal cell androgen receptors, high estrogen receptor alpha in relation to beta, and high progesterone receptor alpha in relation to beta.

When 5-alpha-reductase herbs and nutrients are used, the conversion of testosterone tilts to estradiol, which exerts anti-apoptotic mechanisms at estrogen receptor alpha (ERa) and pro-apoptotic forces at estrogen receptor beta (ERb). As with breast cancer, the use of the above mentioned therapies of formula 101, DIM, NuLignan, and other therapies, should be used to prevent the ERa over ERb mechanisms.

Viscum alba, or European mistletoe, is another herb proven effective with prostate cancer. The flavonoid silibinin has proven anit-cancer activity in vivo and in vitro, specific to prostate cancer. Alcohol extract is recommended at low dose. High dosage is purported to have some reversible toxicity, which is dose dependant, and thus the patient may increase dosage as tolerated. Liver enzymes should be monitored with higher dosages.

Do Medical Doctors actually support Complementary and Integrative Medicine in the overall treatment plan?

Dr. Ka-Kit Hui, Dr. Edward K. Hui, MDs, and Michael Francis Johnston, PhD, from UCLA Center for East-west Medicine wrote in Integrative Cancer Therapies, Vol. 5, No. 1, 56-62 (2006): The Potential of a Person-Centered Approach in Caring for Patients with Cancer: A Perspective from UCLA Center for East-West Medicine: "Evolving patient preferences as well as an expanding evidence base for commonly used complementary and alternative medicine therapies for patient with cancer have led to inroads by integrative medicine into clinical oncology. Traditional Chinese Medicine (TCM) has been used in conjunction with conventional biomedicine in the prevention and treatment of cancer in China for several decades. Methods: the authors, through select review of the existing literature and by drawing on clinical experience, describe a person-centered approach to care of patients with cancer that incorporates TCM concepts and techniques. Two cases are used to illustrate how this approach might address unmet needs and enhance quality of life for patients with cancer. Results: TCM's emphasis on a comprehensive understanding of imbalance in various systems and resultant compromise of homeostatic reserve as well as its ability to treat them with distinctive therapeutic modalities can add unique value to the overall management of the patient with cancer. Conclusions: TCM can be used adjunctively to improve quality of life and functional status during a patient's struggle with cancer. An approach integrating both medicines that is guided by scientific evidence, safety, and patient preferences has the potential to improve modern oncologic care."

History in the West: A long history of medical doctors in Europe has established a firm naturopathic foundation of research and theory in the use of Complementary Medicine in cancer therapy:

The foundation of complementary medical therapies in European cancer protocol rests with the German doctor Max Gershon. Dr. Gershon examined the mechanisms of cell mutation and came up with a comprehensive list of therapies. Alone, these therapies may not be enough to significantly reverse the cancerous mutations, but together, the package of therapies has been shown to be very helpful. Many patients with this approach have gone into cancer remission and survived long term. Cancer Therapy: The Results of Fifty Cases is Dr. Gershon's classic book. Other books available include: The Topic of Cancer, Cancer: A New Breakthrough by Virginia Livingston, author of a number of books. Dr. Gershon utilized diet high in potassium with raw food juices, oxygen therapies, and a variety of techniques combined in naturopathic clinics and hospitals devoted to treatment of the cancer patient.

