Cancer Slide

8/2/2019 Cancer Slide

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St i les Program in In t egrat iveSt i les Program in In t egrat ive

OncologyOncology

Herbal and Natural Products

for Cancer Prevention andTherapy

Richard J. Pietras, PhD, MD

Jonsson Comprehensive Cancer

Center, UCLA


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Herbs and Nat ura l

Produc t s in Canc er

The cancer problem

Brief history of complementary therapy

Unproven and proven therapies

Therapies in development for cancertreatment

Botanical approaches to cancerprevention

What you can do to stop cancer


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CANCER : The

33 Years War

Prayer, Stephanie Atkinson


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CANCER, The 33 Years War

National Cancer Act for War on Cancer passed in 1971Each day, 1,500 Americans die from cancer

More than 40% of men and 33% of women at risk forcancer in their lifetimes


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The Canc er Epidem ic

10,000,000 cases of cancer / year worldwide1,300,000 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 2/3rds of cancers may be avoidable orpreventable (Doll & Peto)

Personal changes in diet, lifestyle, habits

Environmental interventions

Control and vaccination for infection (hepB, h. pylori,

papillomavirus)


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Mul t ip le St eps in TumorForm at ion and Progress ion

normal cellpreneoplastic malignant

metastasis

metastasis

INITIATION PROMOTION PROGRESSION

Heredity Endocrine

Chemicals Nutrition Gene changes

Radiation Inflammation

Viruses

DNA Interaction


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Natura l H ist o ry and Treat m ent o fCancer

INITIATION

PROMOTION

PROGRESSION


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Current Canc er Therapy

Su rgery

Chemot he rapy Radia t ion Therapy

B io logic Therapy

Complem ent a ry Therapy Prevent ive Therapy


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Hippocra tes

Fat her o fmodern

m ed ic ine andherba l

p rac t i t i oner

460 -370 BC

His t ory of Com plem entary

Medic ine


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His to ry o f Com plement ary Med ic ine

Ancient Mesopotamia 3000 BC Sumerian Empire used plantmedicines for fever, stroke, lung and liver disease

Egyptian Medicine 2900-1550 BC Imhotep and >500 herbsfor rheumatism, diabetes, infections

Traditional Chinese Medicine 2900-2600 BC Neiching andyin-yang philosophy. Combines diet, >1800 herbs, and acu-puncture 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 thepatient, not just the disease, with diet as main treatment andherbs when diet alone not adequate


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His t ory o f Com plem ent ary

Med ic ine in t he Am eric as

Aztec and Mayan Medicine 1200 medicinal plants

Inca Medicine botanical medicines, incl coca plant

Native American Medicine > 500 medicinal herbsand natural products

Naturopathy herbs and spa cures in Europeantradition, with American Kellogg brothers at BattleCreek Sanitarium


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Complementary

Medic ines

WHO estimates that 80% of world

population relies on plant-basedmedicines for primary healthcare

75% of all pharmaceuticals werediscovered by examining use ofplants in traditional medicine


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Hope or Hype?Alternative medicine is edging into the

mainstream, with Californians leading the way.

The appeal is complex, and debate rages aboutits effectiveness and scientific oversight

ALTERNATIVE MEDICINE

The $18-Billion Experiment

Los Angeles Times


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Complementary and Alternative Therapies

Complementary Therapies - supportive methods tocomplement evidence-based methods :

meditation to reduce stress

acupuncture for relief of pain and nausea

Alternative Therapies - unproven or disproventreatments promoted as cures :

anecdotal reports

uncontrolled trials

traditional use suggesting lack of harm

American Cancer Society Guide to Complementary and Alternative Cancer Methods


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Al te rna t ive

Therapies


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Al t ernat ive Therap iesDisproven in Cl inic a l T r ia ls

Laetrile: cancer due to deficiency vitamin B17 (no suchvitamin); median survival 4.8 mo in advanced cancer pts

Livingston-Wheeler: cancer due to progenitor cryptocidesbacteria (but bacteria does not exist)

DiBella Multitherapy: cancer asstd with growth hormone

Antineoplaston: NCI trial in glioblastoma, TTP 29 days andall patients died before study closed

High-Dose Vitamin C: No change in colorectal cancersurvival


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Proven Ant i t um or Therap ies

Der ived f rom Nat ura l Sourc esPodophyllum peltatum, P. hexandrum:

etoposide

Catharanthus roseus (Madagascar periwinkle):

vincristine

vinblastine

Taxus brevifolia (Pacific Yew tree):

taxol (paclitaxel)

taxotere (docetaxel)


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Proven Ant i t um or Therap iesDer ived f rom Nat ura l Sourc es

Of 92 antitumor drugs approved 1983-1994, 62 (67%) wereof 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


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Complement a ry Therapies w i th

Pot ent ia l Benef i t in Canc er Prevent ionor Ther apy: Ongoing Cl in ic a l Tr ia l s

Saw Palmetto: BPH, prostate cancer?

