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Integrative Medicine for Colon Cancer - Part II

by Nicholas Calvino DC(more info)

listed in cancer, originally published in issue 99 - May 2004

The Effect of Modified Citrus Pectin (MCP) Fibre and the Phytonutrient/ Antioxidant Quercetin on Colon Cancer

The health benefits of fruits and vegetables have been the subject of numerous investigations over many years. Two natural substances, quercetin (a flavonoid) and citrus pectin (a polysaccharide found in the cell wall of plants) are of particular interest to cancer researchers. Research confirms that quercetin exhibits anti-tumour properties, likely due to immune stimulation, free radical scavenging, alteration of the mitotic cycle in tumour cells, gene expression modification, anti-angiogenesis activity, or apoptosis induction (or a combination of these effects). MCP has also been shown to inhibit metastases. Early research conducted on the effect of oral administration of quercetin on colon-25 tumours in mice showed a significant reduction (50%) in size.[27] In one study, administration of MCP and Quercetin reduced solid tumour size by 29-70%.[28] The largest amount of tumour size reduction was seen when both natural compounds were used together. Again, it is important to realize, however, that reduction in size alone is not a good predictor for extrapolating increases in absolute survival.

Integrative Medicine for Colon Cancer - Part II

MCP

MCP is a water-soluble polysaccharide extracted from orange peel citrus pectin and is further pH-modified in the laboratory.16 Previous studies have shown a link between administration of modified citrus pectin (MCP) and decreased metastasis of prostate tumours in rats and melanoma in mice.[29],[30] Certain cancer cell types, such as prostate cancer, breast cancer, colon cancer, lymphoma, melanoma, glioblastoma, and laryngeal epidermoid carcinoma, all have specific protein molecules on their cell surface, called galectins. It has also been observed that metastatic cells express significantly more galectin-3 than the original primary tumour cells from which they were derived. Galectins are known for their carbohydrate-binding abilities. These proteins on the cancer cell surface are involved in binding between cells. They play an important role in cellular interactions during the metastatic process, binding to galactose on neighbouring cancer cells and oligosaccharides on the surface of normal cells.[31] Human studies of colon, stomach and thyroid cancers showed that the amounts of galectin produced increased proportionally as the cancers progressed from their early to advanced stages.[32] Higher galectin levels permit greater adhesion of cancer cells and increases the ability of these cells to bind to non-cancerous cells at a distant site, where metastasis occurs. Thus, these binding sites and their ability to bind to cancer cell surface carbohydrates appear to be the basis by which cancer cells aggregate together and bind to metastatic target sites. It is felt that MCP works by blocking tumour cell surface galectins, so that tumour cells cannot adhere to other cells. The galactose branch chains on the modified pectin molecule appear to be the part which has an affinity for galectins on the tumour cell surface.[33] The impact of this galectin blockage is twofold: (1) to inhibit aggregation of cancer cells and (2) to inhibit adhesion of cancer cells to host cell surfaces. Due to these affects, MCP may also prevent the formation of organized tumour emboli. Although these results are very promising, more research is needed.

Quercetin

Quercetin is a flavonoid. Flavonoids, found in many plants, fruits and vegetables, are of particular interest for their anticancer properties. In his text Natural Compounds in Cancer Therapy, Boik divides the flavonoids into five categories: anthocyanins, minor flavonoids, flavones or flavonoids, isoflavonoids, and tannins.[34] Quercetin, a member of the flavones group, is thought to be the most widely distributed in nature; approximately 25-50 mg of quercetin is consumed in a normal daily diet.[35] Bioflavonoids have been reported to be involved in several important biological processes including antihistamine effects, immunological modulation, inhibition of platelet aggregation, and anti-tumour activity. Quercetin has been found to inhibit production of heat shock proteins in several malignant cell lines, including colon cancer.[36] Heat shock proteins form a complex with mutant p53, which allows tumour cells to bypass normal mechanisms of cell cycle arrest. Quercetin (10 microM) has been found to inhibit the expression of the p21-ras oncogene in cultured colon cancer cell lines.[37] Mutations in this important gene usually impair cellular GTP-ase, which has the effect of continual activation of the signal for DNA replication. Mutations of ras proto-oncogenes are found in over 50 percent of colon cancers, as well as many other tumour types.[38] Quercetin has a history of use by nutritional physicians as an anti-inflammatory and anti-allergy agent.[39] This action is thought to be largely due to the inhibition of lipoxygenase and cyclooxygenase, leading to a reduced production of eicosanoid inflammatory mediators. Quercetin is thought to inhibit cyclooxygenase more potently than lipooxygenase.[40] Inhibitors of cyclooxygenase (NSAIDS) are currently under research as potential chemotherapeutic agents, particularly for colon cancer.[41]

