Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study.

Little is known about the relation of multivitamin use to breast cancer outcomes. 2,236 women diagnosed from 1997 to 2000 with early-stage breast cancer (Stage I ≥ 1 cm, II, or IIIA) were enrolled about 2 years post-diagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry (83%). Multivitamin use pre-diagnosis and post-diagnosis was assessed via mailed questionnaire. Outcomes were ascertained yearly by self-report and verified by medical record review. Delayed-entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sociodemographic, tumour, and lifestyle factors. Overall, 54 and 72% of the cohort reported using multivitamins pre- and post-diagnosis, respectively. A total of 380 recurrences, 212 breast cancer deaths, and 396 total deaths were confirmed. Compared to never use, multivitamin use after diagnosis was not associated with any outcome (recurrence HR = 0.92; 95% CI: 0.71, 1.20; total mortality HR = 0.92; 95% CI: 0.71, 1.19). Compared to never use, persistent use of multivitamins from pre- to post-diagnosis was associated with a non-significant decreased risk of recurrence (HR = 0.76; 95% CI: 0.54, 1.06) and total mortality (HR = 0.79; 95% CI: 0.56, 1.12). The protective associations were limited to women who had been treated by radiation only (P for trend = 0.048 and 0.083 for recurrence and total mortality, respectively) and both radiation and chemotherapy (P for trend = 0.015 and 0.095 for recurrence and total mortality, respectively). In stratified analyses, women who consistently used multivitamins before and after diagnosis and ate more fruits/vegetables (P for trend = 0.008) and were more physically active (P for trend = 0.034) had better overall survival. Multivitamin use along with practice of other health-promoting behaviours may be beneficial in improving breast cancer outcomes in select groups of survivors.
SOURCE:
Kwan ML, Greenlee H, Lee VS, Castillo A, Gunderson EP, Habel LA, Kushi LH, Sweeney C, Tam EK, Caan BJ. Breast Cancer Res Treat. 2011 Nov;130(1):195-205. Epub 2011 May 11.

Classification of evidence: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02–1.00, p < 0.05).

We determined if soy isoflavones have dose-related oestrogenic and methylation effects. Thirty-four healthy premenopausal women were randomised to 40 mg or 140 mg isoflavones daily through one menstrual cycle. Breast specific and systemic oestrogenic effects were assessed measuring the oestrogenic marker complement (C)3 and changes in cytology, whereas methylation assessment of 5 cancer related genes (p16, RASSF1A, RARbeta2, ER, and CCND2) was performed on intraductal specimens.
Serum genistein significantly increased after consuming both isoflavone doses. Cytology did not significantly change at either isoflavone dose. Serum C3 levels post-treatment were inversely related to change in serum genistein (r =-0.76, P = 0.0045) in women consuming low but not high dose isoflavones. The RAR beta 2 hypermethylation increase post-treatment correlated with the post-treatment genistein level considering the entire group (r = 0.67, P = 0.0017) and those receiving high-dose isoflavones (r = 0.68, P = 0.021). At the low but not the high isoflavone dose, CCND2 hypermethylation increase correlated with post-treatment genistein levels (r = 0.79, P = 0.011). In summary, the inverse correlation between C3 and genistein suggests an antioestrogenic effect. Isoflavones induced dose-specific changes in RARbeta2 and CCND2 gene methylation, which correlated with genistein levels. This work provides novel insights into oestrogenic and methylation effects of dietary isoflavones.
Source:
Qin W, Zhu W, Shi H, Hewett JE, Ruhlen RL, MacDonald RS, Rottinghaus GE, Chen YC, Sauter ER. Nutr Cancer. 2009;61(2):238-44.

Korean Red Ginseng Suppresses Metastasis of Human Hepatoma SK-Hep1 Cells by Inhibiting Matrix Metalloproteinase-2/-9 and Urokinase Plasminogen Activator

Ho Y-L, Li K-C, Chao W, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012), doi:10.1155/2012/965846