Information Resources

  1. An article published in the December 15, 2009, New York Times Health cites a study that showed that only 6% of women with high risk for breast cancer would consider using tamoxifen when the actual risks versus benefits were fully explained. For every 1000 women taking tamoxifen, 9 cases of breast cancer might be avoided, but 21 cases of endometrial cancer would be caused by the drug, 120 would experience serious hormonal symptoms caused entirely by tamoxifen, 31 could develop cataracts, and 21 would be threatened with blood clots that could cause serious strokes: http://www.nytimes.com/2009/12/15/health/15well.html
  2. A 2009 Danish population-based cohort study, supported by the Boston University School of Public Health, and the American Cancer Society, provides data on the incidence of deep vein thrombosis with tamoxifen use: http://www3.interscience.wiley.com/journal/122475387/abstract
  3. A 2007 study at Fox Chase Cancer Center in Philadelphia noted that the main active metabolite of tamoxifen is formed via the liver enzyme product of CYP2D6 gene expression, and that selective serotonin reuptake inhibitors (SSRI anti-depressants) that are prescribed to prevent hot flashes occurring as a side effect of tamoxifen, may work by inhibiting the metabolism of tamoxifen by competing with the enzyme catabolism. This would, of course, seriously weaken the effectiveness of tamoxifen, and account for the decrease in side effect (published in Steroids, Volume 72, Issue 13, November, 2007, Pages 829-842): http://www.sciencedirect.com
  4. A 2006 published initial results of the long-term STAR (Study of Tamoxifen and Raloxifene) study found that long-term use of raloxifene in prevention of recurrence of estrogen receptor positive breast cancer in postmenopausal women was as effective as tamoxifen with fewer risks and side effects, although the number and type of side effects is still alarming: http://mdanderson.org
  5. A 2007 article in Oncology Times gives the facts on rates of noncompliance with tamoxifen use due to side effects: http://journals.lww.com/oncology-times/Fulltext/2007/10100/Non_Compliance_with_Tamoxifen_Increases_Risk_of.9.aspx
  6. A 2009 article by BreastCancer.org reports that a study published in the September issue of Cancer Research found a 4.4-fold higher risk of getting estrogen receptor negative breast cancer in the opposite breast when taking tamoxifen long-term: http://www.breastcancer.org/treatment/hormonal/new_research/20090825.jsp
  7. A study at Tulane University School of Medicine found that selenium was effective as an adjunct therapy to tamoxifen: http://mct.aacrjournals.org/content/4/8/1239.abstract
  8. An article published in JAMA in February of 2008 summarizes scientific findings that synthesized erythropoietin (EPO) and darbepoetin are unsafe for cancer patients in the treatment of post-chemotherapy and radiation: http://jama.ama-assn.org/cgi/content/abstract/299/8/914
  9. An article published in JAMA in September of 2009 and outlined in the New York Times in October summarizes scientific findings that we now know that many cancers slow, stop or reverse into remission without standard therapy, the key being how to enhance this natural process with Complementary Medicine: http://www.nytimes.com/2009/10/27/health/27canc.html
  10. Research in 2013 at the National Yang-Ming University School of Medicine, in Taipei, Taiwan, found that a chemical in the Chinese herb Evoidiae fructus (Wu zhu yu), evodiamine, exerted an inhibition of breast cancer cells lines MCF-7 and MDA-MB-231, downregulating estrogen receptor alpha and beta expression, mediating degradation of the estrogen-receptor pathway, and inducing caspase-dependent pathways to inhibit estrogen-receptor positive breast cancer cell proliferation, in a dose-dependent manner: http://www.ncbi.nlm.nih.gov/pubmed/23840656
  11. Research in 2013 at the National Cancer Research Institute, in Tokyo, Japan, found that the Chinese herbal chemical Curcumin may significantly enhance the effects of a new drug strategy to cure or prevent breast cancers with positive BRCA 1 and 2 gene markers - the drugs called PARP inhibitors work to destroy these cell lines by preventing the fast repair of double stranded DNA - Curcumin was found to enhance the effectiveness of PARP inhibitors greatly (Poly-ADP ribose polymerase inhibitors = Iniparib, Oliparib, Ruciparib et al): http://www.ncbi.nlm.nih.gov/pubmed/23825154
  12. Research in 2013 at Southern Medical University, in Beijing, China found that the herbal polyphenol curcumin, found in a number of Chinese herbs, including Curcumin zedoaria, or E zhu, perhaps the most well-known anti-cancer herb in China, induces apoptosis in breast cancer cells by increasing caspase-3 activation, STAT3, and other antioxidant and cytokine pathways, thus making this herbal extract applicable to both estrogen receptor positive and negative cell lines: http://www.ncbi.nlm.nih.gov/pubmed/23545262
