Stiles Program in Integrative Oncology “Herbal and Natural Products for Cancer Prevention and Therapy” Richard J. Pietras, PhD, MD Jonsson Comprehensive Cancer Center, UCLA Herbs and Natural Products in Cancer The cancer problem Brief history of complementary therapy Unproven and proven therapies Therapies in development for cancer treatment Botanical approaches to cancer prevention What you can do to stop cancer CANCER : The 33 Years War Prayer , Stephanie Atkinson CANCER, The 33 Years War National Cancer Act for “War on Cancer” passed in 1971 Each day, 1,500 Americans die from cancer More than 40% of men and 33% of women at risk for cancer in their lifetimes The Cancer Epidemic 10,000,000 cases of cancer / year worldwide 1,300,000 cases of cancer per year in US 6,000,000 deaths from cancer per year worldwide WHO projects 15 million cases / year in 2020 Up to 2/3rd s of cancers may be avoidable or preventable (Doll & Peto) Personal changes in diet, lifestyle, habits Environmental interventions Control and vaccination for infection (hepB, h. pylori, papillomavirus) Multiple Steps in Tumor Formation and Progression Heredity Chemicals Radiation Endocrine Nutrition metastasis Gene changes Inflammation Viruses normal cell preneoplastic malignant DNA Interaction metastasis INITIATION PROMOTION PROGRESSION Natural History and Treatment of Cancer PROGRESSION PROMOTION INITIATION Current Cancer Therapy • Surgery • Chemotherapy • Radiation Therapy • Biologic Therapy • Complementary Therapy • Preventive Therapy History of Complementary Medicine Hippocrates Father of modern medicine and herbal practitioner 460-370 BC History of Complementary Medicine Ancient Mesopotamia 3000 BC Sumerian Empire used plant medicines for fever, stroke, lung and liver disease Egyptian Medicine 2900-1550 BC Imhotep and >500 herbs for rheumatism, diabetes, infections Traditional Chinese Medicine 2900-2600 BC Neiching and yin-yang philosophy. Combines diet, >1800 herbs, and acupuncture to enhance, restore health Ayurvedic Medicine 800 BC- 1000 AD Indian healing system with diet, herbs, exercise, meditation, massage, light Greek Medicine 500 BC Hippocrates emphasized treating the patient, not just the disease, with diet as main treatment and herbs when diet alone not adequate History of Complementary Medicine in the Americas Aztec and Mayan Medicine 1200 medicinal plants Inca Medicine botanical medicines, incl coca plant Native American Medicine > 500 medicinal herbs and natural products Naturopathy herbs and spa cures in European tradition, with American Kellogg brothers at Battle Creek Sanitarium Complementary Medicines WHO estimates that 80% of world population relies on plant-based medicines for primary healthcare 75% of all pharmaceuticals were discovered by examining use of plants in traditional medicine Hope or Hype? Alternative medicine is edging into the mainstream, with Californians leading the way. The appeal is complex, and debate rages about its effectiveness and scientific oversight ALTERNATIVE MEDICINE The $18-Billion Experiment Los Angeles Times Complementary and Alternative Therapies Complementary Therapies - supportive methods to complement evidence-based methods : meditation to reduce stress acupuncture for relief of pain and nausea Alternative Therapies - unproven or disproven treatments promoted as cures : anecdotal reports uncontrolled trials traditional use suggesting lack of harm American Cancer Society Guide to Complementary and Alternative Cancer Methods Alternative Therapies Alternative Therapies Disproven in Clinical Trials Laetrile: cancer due to deficiency vitamin B17 (no such vitamin); median survival 4.8 mo in advanced cancer pts Livingston-Wheeler: cancer due to progenitor cryptocides bacteria (but bacteria does not exist) DiBella Multitherapy: cancer asstd with growth hormone Antineoplaston: NCI trial in glioblastoma, TTP 29 days and all patients died before study closed High-Dose Vitamin C: No change in colorectal cancer