Korean red ginseng and ginsenosides have been claimed to possess wide spectrum of medicinal effects, of which anticancer effect is one. The present study was undertaken to investigate the antimetastatic effect of Korean red ginseng on human hepatoma as well as possible mechanisms. The inhibitory effect of the water extract of Korean red ginseng (WKRG) on the invasion and motility of SK-Hep1 cells was evaluated by the Boyden chamber assay in vitro. Without causing cytotoxicity, WKRG exerted a dose-dependent inhibitory effect on the invasion and motility, but not adhesion, of highly metastatic SK-Hep1 cells. Zymography analyses revealed significant downregulating effects on MMP-2, MMP-9, and uPA activities in SK-Hep1 cells. Western blot analyses also showed that WKRG treatment caused dose-dependent decreases in MMP-2 and MMP-9 protein expressions. Moreover, WKRG increased the levels of TIMP-1, TIMP-2, and PAI-1. The present study not only demonstrated that invasion and motility of cancer cells were inhibited by WKRG, but also indicated that such effects were likely associated with the decrease in MMP-2/-9 and uPA expressions of SK-Hep1 cells.

In this study, we explored the anti-metastatic effect of Korean red ginseng in human hepatoma SK-Hep1 cells. Analytical data received from the Korean Ginseng Corporation showed that there was a great variation in ginsenoside contents between WKRG and EKRG, most likely due to the different extracting processes. Although the difference in the effect of these two extracts on cell viability was not prominent, there was a great variation in their inhibitory effects on MMP-2/-9 activities. WKRG inhibited MMP-2/-9 activities in a concentration-dependent manner, while EKRG had no significant inhibition on MMP-2/-9 activities at all tested concentrations. Based on the above observation, WKRG was selected to do the follow-up experiments in this paper. We found that WKRG also diminished uPA activity of SK-Hep1 cells. Moreover, WKRG significantly inhibited the invasion (assessed using the transwell assay) and migration (examined by both transwell and wound-healing assays) of SK-Hep1 cells. We further demonstrated that WKRG notably inhibited the protein expressions of MMP-2 and MMP-9 and increased the protein levels of TIMP-1, TIMP-2 and PAI-1. These results indicated that antimetastatic effect of WKRG was related to the inhibition of enzymatically degradative processes of tumor metastasis. To our knowledge, this is the first study that attempted to explore biochemical mechanisms underlying WKRG’s inhibitory effect on the metastasis of SK-Hep1 cells.Panax ginseng is an herb frequently used in traditional oriental medicine for its wide spectrum of medicinal effects such as tonic, immunomodulatory, anticancer, adaptogenic, antiaging, antioxidant, and neuroprotective effects [10].

The major active components of ginseng are ginsenosides. More than forty ginsenosides have, so far, been isolated and each ginsenoside possesses different pharmacological effects [11]. Commercially available Korean ginseng products are classified into fresh ginseng, white ginseng, and red ginseng. White ginseng is fresh ginseng which has been air-dried, while red ginseng is obtained by heating. Although processed differently, both red and white ginseng products are manufactured from 6-year-old fresh ginseng roots; nevertheless Korean red ginseng has higher contents of ginsenosides such as Rh2, Rg3, and Rg5 in comparison to white ginseng [12]. Rh2 is produced from ginsenoside Rg3 through bacterial transformation and belongs to the protopanaxadiol family. Rh2 has attracted considerable attention owing to its potential tumor-inhibitory activity. It constrains cell growth in MCF-7 human breast cancer and SK-Hep1 hepatoma and can induce apoptosis in various cell lines [13]. Ginsenoside Rg3 has been reported to reduce the gelatinolytic activities of MMP-2 and MMP-9 [14]. Other important ginseng saponins with unique chemopreventive actions include Rb2 which may partly contribute to the inhibition of lung tumor metastasis by arresting tumor-associated angiogenesis [15], and Rp1 (a semisynthesized derivative of ginsenoside Rg5) whose anticancer effect is believed to be achieved by strongly inhibiting tumor cell metastasis and viability, presumably through impeding adhesion and vessel formation [16].Cell migration is a complex process involving many types of intracellular and extracellular components and is associated with signaling pathways. Since migration is a critical event in cancer progression and especially in metastasis, the inhibitory effect of WKRG on cell migration was evaluated [4]. We found that WKRG significantly inhibited the migration and invasion of SK-Hep1 human hepatoma cells. Invasion of cancer cells through a coated membrane involves not only ECM degradation, but also the formation of adhesive interactions between cells and the matrix. Therefore, the cell adhesion assay was carried out; however we arrived with the result that WKRG only caused a small reduction in cell adhesion. The slight reduction in adhesion may be associated with the significant decreases in migration and invasion by WKRG treatment.MMPs belong to a family of zinc-dependent endopeptides. They are secreted as inactive proenzymes and are activated by partial proteolytic cleavage. MMP-2, MMP-9 and dominant MMPs are released by most endothelial cells and appear to play important roles in the degradation of type VI collage, a major constituent of basement membrane, in cancer invasion and metastasis [17].