Lycopene: prostate cancerBeta-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


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Trends in use of complementary medicine

42% Americans use some form of complementary therapy

629 million visits to alternative practitioners > primary carevisits

50-70% of breast cancer patients use some form ofcomplementary therapy

30% dietary therapy (megavitamins, supplements)

24% spiritual healing

21% herbal remedies

15% physical methods (acupuncture, massage)

10% psychological methods


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The Com m unic a t ion Gap

Dont ask, dont tell. Patients not talking tophysicians about their use of CAM.

Only 54% of breast cancer patients seeing a

CAM practitioner told their MD (

The doctornever asked)

94% cancer patients discussed their biomedicaltreatments with their CAM providers

On review by pharmacologists, 12% of herbaltreatments could interfere with conventionalcancer therapies


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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 drugeffectiveness; stringent guidelines for testing (preclinicaltoxicity, 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 proofof safety or efficacy required; burden of safety placed onFDA to remove products with compelling evidence of harm

2004 FDA bans dietary supplements with ephedra


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Diet ary Supplem ent s , AdverseEvent s , and Ef f ic ac y

FDA overload: 4,000 unregulated products in 1994when 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 HealthMinistry find 10%-32% of Chinese herbal productscontain undeclared drugs or heavy metals (lead,

mercury or arsenic

Randomized control trial evidence of clinical efficacyexists for < 30 herbs


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Herbal Therapies

Herbal supplements not standardized for safety,purity,efficacy

Standardized ginseng has defined % ginseno-sides, but more than 30 ginsenosides may

contribute to biologic effect; different suppliersprovide different amounts

Natural not necessarily beneficial

Drug effects (PC-SPES reduces PSA prostate CAbut decreases libido, breast enlarge, nausea,diarrhea, thromboembolism)

Unknown drug interactions


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Pot en t ia l Adu l te ran t s and

Cont am inant s in Herba l Preparat ions

Drugs warfarin, anti-inflammatory, corticosteroids,benzodiazepines, sildenafil, diethylstilbestrol

Toxic metals lead, cadmium, mercury, arsenicPesticides chlorinated pesticide, organic phosphate, triazin

herbicide, fungicide, carbamate insecticides

Microbes Staphylococcus aureus, E. coli, salmonella,

shigella, Pseudomonas aeruginosaToxins aflatoxin, bacterial endotoxins

Botanicals digitalis, rauwolfia, belladonna alkaloids

Wood (2002) NEJM 347 : 2046


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St J ohns Wort

Herb-Drug In t erac t ionsIndinavir and SJW

57% reduction in serum AUCof indinavir in 8 healthy ptswhen SJW taken with anti-retroviral (Lancet2000; 355:547)

SJW for clinical depression

increases cyto P450 enzymeand also alters levels of bloodpressure, epilpesy andcontraceptive medicines


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Spec i f ic r i sk s o f com p lem enta ry

t he rap ies in c ancer pa t ien tsTumor CAM Chemorx Concern

NHL echinacea Rituximab stimulates targeted B-cells

breast yam hormonal estrogenic effectsmilk thistle Taxol decrease taxol metabolism

kava kava chemorx hepatotoxicity

prost cod liver oil antithrombotic

ovary laetrile contains cyanide

any milk thistle adriamycin decreases drug metabolism


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Pot en t ia l Sys tem ic Adverse

Ef fec t s o f Herba l Rem ediesCardiotoxicity leigongteng, mahuang, licorice root,

colchicine-rich herbs, cardioactive-glycoside-rich herbs

Hepatotoxicity mahuang, kava rhizome, chaparral,herbs rich in anthranoids, podo-phyllotoxin, pyrrolizidine alkaloids

Renal toxicity chinese yew, impila root, jering fruit,

pennyroyal oil and certain essentialoils, star fruit

Neurotoxicity mahuang, kava rhizome, nuxvomica, aconite root tuber, star fruit


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Interactions in Radiation Therapy?