survival Proven Antitumor Therapies Derived from Natural Sources Podophyllum peltatum, P. hexandrum: etoposide Catharanthus roseus (Madagascar periwinkle): vincristine vinblastine Taxus brevifolia (Pacific Yew tree): taxol (paclitaxel) taxotere (docetaxel) Proven Antitumor Therapies Derived from Natural Sources Of 92 antitumor drugs approved 1983-1994, 62 (67%) were of natural origin: based on natural cmpd: Actinomycin D Vincristine aminoglutethemide Asparaginase Epirubicin cytosine arabinoside Bleomycin Estramustine floxuridine Daunomycin Etoposide fluorouracil Doxorubicin Idarubicin goserelin acetate Mithramycin Irinotecan methotrexate Paclitaxel Megestrol mitoxantrone Streptozocin Vinorelbine tamoxifen Vinblastine Leuprolide faslodex Complementary Therapies with Potential Benefit in Cancer Prevention or Therapy: Ongoing Clinical Trials Saw Palmetto: BPH, prostate cancer? Lycopene: prostate cancer Beta-Glucans: lymphoma, activate complement receptor-3 to promote antitumor immunity Squalamine: non-small cell lung cancer, ovarian cancer Scutelleria: prostate, breast cancers Green tea: breast cancer, prostate cancer, oral cancers Trends in use of complementary medicine 42% Americans use some form of complementary therapy 629 million visits to alternative practitioners > primary care visits 50-70% of breast cancer patients use some form of complementary therapy 30% dietary therapy (megavitamins, supplements) 24% spiritual healing 21% herbal remedies 15% physical methods (acupuncture, massage) 10% psychological methods Why Do People Use Complementary Therapy? Safer and more natural Holistic My complementary practitioner spends more time and treats me as a whole person Symptom relief (pain, nausea) The Communication Gap Don t ask, don t tell. Patients not talking to physicians about their use of CAM. Only 54% of breast cancer patients seeing a CAM practitioner told their MD ( The doctor never asked ) 94% cancer patients discussed their biomedical treatments with their CAM providers On review by pharmacologists, 12% of herbal treatments could interfere with conventional cancer therapies Federal Drug Law 1906 Pure Food and Drug Act : truthful labeling (TR) 1938 Food, Drug and Cosmetic Act : safety testing 1962 Food, Drug and Cosmetic Act : proof of drug effectiveness; stringent guidelines for testing (preclinical toxicity, efficacy, controlled clinical trials)(JFK) thalidomide and phocomelia 1994 Dietary Supplement Health and Education Act : allows OTC sale of herbals and food supplements for general health maintenance without FDA review; no proof of safety or efficacy required; burden of safety placed on FDA to remove products with compelling evidence of harm 2004 FDA bans dietary supplements with ephedra Dietary Supplements, Adverse Events, and Efficacy FDA overload: 4,000 unregulated products in 1994 when DSHEA passed, but more than 29,000 now In 2001, FDA had 500 reports of adverse events due to supplements; and 19,468 at poison-control centers FDA, California Dept of Health and Japanese Health Ministry find 10%-32% of Chinese herbal products contain undeclared drugs or heavy metals (lead, mercury or arsenic Randomized control trial evidence of clinical efficacy exists for < 30 herbs Herbal Therapies Herbal supplements not standardized for safety, purity,efficacy Standardized ginseng has defined % ginsenosides, but more than 30 ginsenosides may contribute to biologic effect; different suppliers provide different amounts Natural not necessarily beneficial Drug effects (PC-SPES reduces PSA prostate CA but decreases libido, breast enlarge, nausea, diarrhea, thromboembolism) Unknown drug interactions Potential Adulterants and Contaminants in Herbal Preparations Drugs warfarin, anti-inflammatory, corticosteroids, benzodiazepines, sildenafil, diethylstilbestrol Toxic metals lead, cadmium, mercury, arsenic Pesticides chlorinated pesticide, organic phosphate, triazin herbicide, fungicide, carbamate insecticides Microbes Staphylococcus