In this study, we observed up to 62.6% and 81.5% downregulations of MMP-2 and MMP-9 activities by WKRG as compared with the control. Although these are not direct inhibitions of enzymatic activity, they seem to be enough to decrease cancer metastasis, based on other studies [18].The expression of uPA has been suggested to play a critical role in local fibrin deposition/dissolution [17]. Conversion of plasminogen into active plasmin by plasminogen activators, such as uPA, is primary for fibrinolysis to occur. Plasmin degrades fibrin and prevents its extracellular deposition. WKRG caused a reduction in cell surface plasmin activity as evidenced by the uPA activity assay. The importance of fibrinolytic system in wound healing has been demonstrated in plasminogen-deficient mouse models, where healing is weakened primarily due to impaired fibrinolysis, a consequence of insufficient plasmin generation [19]. Furthermore, uPA plays prominent roles in cellular migration and is vital during the initial phases of wound healing [20]. We used the wound healing assay in vitro to observe the effect of WKRG on cellular migration. WKRG potently retarded the migration of cells towards the wounded area. The results of this study demonstrated that WKRG inhibited fibrinolysis and cell migration which are vital during the early phase of wound healing.To further explore the mechanisms underlying the anti-metastatic effect of WKRG, we detected the alteration in levels of several proteins by lysing SK-Hep1 cells after they had been incubated in the presence or absence of WKRG, including MMP-2, MMP-9, TIMP-1, TIMP-2, and PAI-1.

There is in vitro evidence that MMPs and TIMPs are critical in determining the invasive potential of proliferating tumor cells. MMP-2 and MMP-9 are necessary for the migration of many normal cell types and tumor cells [21]; on the other hand, TIMPs are believed to play important roles in the inhibition of growth and migration, especially in hepatocellular carcinomas [22]. These documented findings strongly suggest anti-metastatic potential of WKRG, as we have demonstrated that WKRG suppressed MMP-2/-9 and enhanced TIMP-1/-2 expressions in terms of protein levels.PAI-1 is a serine protease inhibitor which inactivates uPA to prevent it from binding to the uPA receptor (uPAR). uPAR is part of the plasminogen activation system which is also involved in the regulation of cell adhesion, migration, and invasion. It can transmit uPA-mediated extracellular signals inside the cell, probably through the association with different types of integrins and ECM components. Thus PAI-1 has the ability to arrest the proteolysis cascade following uPAR activation [23]. Our experiment by Western blot demonstrated that the protein level of PAI-1 was enhanced in a dose-dependent manner by WKRG treatment. In summary of the above results, it is suggested that WKRG’s influences on MMP-2, MMP-9, uPA, PAI-1, TIMP-1, and TIMP-2 expressions may have a synergic suppressive effect on the migration and invasion of tumor cells.In conclusion, we explored the anti-metastatic effects and mechanistic actions of WKRG in human hepatoma SK-Hep1 cells. It was found that WKRG significantly inhibited the invasion and migration of SK-Hep1 cells. Then, we carried forward the study by showing that WKRG notably inhibited the expressions of MMP-2, MMP-9, and uPA and elevated the protein levels of PAI-1, TIMP-1, and TIMP-2. These results not only evidenced anti-metastatic effect of WKRG but also showed that such effect was associated with the inhibition of enzymatically degradative processes of tumor metastasis. The present study suggests that Korean red ginseng may be developed into a promising agent for cancer therapy. As to which ginsenosides are predominantly responsible for the anti-metastatic effect of Korean red ginseng remain primarily unclear and would require further studies.

References:
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In Vitro and In Vivo Effects of Phenolic Antioxidants against Cisplatin-Induced Nephrotoxicity

Rao M, Kumar MM, Rao MA. J Biochem (1999) 125 (2): 383-390.