Biological Response Modifiers (BRMs), Proteoglycan Molecules (PGMs) and Muraly Polysaccharide Complex (MPG)

Recently anti-angiogenesis properties of a common weed, Convolvulus arvensis, have been discovered. Convolvulus is derived from the Latin, convolere, meaning to entwine, and arvensis means 'of fields'.[42] The genus Convolvulus contains about 250 species. Convolvulus is a ubiquitous weed, but arvensis is understood to contain alkaloids that are toxic. However, extracts of the plant, largely comprised of proteoglycan molecules (termed PGMs), appear non-toxic in animal studies and have been shown to have potent anti-angiogenesis effects.[43] Many lay and professional people assume weeds have no therapeutic value. However, the difference between 'weeds' and 'herbs' may merely be our understanding of them. The basic definition of a weed is that it is an unwanted plant. Weeds are also considered harmful, as they often compete with crops for light, moisture and nutrients and harbour insects and diseases harmful to crops. For farmers and agriculture specialists, weeds are unwanted plants; but for herbalists, all weeds are useful plants.[44] Such is the case of Convolvulus arvensis, as new research is showing that it has great promise as a useful, safe and non-toxic chemotherapeutic agent.

As tumours grow they secrete substances that promote new blood vessel growth (angiogenesis). Recruitment of new blood vessels plays a crucial role in tumour survival and growth, and every aspect of tumour growth requires rapid vascular development. Tumours secrete substances which block local regulatory control measures and allow for unnaturally fast growth and replication. Many natural and chemical agents have been employed with the aim of halting or blocking angiogenesis, in an attempt to arrest malignant growth, development and metastasis. One well-known natural substance promoted for its ability to halt tumour growth is shark cartilage. The data supporting shark cartilage is conflicting and its popularity has made it a high price item due to supply and demand laws of economics and the lack of abundant availability of the source. Finally, environmental and ecological concerns limit the usefulness of shark cartilage as a chemotherapeutic agent. However, PGMs have been found to inhibit angiogenesis 100 times more than shark cartilage and is widely available due to its ubiquitousness.[44] Because of this, extracts of this common weed, Convolvulus arvensis, hold great promise as a tool in the fight against cancer. Ironically, this herb has great promise in cancer but has a common name of 'the cancer of weeds' among others. After an anecdotal report of complete remission of human ovarian carcinoma after ingestion of an extract of Convolvulus arvensis, this 'weed' was tested for its anti-angiogenic and immunogenic effects. It was found that a high molecular weight water extract of the plant contains almost no appreciable amount of alkaloids (devoid of its inherent toxicity), which are depleted during the extraction or manufacturing process. This proprietary extract is comprised primarily of proteoglycan molecules, termed PGMs, and marketed in the US under the brand name C-Statin®.

In models of angiogenesis, mouse sarcoma, mouse Lewis lung carcinoma and human lyphocytoma, PMG was found to have potent anti-angiogenic and tumour inhibitory effects. Inhibition on angiogenesis was from 18-73%. Inhibition of tumour growth was 35-80% in the cancer models represented and lymphocytes were increased 12-46% in respective models. Angiogenesis plays a significant role in tumour growth and metastasis. New blood vessels that develop locally as a result of angiogenic signalling allow for tumour growth by transporting nutrients and metabolic waste. Tumours cannot grow larger than 2 mm (the size of a pea) without inducing angiogenesis. The larger the volume of viable tumour in the body the more angiogenesis occurs, in turn increasing the amount of tumour. This circuitous process can ultimately lead to the demise of the host. There are many molecular factors in the human body that exhibit angiogenic activity. The family of vascular endothelial growth factors (VEGF) are the most potent endogenous angiogenic peptides presently known. Three characteristics of VEGF make it an interesting target for cancer treatment: 1) It stimulates endothelial cell proliferation and chemotaxis, thus acting as a 'recruitment signal' to induce cell migration towards the signal and subsequent formation of capillaries therein; 2) It suppresses the immune system, most particularly by inhibiting dendritic cell maturation in vivo; and 3) Abnormally high VEGF levels have been shown to correlate with poor prognosis and decreased survival time in people with cancer.