aureus, E. coli, salmonella, shigella, Pseudomonas aeruginosa Toxins aflatoxin, bacterial endotoxins Botanicals digitalis, rauwolfia, belladonna alkaloids Wood (2002) NEJM 347 : 2046 St John’s Wort Herb-Drug Interactions Indinavir and SJW 57% reduction in serum AUC of indinavir in 8 healthy pts when SJW taken with antiretroviral (Lancet 2000; 355:547) SJW for clinical depression increases cyto P450 enzyme and also alters levels of blood pressure, epilpesy and contraceptive medicines Specific risks of complementary therapies in cancer patients Tumor CAM Chemorx Concern NHL Rituximab stimulates targeted B-cells hormonal estrogenic effects milk thistle Taxol decrease taxol metabolism kava kava chemorx hepatotoxicity echinacea breast yam prost cod liver oil antithrombotic ovary laetrile any milk thistle contains cyanide adriamycin decreases drug metabolism Potential Systemic Adverse Effects of Herbal Remedies Cardiotoxicity leigongteng, mahuang, licorice root, colchicine-rich herbs, cardioactiveglycoside-rich herbs Hepatotoxicity mahuang, kava rhizome, chaparral, herbs rich in anthranoids, podophyllotoxin, pyrrolizidine alkaloids Renal toxicity chinese yew, impila root, jering fruit, pennyroyal oil and certain essential oils, star fruit Neurotoxicity mahuang, kava rhizome, nux vomica, aconite root tuber, star fruit Interactions in Radiation Therapy? Vitamin E and other antioxidants may disrupt efficacy of radiation therapy (data based on animal studies) Some research suggests that combinations of vitamins A,C,E in higher doses may promote damage to cancer cells and protect normal cells; clinical trial of this strategy ongoing at Henry Ford Hospital in Michigan Many botanicals contain substances that can enhance photosensitivity and increase peripheral tissue damage Buyer Beware: Consumers Can’t Trust That Plant was accurately identified Potency will be the same bottle-tobottle Herb is pure Herb is safe Herb is effective Advice for Patients Taking Herbs Purchase only products labeled with name and part of herb, batch or lot #, expiration date, name and address of manufacturer Choose manufacturer in business for a while or herbal products of major pharmaceutical firms Use multiple herbs with caution Talk with your practitioner and pharmacist about possible herb-drug interactions Consider stopping herbs before elective surgery Learn as much as you can How to Find a Quality Product Use information from independent testing laboratories, such as ConsumerLab.com Look for a seal of approval , such as USP, NSF Look for products that have been tested in clinical trials Learn As Much As You Can On the Internet: Medline, PubMed http://nccam.nih.gov canceralternatives.mednet.ucla.edu mskcc.org/aboutherbs NaturalStandard.com Books: Evidence-Based Herbal Medicine by Rothblatt & Ziment American Cancer Society Guide to Complementary and Alternative Cancer Methods Lobby for New Regulatory Safeguards in Federal DHSEA 1. Register with FDA address, contact names of those manufacturing dietary supplements for sale in US 2. Provide evidence of good manufacturing practices to prevent adulteration, to standardize products 3. Premarketing FDA approval to show that products have no risk of injury with recommended use 4. Manufacturers to report to FDA all adverse events 5. Labels to list all constituents and inform about on adverse effects, including herb-drug interactions Evidence-Based Research: Approaches to Discovery of New Therapies Surveys Observational cohort studies Case-Control Studies Laboratory/Pre-clinical Models Prospective Trials (phase I/II) Controlled randomized trials (Phase III) Strategies for Botanical Drug Discovery Herbs or regimens used historically for specific indications Phase I/II safety and efficacy studies Randomized, Controlled Phase III Trials Laboratory studies of herbal extracts HPLC or other compound isolation strategy Modified from Tripathy (2004) Use of scientific principles to develop antitumor medicines from plants