We have investigated the effect of phenolic antioxidants on cisplatin-induced cytotoxicity in vero (African Green Monkey Kidney) cells and in rat renal cortical slices in vitro, and on cisplatin-induced nephrotoxicity in rats in vivo. Incubation of cisplatin with vero cells resulted in time- and concentration-dependent cytotoxicity, as characterized by decreased tryphan blue exclusion (TBE) and increased release of lactate dehydrogenase (LDH) into the medium. Cisplatin also caused reduction of glutathione (GSH) in a concentration-dependent manner. In the rat renal cortical slices model, incubation of cisplatin for 120 min caused an increase in malondialdehyde (MDA), a decrease in GSH and inhibited p-aminohippurate (PAH) uptake in a concentration-dependent manner. Among phenolic antioxidants, iso-eugenol (IG) was found to be more active against cisplatin-induced cytotoxicity in vero cells as well as in rat renal cortical slices than eugenol (EG) and dehydrozingerone (DZ). However none of the test compounds were able to arrest the reduction of the GSH content induced by cisplatin in either the vero cells or the renal cortical slice model. Administration of cisplatin (3 mg/kg) i.p. to rats resulted in significant reduction of body weight, and elevation of blood urea nitrogen (BUN) and serum creatinine. Treatment with IG 10 mg/kg i.p. 1 h before cisplatin resulted in partial but significant protection against the cisplatin-induced reduction of body weight, and elevation of BUN and serum creatinine, the protection being 34,46, and 62%, respectively. EG and DZ (10 mg/kg, i.p.) were found to be inactive in vivo. Because IG is a potent free radical scavenger and protects against cisplatin-induced toxicitiy, the present results have many clinical implications in cisplatin chemotherapy and thus warrants further investigation.

Consensus Builds on High-Dose Vitamin D for Breast Cancer Prevention–Despite IOM Report

By Janet Gulland. Holistic primary Care. Vol. 11, No. 4. Winter, 2010

The role of vitamin D in cancer care was the subject of considerable attention at the recent Society for Integrative Oncology 7th annual assembly. Researchers and clinicians gathered at the meeting seemed to be moving toward a consensus that high-dose vitamin D supplementation has potential to markedly reduce risk of primary breast cancer as well as breast cancer recurrence, with minimal risk of toxicity.
Data presented at the meeting–held just two weeks before the Institute of Medicine’s Nov. 30 consensus statement dismissing the potential of vitamin D beyond bone health—indicate that women with serum levels under 20 ng/ml are at significantly increased risk of breast cancer, that raising levels to 50 ng/ml mitigates that risk, and that oral doses upwards of 10,000 IU/day are safe for women at risk of breast cancer.
While there are still many unanswered questions about the role of vitamin D in cancer prevention and treatment, speakers at the conference were largely in agreement that the standard Recommended Daily Allowance of 400 IU/day is grossly inadequate and has little scientific basis. The Institute of Medicine’s new recommendation of 600 IU for adults—including post-menopausal women won’t likely change anything.

A 40% Risk Reduction
Some of the strongest recent data comes from the Long Island Breast Cancer Study Project, which involved 1,026 women with breast cancer diagnosed between 1996 and 1997 compared with 1,075 matched controls. Vitamin D deficiency, defined as a serum level under 20 ng/ml, was common in both groups, but more prevalent among the women with cancer, reported Katherine Crew, MD, an epidemiologist at Columbia University College of Physicians & Surgeons, and lead investigator on the study.
Thirty-three percent of the cancer cohort was frankly deficient versus 28% of the cancer-free controls.
But the real message is in the analysis of odds ratios. The women who had blood levels of 40 ng/ml or greater had 40% lower odds of breast cancer versus those with serum levels of 20 ng/ml or lower. There was even a small 16% odds reduction among the women with serum levels of 20-29 ng/ml, which is low but not technically deficient. Dr. Crew noted that the data were adjusted for age, race, parity, family history of breast cancer, and other key variables (Crew KD, et al. Cancer Prev Res. 2009; 2(6): 598-604)
“Higher levels of 25-hydroxy-vitamin D confer lower risk of breast cancer. This was consistent for both estrogen receptor-positive (ER+) and negative (ER-) breast cancer, which is important because we really don’t have effective chemotherapy for ER- breast cancer,” Dr. Crew told attendees.

The study turned up several other interesting findings, including the fact that vitamin D deficiency correlates with obesity, which also increases cancer risk. The researchers found deficiencies in 36% of the women with body mass indices over 30, but only 23% of those with BMI’s under 25. The explanation is not yet clear, but Dr. Crew suggested that there may be a fat sequestration effect wherein vitamin D is being stored in adipose tissue, thus lowering serum levels in the obese women.