VEGF suppression is being studied as an anti-tumour strategy. Most recently a clinical trial of an anti-VEGF monoclonal antibody as a treatment for inflammatory breast cancer is underway under sponsorship of the National Institutes of Health. As part of a comprehensive approach to treating people with metastatic disease, 10 patients (with a variety of primary tumours) were prescribed two angiogenesis inhibitors, PGM and MPGC, at an average dose of 4 capsules 3 times per day by mouth. Baseline plasma VEGF concentration was determined prior to treatment. At intervals ranging from 12 to 42 days, a second plasma VEGF was measured. There was a significant (p<.05) reduction in plasma VEGF in this population. Interestingly, the subjects with the highest plasma concentration dropped the most. 4 of 5 subjects whose concentration was outside of the reference normal range (33-86 pg/mL) had normalization.

Bindweed Extract, or Convolvulus arvensis, contains proteoglycans known to inhibit angiogenesis. MPGC is a cell wall extract from the bacterium Lactobacillus fermentum. MPGC up regulates the production of interleukin 12 (IL-12) by peripheral mononuclear cells. IL-12 is a potent angiogenesis inhibitor via downstream cytokine regulation. This is interesting in that a significant reduction of plasma VEGF was seen in a relatively short treatment interval. VEGF plays a role in: 1) Angiogenesis; 2) Suppression of the localized immune response in and around tumour tissue. In particular VEGF in combination with other molecules – most notably interleukin 10 – suppresses antigen presentation from dendritic cells to cytotoxic T lymphocytes. It does this by inhibiting the maturation of dendritic cells; and 3) Mediation of lymphangiogenesis in tumours – a major component of the metastatic process.

Freidrich Douwes, MD, head of the German Oncological Society and Chief Medical Officer of St. George Clinic, has clinically used and tested a PGM containing extract called C-Statin® in patients with cancer. He has the following to say on the usefulness of PGM extracts in cancer: "Using new technology, we are now capable of culturing tumour cells from a patient's blood. We can then culture those cells and test whether they are likely to be susceptible to a variety of treatments: cytostatic agents, hormones and angiogenesis inhibitors. We tested PGM (bindweed extract), and several other angiogenesis inhibitors, including pharmaceutical angiogenesis inhibitors, for their ability to inhibit the expression of VEGF (vascular endothelial growth factor). VEGF is a powerful inducer of new blood vessel growth in tumours. Without angiogenesis, no new metastases can occur. In the majority of patients tested, PGM is the most effective suppressor of VEGF. Because of this new information, we are using PGM in the management of most our patients."

In summary, an extract of a common weed, Convolvulus arvensis, shows profound promise as an Anti-Cancer Agent, largely through its ability to inhibit angiogenesis and its stimulatory effect on the immune system. The exact details regarding the anti-angiogenesis mechanism of bindweed extract are not completely understood. This extract should be studied further to elucidate its anti-tumour effects and mechanisms of action. Whether or not a decrease in plasma VEGF correlates with clinical response remains to be seen. There is encouraging data demonstrating that VEGF suppression results in a more positive prognosis. Well-designed clinical trials will help elucidate the effects of VEGF suppression in people with cancer.

Omega-3 Fatty Acids

Omega-3 fats inhibit expression of other gene agents, such as farnesyl protein transferases.45,46 That relates to reduced colon cancer, reduced cytokine production, and reduced inflammation.47 Omega-3 fatty acids have proven immune modulating and inflammatory modulating effects.

Enzymes

In 1902, John Beard (an embryologist at a Scottish medical school) wrote several texts and published many papers. His premise was that cancer cells are much like the trophoblasts of a pregnant woman in that they grow wildly. What makes the trophoblasts stop growing at three months and stop invading the uterus? He found that was the same time as the pancreatic enzymes of the embryo kicked into synthesis. So he argued that using high doses of pancreatic enzymes could turn off cancer. That's exactly what we saw, and there's data to support this. In many studies, it has been shown that bromelain is a better protease inhibitor than the protease-inhibiting drugs. One study showed that enzymes will actually dissolve off the sialoglycoproteins that coat a cancer cell, making it immune from the immune system so that now it can be seen and destroyed by the enzyme.

