Once regarded as fringe therapies, dietary supplements and botanicals have become the subjects of serious cancer research, particularly at the National Institutes of Health’s (Bethesda, MD) National Center for Complementary and Alternative Medicine (NCCAM) and Office of Dietary Supplements (ODS).
Clinical trials are proliferating. NCCAM, ODS, and the National Cancer Institute (NCI) are currently recruiting subjects for six cancer-related clinical trials with dietary supplements. Among the studies: the role of creatine in the treatment of amyotrophic lateral sclerosis; soy protein’s effect on hot flashes in postmenopausal women receiving tamoxifen; isoflavones and stage I or II prostate cancer; and a comparison of isoflavones and lycopene in presurgery stage I or II prostate cancer patients.
Armed with a research budget that grew from $10 million to $76 million, NCCAM has sponsored dozens of cancer-related studies. Many involve dietary supplements. For example, in a study released in April, researchers at Beth Israel Medical Center (New York City) found L-carnitine supplementation may benefit cancer patients suffering from fatigue. Columbia University (New York City) is recruiting for a study that will assess whether phytoestrogen dietary interventions can result in favorable effects on hormone-dependent cancers, cardiovascular disease, and osteoporosis. And the University of Kansas Medical Center (Kansas City, KS) is recruiting for a double-blind randomized ginseng and ginkgo study. The investigation will examine ginseng and ginkgo and enzymes implicated in cancer chemoprevention.
Why the emphasis on supplements? Despite the torrid pace of medical advances, Americans are turning to alternative therapies in ever-increasing numbers. According to NCCAM, about 83 million people spend $22 billion on alternative therapies. NCCAM feels it is essential to evaluate the safety and efficacy of these treatments, including the use of dietary supplements. So does ODS. Its 2005 priorities include “expanded emphasis on the application of new and emerging technologies such as genomics and proteomics to identify specific actions of selected dietary supplements on subcellular and cellular systems as well as on tissues and organ systems in order to enhance knowledge of how these substances produce or influence harmful biochemical, physiological, and psychological effects.”
Clearly, interest in alternative therapies will push government-sponsored and independent research for years to come. The following small sample of recent studies shows the depth of current research concerning botanicals and specialty ingredients.
ZINC AND PROSTATE CANCER
Zinc has been found in high concentrations in the prostate, leading researchers to speculate about the relationship between zinc and prostate cancer. Researchers at the University of Maryland’s department of biomedical sciences (Baltimore) reported in the June issue of Prostate Cancer and Prostatic Diseases that the most consistent biochemical characteristic of prostate cancer is a decrease in zinc and citrate levels in malignant cells. The inability to accumulate zinc was identified as an important factor in the development and progression of prostate malignancy. The researchers recommended further studies to determine if restoring high zinc levels in malignant cells could be an efficacious treatment for prostate cancer.
That study builds on a previous one published in the Journal of the National Cancer Institute in July 2003. A National Cancer Institute team studied the link between supplemental zinc intake and prostate cancer risk in 46,974 men participating in the 14-year Health Professionals Follow-Up Study. They found supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, they also found that men who consumed more than 100 mg/day of supplemental zinc had a slightly higher relative risk of advanced prostate cancer. The results might have been confounded by supplemental calcium intake or unmeasured correlate of zinc supplement use. However, the researchers felt the result warranted further investigation.
Lycopene is the supplement most strongly associated with positive effects on prostate cancer. The mechanism by which lycopene affects cancerous prostate epithelial cells was studied by the Carotenoid Section of DSM Nutritional Products’ Human Nutrition and Health group (Basel, Switzerland). The group published an investigation of lycopene in the Archives of Biochemistry and Biophysics.
DSM’s preclinical studies showed that lycopene acts via different mechanisms, which have the potential to cooperate in reducing the proliferation of normal and cancerous prostate epithelial cells, in reducing DNA damage, and in improving oxidative stress defense. The mechanisms include inhibition of prostatic IGF-I signaling, IL-6 expression, and androgen signaling. The novel finding that lycopene reduces local androgen signaling in the prostate also suggests efficacy in the prevention of benign prostate hyperplasia. Intervention trials in humans are required to finally prove clinical efficacy of the lycopene molecule in prostate health.
In September, Columbia University Medical Center began what may be the first Phase I clinical study to determine if an herbal supplement commonly used as an antiinflammatory can prevent prostate cancer in patients with prostatic intraepithelial neoplasia (PIN). Without intervention, men diagnosed with PIN have a 50–70% chance of developing prostate cancer, according to Aaron Katz, MD, associate professor of urology at Columbia University College of Physicians and Surgeons, director of the Center of Holistic Urology at Columbia University Medical Center, and principal investigator of the study.
Up to 48 men aged 40–75 will receive the herbal supplement Zyflamend three times a day for 18 months. Zyflamend, from New Chapter Inc. (Brattleboro, VT), is composed of standardized extracts of herbs with COX-2 inhibitory activity. According to Katz and colleagues at Columbia University in New York, the herbs include rosemary, turmeric, ginger, holy basil, and green tea. Other components of Zyflamend are derived from hu zhang, Chinese goldthread, barberry, oregano, and Scutellaria baicalensis.