Sense in Supplementation
The Long Island data are compelling, but Dr. Crew urged caution in drawing definitive conclusions. “These are observational findings based on one measurement of serum vitamin D status; we don’t know from this study if raising the vitamin D level would lower breast cancer risk, and even if it does, we don’t know the best and safest method for doing this.”

Other studies, however, are pointing the way toward clear risk reduction strategies.
For example, the Women’s Health Initiative’s 2007 report, while showing no significant risk reduction from vitamin D at the standard 400 IU/d dose, did show a 20% reduction in breast cancer incidence among the women who reported taking additional vitamin D, on their own, beyond the “official” 400 IU dose. The biggest incidence reduction was for ER- cancers. Dr. Crew said the findings are definitely significant though they have been largely overlooked.
Also in 2007, Lappe and colleagues published a study of 1,179 post-menopausal women showing that those taking 1,100 IU/d of vitamin D plus calcium (1,500 mg/d) had far lower incidence of breast cancer versus those taking placebos (2% versus 6.8%). A third subgroup, taking calcium alone, also had fewer breast cancers but the incidence reduction was not as great (3.6% versus 6.8%) (Lappe et al. Am J Clin Nutr. 2007; 85(6):1586-91).
Looking at the best available data, it seems that breast cancer odds ratios begin to drop significantly as serum vitamin D levels get over 50 ng/ml. According to Garland and colleagues, you see a 50% risk reduction right around a serum level of 52 ng/ml (Garland et al. J Steroid Biochem Mol Biol. 2007; 103(3-5): 708-11). Progressive, nutrition-oriented oncologists agree that 40-60 ng/ml is the target range.

How Much?
So, how much vitamin D does a woman have to take to get up to the cancer-prevention range? At least 3,000-4,000 units per day, depending on the extent of the deficiency. This is almost an order of magnitude higher than the Institute of Medicine’s new RDA of 600 IU, but within range of the new Upper Limit.
What about toxicity? The most worrisome potential adverse effects of excessive vitamin D would be hypercalcemia, bone demineralization, nephrocalcinosis, and cardiac arrhythmias. However, these problems don’t really arise until serum levels get above 150 ng/ml, said Dr. Crew. Someone would have to take a lot of vitamin D over a long period to get the blood level up in that range.
Back in 2004, Vieth and colleagues studied daily doses of 10,000 IU for up to 5 months, and found no evidence of toxicity (Vieth et al. J Steroid Biochem Mol Biol. 2004; 89-90(1-5): 575-9).

Safe at 30,000 IU per Week
Dr. Crew’s group at Columbia is assessing the effect of cholecalciferol (vitamin D3) at high doses of 20,000 IU and 30,000 IU per week, in vitamin D deficient pre- and post-menopausal women at high breast cancer risk. The women will be treated for a full year. Breast-specific outcome measures include tissue changes on biopsy, imaging of breast fibrodensity, as well as urine and serum markers.
If looked at in terms of daily doses, these weekly dose levels—roughly 2,800 IU and 4,300 IU per day—are considerably higher than the IOM’s new recommendation of 600 IU per day. However, Dr. Crew said in an interview with Holistic Primary Care that they do fall close to the IOM’s new safe upper limits for women in this age bracket.
According to Julie Campbell, a research fellow who presented preliminary findings at the SIO conference, the study will ultimately involve 80 women in total. So far, 20 pre-menopausal and 14 post-menopausal women have completed the trial, with no evidence of any adverse effects at either dose level. “There have been no cases of hypercalcemia so far, and only one woman has show high urine calcium levels,” said Ms. Campbell.
She pointed out that that high-dose supplementation leads to rapid correction of deficiencies. Among the pre-menopausal women, mean levels were up in the 50-60 ng/ml range within 3 months, with the 30,000 IU weekly dose giving larger rises than the 20,000 IU weekly dose. It is important to note that even at these high doses, none of the subjects got up into the potentially toxic 150 ng/ml serum range.
The study is ongoing, and investigators have not yet completed analysis of vitamin D’s effects on breast tissue. However, the available data indicate that two of the 20 pre-menopausal women receiving 30,000 IU per week had a 15% reduction in fibrodensity, a surrogate marker for cancer risk.