Estimated 287,000 higher terrestrial plants, with < 10% investigated for medical application Ethnobotanical data important for drug leads Rational target-based drug discovery for screening using data from DNA microarrays, proteomics, molecular signal transduction Evaluation of purity, safety, interactions Natural products as templates for new drug discovery Natural Products in Testing for Cancer Prevention and Treatment Squalamine for lung and ovarian cancer Scutellaria baicalensis for breast and prostate cancer Beta-Glucans in antitumor antibody therapy Natural foods in the diet and survival in ovarian and colorectal cancer Lung Cancer The leading cause of cancer mortality in men and women Lung Cancer in US Women A Contemporary Epidemic Age-adjusted death rates for lung cancer and breast cancer among women, US, 1930-1997 (Patel et al. JAMA 291 : 1763, 2004) Therapy for Advanced Lung Cancer Modest improvement in past 20 years Response rates to combination cytotoxic chemotherapies about 20-25% Median survival 8-10 months Need for development of rationally designed therapeutics, possibly targeting tumor and tumor-associated cells Schiller et al. NEJM 2002 TumorAssociated Angiogenesis SQUALAMINE Blocks blood vessel growth in tumors H3C H3C Starves tumors H3C O O S O O CH3 CH3 + H3N + N H 2 + N H 2 H OH • Natural steroid, now synthesized in laboratory • Recent “orphan drug” designation by FDA Squalamine blocks vascular growth factor (VEGF)-induced reorganization and growth of tumor-associated endothelial cells CON SQ VEGF VEGF + SQ pFAK (Focal Adhesion Kinase) / F-actin (phalloidin) Phase I/IIA study of squalamine in lung cancer Stage IIIB/IV chemo-naïve non-small cell lung cancer: squalamine (5day CI) + paclitaxel (225 mg/m2) + carboplatin (AUC 6) Q 21 days 45 pts enrolled (18 phase I, 27 phase IIA) Little to no squalamine-related toxicity and no drug interactions 43 evaluable for response : 28% PR, 19% stable disease based on ITT Clinical benefit 47% Median survival = 10 months; 1-year survival = 40% 40% completed full 6-cycle regimen as planned More frequent dosing of squalamine showing improved RR in new phase II trials underway Clin Cancer Res 2003 Antitumor Activity of Squalamine in Human Ovarian Cancer 4000 CA-125 LEVEL 3000 2000 1000 0 0 50 100 150 200 250 Days after treatment Phase II clinical trials in patients with advanced platinum-refractory or-resistant malignancy Proc. ASCO (2003) Herbals from Traditional Chinese Medicine (TCM) for Breast Cancer Centuries-long Tradition of Use and Experience Based on Written Texts and Documentation Some Conformity and Reproducibility in Practice Licensed Profession in Many States and in Wide Use by Patients Preparation of Extracts from Chinese Herbs for Preclinical Testing More than 120 herbs reported to have breast selectivity in TCM practice Preparation of selected herbal extracts (UCLA’s CDSRB) Campbell et al. (2002) Herb, Scutellaria baicalcinosis, blocks activation of MAP Kinase by growth factors and estrogen in human breast cancer cells CON GF GF/HE Growth Factor (GF) Scutellaria (HE) Scutellaria Stops Breast Cancer Cell Growth 100 Cell proliferation (% control) 90 80 MCF-7/HER-2 70 60 50 40 30 MCF-7 Parent 20 10 0 0 10 20 30 40 50 60 70 80 Herbal extract (mcg/ml) 90 100 β-Glucans and Antitumor Antibodies β-glucans are polymers of glucose extracted from barley, mushroom, yeast and seaweed β-glucans prime white blood cells bearing complement receptors (CR3) for enhanced tumor cell killing and may synergize with antitumor antibodies, such as Rituxan, Herceptin, Erbitux Oral forms in testing Percentage tumor size β-Glucans Enhance Antitumor Effect of Herceptin in Preclinical Model 175 165 155 145 135 125 115 105 95 85 H erceptin β-glucan combination 0 Figure 3. 