Download “Herbal and Natural Products for Cancer Prevention and Therapy” Stiles Program in Integrative

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