“These are pilot data but they are compelling,” Ms. Campbell said. “High dose vitamin D supplementation can successfully raise serum levels to target range within a year, without significant toxicity. Based on imaging and biomarkers, there are possible preventive effects.”
Though the IOM report seems to dismiss the potential anti-cancer benefits of vitamin D supplementation, while raising a specter of alarm based on little evidence of actual toxicity incidence, the Columbia experience suggests little downside to supplementing in the range of 10,000-30,000 IU per week. The only major caveat being that one needs to watch calcium closely. Raising the serum vitamin D level will tend to increase calcium absorption, so if a patient is taking a lot of calcium the vitamin D boost could potentially increase risk of kidney stones.
The role of vitamin D in primary breast cancer prevention should become more clear on publication of a new Phase IIB intervention trial by the Southwest Oncology Group. The study involves 200 high-risk women randomized to placebo or 20,000 IU per week and followed for a year.

Improving Survival, Preventing Recurrence
There’s growing evidence that serum vitamin D level is inversely correlated with risk of recurrence in women who’ve already had breast cancer. Researchers in Toronto studied 512 women diagnosed with early-stage breast cancer from 1989-1996, and followed them for an average of nearly 12 years. The women had a mean vitamin D level of 23 ng/ml at baseline, with 37.5% in frank deficiency (<20 ng/ml) and 38.5% showing insufficient levels (20-29 ng/ml).
The women who were vitamin D deficient had a roughly two-fold increased risk of cancer recurrence and death at 12 years compared with those who had “sufficient” vitamin D levels (Goodwin et al. J Clin Oncol. 2009; 27(23):3757-63).
Dr. Crew said her team saw a similar effect in the Long Island study, with a near doubling in the adjusted hazard ratio of death within 8 years among the vitamin D deficient women compared with those who had blood levels over 30 ng/ml.
Interestingly, women in northern latitudes diagnosed with breast cancer in the Summer or Fall have statistically better survival rates compared with those diagnosed in the Winter or Spring. Further, breast cancer has a 25% higher mortality rate in the Northeastern US compared with the Southwest. While there are many potentially confounding variables in epidemiological findings like this, Dr. Crew said there could very well be a vitamin D effect in play.

The Sunshine Vitamin is clearly a subject of great interest to cancer researchers these days, and future studies should help clarify optimal treatment strategies.
The new IOM report states that for the general population there’s no strong evidence for pushing supplementation beyond the 600 IU range, a conclusion that many are questioning. For women at-risk of breast cancer, the available data suggest a conclusion that runs counter to the IOM’s recommendations.
It makes good sense to test vitamin D levels in all at-risk women, and to do whatever is possible to get serum levels into the 40-60 ng/ml range.

Immune Enhancement, Avoidance of Interactions Are Keys to Chemotherapy Support

By Janet Gulland. Holistic Primary Care. Vol. 12, No. 1. Spring, 2011

It is no secret that many people with cancer take nutraceuticals and botanical medicines in conjunction with conventional chemotherapy, in the hope of enhancing the therapeutic effect, minimizing side effects, and improving their odds of a long, relatively healthy life.
The impulses are certainly understandable, but the mixing of supplements and other natural products with anti-cancer pharmaceuticals raises concern about the potential for supplement-drug interactions.
Until recently, there’s been a void of good science about the ways in which commonly used supplements interact with common chemotherapeutic drugs. With the emergence of integrative oncology emerges as a clinical discipline, researchers have begun to turn serious attention to this issue.
There are essentially two types of interactions: those in which one substance speeds the metabolism and clearance of another, thus decreasing the latter’s efficacy; and those in which one substance inhibits the clearance of another, making it toxic. It all comes down to how various drugs, nutrients, and botanical compounds are processed by the liver.
Roughly 75% of all known drugs are metabolized through the cytochrome P450 class of enzymes, making this a key locus for research on interactions.