In previous studies, incubation of LNCaP prostate cancer cells with Zyflamend led to a 78% reduction in cell number after 72 hours. Analysis of PARP cleavage products and caspase-3 activity suggest that the cell reduction was due to apoptosis. Furthermore, Zyflamend activity was greater than that exerted by curcumin alone, the active ingredient in turmeric. The researchers’ findings also indicate that COX-2 activity was significantly decreased even though COX-2 protein expression was unaffected.
Katz recommends Zyflamend for patients at high risk for recurrence after surgery or radiation therapy for prostate cancer. “It’s too early to tell if it will prevent recurrence, but I do know the extract was well tolerated,” he says. “From our results in the lab, I feel that Zyflamend is a promising, novel phytotherapeutic agent for prostate cancer.”
SUPPLEMENT USAGE STUDIES
How dietary supplements are used is an important question for research scientists. The University of Cincinnati and the Veterans Administration Medical Center (Cincinnati) collaborated to study the patterns of dietary supplement use in veterans with cancer. The study, published in the Journal of Alternative and Complementary Medicine, concluded that veterans with cancer commonly use dietary supplements. The authors recommended that healthcare professionals should inquire about supplements in a systematic fashion and provide counseling if necessary.
In the study, 200 volunteers, median age 68 years old, with malignancies, recorded the type, frequency, reason for use, and source of the dietary supplements they consumed, along with the perceived benefits. The majority—61%—took dietary supplements. Approximately 80% took multivitamins, 41% took minerals, and 10 patients took herbal supplements. Some 38% of the patients did not disclose dietary supplement use to their physicians. Another 38% learned about dietary supplements from their physicians. About 25% obtained their dietary supplements from the VA hospital.
The number of patients using dietary supplements reflects estimates that herbal products have made significant inroads among cancer patients. Unfortunately, the study also suggests many patients do not tell their healthcare provider about their supplements.
NCI performed a literature review to determine if known or suspected interactions exist among the 15 best-selling herbs in the United States and allopathic therapies for cancer. As published in the Journal of Clinical Oncology, herbs with the potential to alter the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and the drug transporter P-glycoprotein, include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St. John’s wort (Hypericum perforatum), and kava (Piper methysticum). NCI suggested that healthcare professionals communicate with patients about the potential for adverse reactions. The study also urged doctors to talk with patients whose disease is not responding to treatments as expected, as herbs could affect their care.
Scientific interest in long-chain polyunsaturated fatty acids (LCPUFAs), particularly omega-3s, is intensifying. Researchers are investigating LCPUFAs’ preventive effects as well as their effects on cancer symptoms. The Université de Montréal’s Epidemiology Research Unit recently published evidence that a diet rich in both lutein, zeaxanthin, and LCPUFAs may help prevent colon cancer in French-Canadian females. A total of 200 male and 202 female colorectal patients, and 688 population-based control subjects matched for age, gender, and place of residence, were interviewed. Dietary intake information on more than 200 food items and recipes was collected and assessed with a validated food-frequency questionnaire. After adjusting for variables such as total energy intake, no association was found between dietary intake of carotenoids and colon cancer risk. However, an inverse relationship was found in women with high intakes of lutein, zeaxanthin, and LCPUFAs.
Among people who had never smoked, a significantly reduced risk of colon cancer was associated with intake of beta-carotene, whereas an inverse association was found between lycopene intake and colon cancer risk.
High doses of fish oil may help slow weight loss for patients with malignancy-related cachexia, according to a report in the July issue of Cancer. Researchers at the University of Iowa’s Roy J. and Lucille A. Carver College of Medicine (Iowa City, IA) gave 43 patients with advanced malignancy and weight loss (2% of body weight in the month before the study) omega-3 fatty acid capsules consisting of 7.5 g of eicosapentaenoic acid and docosahexaenoic acid per 70 kg of body weight. The median treatment was 1.2 months.
Of the 36 patients who took at least 1 capsule and did not have edema, weight change ranged from –6.2 kg to +3.5 kg, with an overall median weight loss of 0.8 kg. The weight of 24 patients stabilized, while six patients gained more than 5% of their body weight. Six patients lost at least 5% of their body weight. The researchers noticed variability in the tolerability of the capsules, and gastrointestinal side effects. While the majority of patients did not gain weight, the research team felt omega-3 fatty acids had potential utility at the study doses, which were more than twice the doses used in published Phase III studies.
Like all research involving supplements, the results are far from conclusive. In the July issue of the American Journal of Clinical Nutrition, NCI’s Nutritional Epidemiology Branch published a reminder that more work must be done. Scientists investigated whether omega-3 fatty acids inhibit, and omega-6 fatty acids stimulate, prostate tumor growth. They found increased dietary intakes of alpha-linolenic acid (ALA; 18:3n-3) may increase the risk of advanced prostate cancer, while eicosapentaenoic acid (EPA; 20:5n-3), and docosahexaenoic acid (DHA; 22:6n-3) may reduce the risk of total and advanced prostate cancer.
During the study, 47,866 men aged 40–75 with no cancer history were followed from 1986 to 2000. A total of 2965 new cases of prostate cancer developed, 448 of which were advanced. ALA intake was unrelated to the risk of total prostate cancer. But the multivariate relative risks of advanced prostate cancer from comparisons of extreme quintiles of ALA from nonanimal sources and ALA from meat and dairy sources were significantly higher than those for EPA and DHA.
Like the vast majority of studies, the conclusions are by no means definitive. More work is needed to pinpoint the role of nutrition in the battle against cancer. Fortunately, with help and support from NCCAM and ODS, the effort to find the answers is under way.