  13. Evidence-based herbal medicine: Anticancer and antitumor effects of a common Chinese herb, Huang qin, or Scutellaria baicalensis, conducted in 2003 at the Mount Sinai School of Medicine in New York: http://cancerres.aacrjournals.org/cgi/content/abstract/63/14/4037
  14. Anticancer and antitumor effects of a common Chinese herb, Ulmus macrocarpa or davidiana, widely used in Korean herbal medicine: http://www.ncbi.nlm.nih.gov/pubmed/18378057?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
  15. Anticancer and antitumor effects of a common Chinese herb, Ban zhi lian, or Scutellaria barbata: http://www.ncbi.nlm.nih.gov/pubmed/14599863?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
  16. Anticancer and antitumor effects of a common Chinese herb, Yun Zhi, or Coriolus versicolor, commonly called turkeytail mushroom: http://www.ncbi.nlm.nih.gov/pubmed/15183073?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed
  17. Further research into the activities that make the Chinese herb, Yun Zhi, or Coriolus versicolor, commonly called turkeytail mushroom, effective against breast cancer cells: http://www.ncbi.nlm.nih.gov/pubmed/15908782?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed
  18. Research in 2011, at the Cancer Prevention Research Program in Montvale, New Jersey, found that the Chinese herb Cornus officinalis, or Shan zhu yu, when taken at the effective dosage, resulted in a five fold increase in the anti-proliferative estradiol metabolite 2-hydroxyestrone (2-OHE1), and a 64 percent decrease in the formation of pro-mitogenic 16alpha-hydroxyestrone, to exert a significant anti-cancer effect in estrogen receptor positive breast cancer: http://www.ncbi.nlm.nih.gov/pubmed/21971582
  19. Research in Argentina in 2006 found that parthenolide in Magnolia grandiflora and Feverfew was effective in vitro in achieving dose dependant nontoxic cell death of cancerous B-cells in chronic lymphocytic leukemia: http://www.209.85.173.132/search?q=cache:OdzpuJNgUvgJ:www.zsf.jcu.cz/jab/4_3/marin2.pdf+herb+herbal+chronic+lymphocytic+leukemia&cd=36&hl=en&ct=clnk&gl=us&client=firefox-a
  20. Research in France in 2006 found that St. Johns' Wort, or Hyperforin, was effective ex vivo in achieving dose dependant nontoxic cell death of cancerous B-cells in chronic lymphocytic leukemia, and also inhibiting the cancer cell capacity to secrete a chemical that stimulates the cancerous creation of new blood vessels: http://www.nature.com/leu/journal/v20/n4/abs/2404134a.html
  21. Research in 2008 at the University of Alabama Birmingham's Department of Comprehensive Cancer Center found that proanthocyanidins in whole grape extract prevented the malignant spread of metastatic cancer in a number of novel metabolic ways: http://www3.interscience.wiley.com/journal/121369644/abstract?CRETRY=1&SRETRY=0
  22. Research published in Clinical Cancer Research reveals that resveratrol, an herbal chemical found in Hu zhang, or polygonum cuspidatum, significantly inhibited excess growth factors in at least 5 cancer cell lines: http://clincancerres.aacrjournals.org/content/8/3/893.full
  23. Information on DIM and its uses and activities: http://www.digitalnaturopath.com/treat/T271617.html
  24. A variety of potent anticancer activities, as well as treatment and prevention of chronic systemic inflammation that drives cancer, is found in research conducted in 2009 at the University of Insubria, Varese, Italy: http://www.ncbi.nlm.nih.gov/pubmed/20005305
  25. Significant anticancer actiivity of NuLignan specific to breast cancer was first discovered in animal studies in Finland in 2000: http://www.ncbi.nlm.nih.gov/pubmed/10890032
  26. Further studies at the University of Turku in Finland, in 2001, showed a specificity of NuLignan for well-differentiated adenocarcinoma: http://www.ncbi.nlm.nih.gov/pubmed/12094633
  27. Studies of NuLignan at the University of Insubria, Italy, in 2007 found that 7-hydroxymatairesinol potassium acetate (NuLignan) converted well to enterolactone, and was active at substituting for estradiol in estrogen receptors that drove breast cancer, effectively blocking this activity. They also found that when given at the same time as tamoxifen, that these effects were reduced: http://www.ncbi.nlm.nih.gov/pubmed/17572100
  28. Research in 2009 at Wake Forest University Comprehensive Cancer Center found that glutathione was protective against the strong carcinogen benzopyrene aromatic hydrocarbon (linked to breast cancer): http://www.ncbi.nlm.nih.gov/pubmed/19330882?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=2
  29. Research in 2005 by Edward Friedman of the University of Chicago assessed the contradictory data of prostate cancer research to find the correct model for what actually creates and drives prostate cancer: http://www.www.ncbi.nlm.nih.gov/pubmed/15777479