Filling a Data Void
Researchers at MD Anderson Cancer Center, Houston, are engaged in a wide-ranging pharmacologic assessment of roughly 30 commonly used natural products, and their potential for interaction with common chemo drugs. This line of work will be important for guiding clinical care of people with cancer.
“When they don’t have any data, oncologists tend to tell patients not to risk it with natural products,” said Judith A. Smith, Pharm, D, Director of Pharmacology Research at MD Anderson’s Department of Gynecologic Oncology. This may be prudent, but it can result in patients missing out on the benefits that some natural products might confer.
Though work in this field is still at an early stage, Dr. Smith told Holistic Primary Care that her team has already identified a couple of nutraceuticals & natural products that pose little risk of interaction. They’ve also hit on one that should definitely be avoided.
Her group recently published a paper in the Journal of the Society for Integrative Oncology, on the interaction potential of AHCC (active hexose correlated compound), an extract obtained from a hybridization of several species of medicinal mushrooms. AHCC is supported as a cancer care adjunct by over 25 studies, and has been shown to decrease side effects of chemotherapy — including hair loss and bone marrow suppression.
In Japan, where AHCC was developed, it is often used in conventional practice, and it has attracted the interest of several prominent American oncologists.

AHCC: Little Risk of Interaction
Dr. Smith’s team conducted two studies: an in vitro metabolism study, to determine whether AHCC can inhibit P-450 detox pathways (i.e. if it might increase a drug’s toxicity), and an ex vivo human liver cell induction study, to evaluate whether it induces P-450 activity (i.e. if might reduce a drug’s efficacy).
The in vitro work indicates that AHCC does not inhibit the major P450 detoxification pathways, meaning it will not delay breakdown of most chemo drugs. “AHCC is unlikely to result in increased toxicity when used in combination with chemotherapy or supportive therapies such as anti-nausea medications or antidepressants.”
The ex vivo study indicated that AHCC does increase CYP450 2D6 activity. Therefore, it may have the potential to modulate the effect of drugs metabolized through that pathway. Fortunately, this is not a predominant pathway for metabolism of commonly used chemo agents, with the exception of doxorubicin and tamoxifen.
Tamoxifen must be metabolized by the 26D pathway to be converted to its active form, so induction of 26D might increase the effect of the drug. There are some case studies suggesting this does occur, though the interaction is not well understood. It is also possible that AHCC’s induction of 26D would increase tamoxifen toxicity, though this has not been observed. Until more is known, it is wise to be cautious in combining AHCC with tamoxifen. But since most other chemo drugs are not metabolized via 26D, there is little risk of interactions.
Among the other compounds Dr. Smith’s group has studied, L-glutamine is the only other so far that shares AHCC’s low potential for interactions. Some clinicians—and many cancer patients—believe L-glutamine supplementation bolsters immune function and diminishes mucosal injury from radiotherapy.
Noni juice, popular among cancer patients and promoted for immune strengthening, is a must-to-avoid with chemotherapy, said Dr. Smith. The foul-smelling, anthraquinone-rich juice from this Polynesian fruit is a powerful inducer of CYP450 enzymes.

Reducing Toxicity, Improving Lives
Lise Alschuler, ND, FABNO, an integrative oncologist in Bedford, NH, said it is important to understand and to respect the motives that drive cancer patients to augment allopathic cancer treatments with natural products.
“The prospect of having cancer invokes fear of pain, suffering and death. The treatments are, for many, as terrifying as the disease itself. Chemotherapy, the mainstay of conventional treatment, is perhaps the most feared of all. Nausea, diarrhea and/or constipation, mouth sores, fatigue, numbness and tingling of the extremities are common and sometimes severe. The need for additional therapies that will reduce the toxicity of chemotherapy is great.”
Dr. Alschuler, is co-author, with Karolyn Gazella, of The Definitive Guide to Cancer: An Integrated Approach to Prevention, Treatment, and Healing, now in it’s 3rd edition. Herself a breast cancer survivor–or “thriver” as she prefers it—Dr. Alschuler is particularly enthusiastic about AHCC’s potential.
“What makes it so exciting is its ability to improve both duration and quality of life. Two studies of patients with highly incurable primary liver cancer have shown that the individuals given AHCC experienced a significant prolongation of life as well as dramatic improvement in their quality of life.”
In these trials, AHCC reduced side effects while enhancing the tumor killing, translating into higher quality of life and increased survival times (Cowawintaweewat S, et al. Asian Pacific J Allergy Immunology. 2006;24:33-45. Gao Y, et al. Cancer Immunol Immunother. 2006; 55:1258-1266).