5 10 15 20 25 30 Days from first treatm ent Cancer Immunol Immunother (2002) Dietary influence on survival after ovarian cancer 609 women with new diagnosis ovarian cancer followed for 7 years after diagnosis and treatment Those who ate most vegetables and vitamin E-rich foods in year before diagnosis most likely to survive 5 years after diagnosis Nutrients via supplements had less effect Cruciferous vegetables (cabbage, cauliflower, broccoli) had greatest benefit Nagle et al. Int J Cancer 106 : 264, 2003 Vegetable Consumption Improves Survival of Cancer Patients High > 5.6 Med 3.9-5.6 Low < 3.9 Int. J. Cancer 106 : 264 (03) Nutrition, lifestyle and colorectal cancer incidence: a prospective investigation of 10,998 vegetarians and non-vegetarians in the United Kingdom In a cohort of 10,998 men and women, 95 incident cases of colorectal cancer were recorded after 17 years. Risk increased in association with smoking, alcohol, and white bread consumption, and decreased with frequent consumption of fruit. The relative risk in vegetarians compared with nonvegetarians was 0.85 (95% CI) British Journal of Cancer (2004) Chemoprevention Initiatives People eating 5 servings/day friuts & veggies have 1/2 risk of developing cancer of those who eat < 2 servings/ day NCI identified 35 plant-based foods with cancerpreventive activity : garlic, soybean, ginger, onion, tumeric, tomatoe and cruciferous vegetables NCI Five-A-Day for Better Health Program encourages eating fruits & veg 5 servings/day European Prospective Investigation of Cancer & Nutrition (EPIC) - enrolled 520,000 subjects to identify dietary determinants of cancer Micronutrients and Phytochemicals Antioxidant vitamins in dark, leafy green vegetables and yellow/orange fruits and vegetables reduce cancer risk, especially the dietary ACE vitamins (caution : excessive amounts promote some cancer) About 1,000 non-nutritive phytochemicals have cancer-preventive activity, and more than 100 phytochemicals are in one serving of vegetables More than 400 potential agents now under investigation, and NCI sponsored 65 Phase I-III trials last year Nature Reviews /Cancer (2003) Nutragenomics Herbal and natural product compounds disrupt molecular signaling pathways in precancerous and cancer cells Specific genes may contribute to individual differences in susceptibility to cancer With identification of high risk groups in the future, specific dietary supplements may restore normal cell signaling events Designer foods and natural products Recommendations Obtain most your nutrients and phytochemicals from foods rather than supplements Eat in moderation from a variety of food groups, especially fruits and vegetables (5 per day) Favor dishes with multi-plant based ingredients: salads, soups; add leafy greens to sandwiches Maintain a healthy weight DO NOT SMOKE The Promise of New Antitumor Products Valuable plants and natural products may be lost before their medical use can be discovered Deforestation and the loss of species Threatened Species in 2003 Group Mammal Number known Threatened 4,842 1,130 Fish 28,100 750 Molluscs 70,000 967 287,655 6,774 Plants “Silent Spring” in the Los Angeles Basin Agri-chemicals Pesticides Chromium 6 Organophosphates MTBE PCBs Mercury DDT SMOG Asbestos Dioxin A Toxic Landscape Dozens of toxic chemicals indoors in American homes Study of 120 residential homes in Massachusetts showed 67 carcinogenic chemicals in nail polish, hair-spray, some detergents, household cleaners, pesticides DDT, banned in US 30 years ago, found in dust of 65% of homes Environmental Science & Technol, 2003 Support Cancer Research : It Saves Lives Federal National Cancer Institute budget for 2004: $4.77 billion (0.2% of federal spending) New NCI budget falls below funds received in FY2003 California Cancer Research Program budget for 2004: $ 0 (applications closed) State support for the University of California for 2004: 16% less than 2003 (32% less than 2002) Acknowledgements Stiles Fund JCCC/UCLA Dr. Michael Tobias Diana Marquez Jane Morrison Hsiao-Wang Chen Rebecca Rausch Cary Freeny Wells Fargo Foundation David Heber Steve Dubinett California BCRP Judith Gasson Lonnie Zeltzer US Army OCRP Dennis Slamon