"A cohort of 1,242 patients with colorectal cancer was documented in 213 centres; 616 patients receiving complementary treatment with oral enzymes (182 (OE) only; 405 other complementary drugs; 29 protocol violators), and 626 patients not receiving OE (368 control only; 229 other complementary drugs; 29 protocol violators). 1,162 patients underwent primary surgery, of whom 526 received adjuvant chemotherapy and 218 radiotherapy. The median follow-up time for the OE-group was 9.2 months; for the control group 6.1 months. The primary test criterion of efficacy for OE treatment was the multivariate effect size (Wei, Lachin, 1992) of the changes from baseline of the disease, and therapy-associated signs and symptoms (nausea, vomiting, changes in appetite, stomach pain or stomach disorder, tiredness, depression, memory or concentration disorder, sleep disturbance, dizziness, irritability, dyspnea at rest, dyspnea during activity, headache, tumour pain, cachexia, skin disorders and infections). Tumour related events e.g. death, were evaluated by the number of events observed and time to event. Safety of treatment with OE was analysed by number and severity of adverse events, their duration, treatment and outcome.

A significant reduction in disease-associated signs and symptoms was observed in patients treated with OE alone, but not in those patients receiving OE in addition to other complementary treatments. Adverse reactions of chemo- or radiotherapy were diminished in all patients receiving OE. Analysis of survival did not demonstrate a reduced number of deaths in the OE group. However, a trend to prolongation of survival could be demonstrated, particularly in the patients with disease stage Dukes D, receiving OE treatment in the subgroup, receiving OE in addition to other complementary treatments. Similar but less pronounced trends were observed for disease stages Dukes B and C. In the OE-group, 21 of 616 patients (3.4%) experienced OE associated adverse reactions, all of them reported as mild to moderate gastrointestinal symptoms.

Complementary treatment of colorectal cancer patients with OE improves their quality of life by reducing both the signs and symptoms of the disease, and the adverse reactions associated with adjuvant anti-neoplastic therapies. This epidemiological retrolective cohort analysis provides evidence that the patients may also benefit by a prolongation of survival time. OE preparations were generally well tolerated."[48-53]

Artemisinin

Artemisinin has been used for about 30 years in Vietnam and China for cancer treatment. And the experience with artemisinin for this purpose is increasing. This history probably lead to the recent cited cancer research with artemisinin. For the past ten years, the Hoang medical family, with three generations of sophisticated physicians, have used artemisinin in combination with several other herbs to treat cancer, and eliminate necrotic material from the body. In 1995, a paper by Lai appeared in Cancer Letters concerning the use of artemisinin against numerous cancer cell lines in vitro. This article has mobilized interest in artemisinin as an addition to anticancer treatment.[54] There are a number of properties shared by cancer cells which favour the selective toxicity of artemisinin against cancer cell lines, and against cancer in vivo. Cancer cells have higher rates of iron flux via transferring (iron) receptors, than normal cells and are particularly sensitive to oxygen radicals.[55] A subsequent article appeared in Life Science in 2001 by Singh and Lai on the selective toxicity of artemisinin and holotransferrin towards human breast cancer cells.[56] Artemisinin becomes cytotoxic in the presence of ferrous iron. Since they showed iron influx is naturally high in cancer cells, artemisinin and its anagoges selectively kill cancer cells under conditions in vivo. Further, it is possible to increase or enhance iron flux in cancer cells using the conditions that increase intracellular iron concentrations. They report on the incubation of holotransferrin, which increases ferrous iron in cancer cells, in combination with artemisinin, and demonstrate its effectiveness in a type of radiation resistant human breast cancer cell line in vitro. A third paper, by Efferth et al, published in Oncology in 2001 stated that the anti-malarial artesunate is also active against cancer.[57] Artesunate (ART) is a semi-syn thetic derivative of artemisinin, and has been analyzed for its anticancer activity against fifty-five cell lines by the Developmental Therapeutics program of the National Cancer Institute, USA. ART was most active against leukaemia and colon cancer cell lines. Mean growth inhibition was 50%. Intermediate GI 50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Most important, a comparison of ART's cytotoxicity with those standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumour drugs. Leukemia lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea were tested. None of these drug resistant lines showed any resistance to ART.

To Be Continued.
Part III will further review nutritional elements in the treatment of colon cancer.

References

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About the Author
Nicholas Calvino is a Chiropractic Physician and Master Herbalist Candidate. He is the co-author of an upcoming book, Eat This! An Introduction To The New World Food Order, and in private practice in Southern Arizona. He can be reached through his virtual practice at www.drcalvino.com

Further Information

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About Nicholas Calvino DC

Nicholas Calvino DC is a practising clinician, nutritional consultant and author and lecturer on the subject of health and nutrition. He is currently the president of Natural Health Partners, LLC, a practice 'enhancement' company focusing on assisting doctors in marketing and managing secondary profit centres. He can be contacted at PO Box 160, North Street, MI 48049; Tel: 810-385-6737; drcalvino@msn.com

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