AHCC & the Immune System
One reason cancer cells are so dangerous is that they directly suppress immune function. Specifically, they suppress dendritic cells, the roving “eyes” of the immune system. Normally, when these cells encounter a cancerous or otherwise aberrant cell, they send out chemical signals (namely IL-12) that activate cytotoxic T cells and natural killer (NK) cells. Inhibition of dendritic cell signaling effectively disarms this entire branch of the immune system.
Chemotherapy can cause further damage because it can be very damaging to the stem cells in the bone marrow.
In a sense, the immune systems of people getting chemotherapy are slammed from both sides: the cancer itself blinds T cells and NK cells, and the drug-induced myelosuppression diminishes immune cell counts. Reversing and restoring suppressed immune function is an essential aspect of cancer care.
AHCC increases the number of dendritic cells and their ability to stimulate the rest of the immune system. It increases production of IL-12 and IFN-γ.
In addition, AHCC specifically increases the activity of NK cells in cancer patients. “The combined effect is to unchain the immune system and to allow it to respond to, and destroy, cancerous cells,” Dr. Alschuler said. These immune-mediated anti-tumor effects have been demonstrated against melanoma and lymphoma cancer cells in tumor-bearing rodents.

The immune enhancing effect of AHCC is reason enough to consider it for patients needing immunosuppressive chemotherapy. It is particularly helpful in conjunction with cisplatin, one of the most common drugs for solid tumors. Cisplatin causes nausea, kidney damage, nerve damage, hearing loss, and overall malaise, making treatment quite distressing for patients. The side-effect burden sometimes limits the dose and duration, thereby decreasing efficacy.
Researchers in Japan have reported some preliminary findings that further support the syngergistic role of AHCC and many other chemotherapy agents including 5-fluorouracil, paclitaxel (Taxol), cyclophosphamide (cytoxan), 6-mercaptopurine (Purinethol), methotrexate, and cytosine arabinoside (Ara-C).
Human studies are bearing out the expectations set by the animal trials. Dr. Reiki Ishizuka of the Tajima Clinic in Sapporo, has reported on increased survival and improved quality of life in patients with lung, breast and colon cancers who were taking AHCC along with their conventional chemotherapy treatments. Those taking AHCC had improved immune function. Although these findings are preliminary, there is a growing body of evidence to support the use of AHCC along with chemotherapy – to improve its benefits and to reduce its side effects.

Anti-cancer effect of polysaccharides isolated from higher basidiomycetes mushrooms

AS Daba, OU Ezeronye. African Journal of Biotechnology Vol. 2 (12), pp. 672-678, December 2003
Abstract
Anti-tumor activity of mushroom fruit bodies and mycelial extracts evaluated using different cancer cell lines. These polysaccharide extracts showed potent antitumor activity against sarcoma 180, mammary adenocarcinoma 755, leukemia L-1210 and a host of other tumors. The antitumor activity was mainly due to indirect host mediated immunotherapeutic effect. These studies are still in progress in many laboratories and the role of the polysaccharides as immunopotentiators is especially under intense debate. The purpose of the present review is to summarize the available information in this area and to indicate the present status of the research.

Active Hemicellulose Compound (AHCC) Enhances NK Cell Activity of Aged Mice in Vivo

Active Hemicellulose Compound (AHCC) is hemicellulose which originated from rice and is biologically modified using carbohydrase separated from Lentinus Edodes to increase its immunomodulatory function. In the present investigation, we evaluated the ability of AHCC to stimulate in vivo NK cytotoxic reactivity. Old C57BL/6 mice were injected i.p. daily at a concentration of 30 mg/kg/day. At 2, 5 and 14 days at post treatment, peritoneal erudite and apleen were examined for tissue cellularity and NK activity using 4-hr. Cr-release assay against YAC-1 tumor cells. The results demonstrate that; 1) AHCC generated peritoneal cytotoxic cells having the characteristics of NK cells with high levels of granularity. The induction was observed as early as 2 days, (750-900% of control) and maintained at high levels with continuous injections, 2) Peritoneal macrophage did not exhibit antitumor activity nor act as accessory cells for NK cells, 3) No significant induction of splenic NK cell activity, and 4) AHCC treated mice induced a significant increase in peritoneal (300-500%) and splenic cellularity (150-190%), suggesting that AHCC acts a mitogen factor in vivo. AHCC could be considered as a potent biological response modifier and its anti-cancer activity may be through post NK immunomodulation.
M. Ghoneum, Y. Ninomiya, M. Torabi, G. Gill and A. Wojani. C.