Vitamin E and other antioxidants may disruptefficacy of radiation therapy (data based onanimal studies)

Some research suggests that combinations ofvitamins A,C,E in higher doses may promotedamage 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 peripheraltissue damage


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Buyer Bew are:

Consum ers Cant Trust That Plant was accurately identified

Potency will be the same bottle-to-bottle

Herb is pure

Herb is safe

Herb is effective


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Adv ic e for Pat ient s Tak ing Herbs

Purchase only products labeled with name andpart of herb, batch or lot #, expiration date, nameand address of manufacturer

Choose manufacturer in business for a while orherbal 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


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How t o Find a Qual i t y

Product

Use information from independenttesting laboratories, such asConsumerLab.com

Look for a seal of approval, such asUSP, NSF

Look for products that have beentested in clinical trials


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Learn As Muc h As You Can

On the Internet:

Medline, PubMed

http://nccam.nih.gov

canceralternatives.mednet.ucla.edu

mskcc.org/aboutherbsNaturalStandard.com

Books:Evidence-Based Herbal Medicine by Rothblatt &

ZimentAmerican Cancer Society Guide to Complementary

and Alternative Cancer Methods


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Lobby for New Regulat orySafegua rds in Fede ral DHSEA

1. Register with FDA address, contact names of thosemanufacturing dietary supplements for sale in US

2. Provide evidence of good manufacturing practicesto prevent adulteration, to standardize products

3. Premarketing FDA approval to show that productshave no risk of injurywith recommended use

4. Manufacturers to report to FDA all adverse events

5. Labels to list all constituentsand inform about onadverse effects, including herb-drug interactions


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Evidenc e-Based Researc h:

Approac hes t o Disc overy o fNew Therapies

Surveys

Observational cohort studies

Case-Control Studies

Laboratory/Pre-clinical Models

Prospective Trials (phase I/II)

Controlled randomized trials (Phase III)


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St ra t eg ies for Bot an ic a l

Drug Disc overyHerbs or regimens

used historically forspecific indications

Phase I/IIsafety and

efficacystudies

Laboratorystudies of herbal

extracts

HPLC or othercompound

isolation strategy

Randomized,Controlled

Phase III Trials

Modified from Tripathy (2004)


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Use of scientific principles to develop

antitumor medicines from plants

Estimated 287,000 higher terrestrial plants, with 5.6

Med 3.9-5.6

Low < 3.9

Int. J. Cancer 106

: 264 (03)


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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, 95incident cases of colorectal cancer wererecorded after 17 years. Risk increased inassociation with smoking, alcohol, and whitebread consumption, and decreased with

frequent consumption of fruit. The relative riskin vegetarians compared with nonvegetarianswas 0.85 (95% CI)

British Journal of Cancer (2004)


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Chem opreven t ion Ini t i a t i ves

People eating 5 servings/day friuts & veggies have1/2 risk of developing cancer of those who eat < 2servings/ day

NCI identified 35 plant-based foods with cancer-

preventive 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 toidentify dietary determinants of cancer


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Mic ronut r ien t s and

Phytochemica lsAntioxidant vitamins in dark, leafy green vegetablesand yellow/orange fruits and vegetables reducecancer risk, especially the dietary ACE vitamins

(caution : excessive amounts promote some cancer)

About 1,000 non-nutritive phytochemicals havecancer-preventive activity, and more than 100phytochemicals are in one serving of vegetables

More than 400 potential agents now underinvestigation, and NCI sponsored 65 Phase I-IIItrials last year


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Nature Reviews

/Cancer (2003)


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Nut ragenomics

Herbal and natural product compounds disruptmolecular signaling pathways in precancerousand cancer cells

Specific genes may contribute to individualdifferences in susceptibility to cancer

With identification of high risk groups in the

future, specific dietary supplements may restorenormal cell signaling events

Designer foods and natural products


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Recommendat ions

Obtain most your nutrients and phytochemicals fromfoods 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


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The Prom ise of NewAnt i t umor Produc t s

Valuable p lants andnatura l p roduc t s may be

los t be fore the i r m ed ica luse can be d isc overed


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Defores t a t ion and t he loss o f spec ies


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Threat ened Spec ies in 2003

Group Number known Threatened

Mammal 4,842 1,130

Fish 28,100 750

Molluscs 70,000 967

Plants 287,655 6,774


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Diox inDiox in

MTBEMTBE

Chromium 6Chromium 6

SMOGSMOG

Agr iAgr i --chemica lschemica lsPest ic idesPest ic ides

OrganophosphatesOrganophosphates

Si len t Spr ing in t he Los Angeles Bas in

Mercury

DDT

PCBsAsbestosAsbestos


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A Tox ic Landsc ape

Dozens of toxic chemicals indoors inAmerican homes

Study of 120 residential homes inMassachusetts showed 67 carcinogenicchemicals in nail polish, hair-spray, somedetergents, household cleaners, pesticides

DDT, banned in US 30 years ago, found indust of 65% of homes

Environmental Science & Technol, 2003


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Suppor t Canc er Researc h :

I t Saves L ivesFederal 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)


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Acknow ledgemen ts

Stiles Fund JCCC/UCLADr. 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

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