Transcript Slide 1

Cancer, Supplements, and Food
When and What is OK?
Dr. Tom Archie, MD, DABFP, DABMA
Wood River Cancer Guides - Hailey, ID
Updated as of 2006
www.drtomsalchemy.com
What is a
Cancer Guide?
If each day falls
inside each night,
there exists a well
where clarity is imprisoned.
We need to sit on the rim
of the well of darkness
and fish for fallen light.
- Pablo Neruda
Information Sources





CancerGuides – Center for Mind-Body
Medicine, National Cancer Inst, NIH
Food as Medicine (same institutions)
Journal: Integrative Cancer Therapies
Society for Integrative Oncology
John Boik: Natural Compounds in Cancer
Therapy
Information Sources




Yance and Sagar. Targeting Angiogenesis with Integrative
Cancer Therapies. Integrative Canc Ther. 2006;5(1):9.
Moss. Should Patients Undergoing Chemotherapy and
Radiotherapy Be Prescribed Antioxidants? Integr Canc Ther.
2006;5(1):63.
Lamson and Brignall. Antioxidants and Cancer Therapy: Their
Actions and Interactions with Oncologic Therapies. Altern Med
Rev. 1999;4(5):304.
McCarty and Block. Multifocal Angiostatic Therapy: An Update.
Integr Canc Ther. 2005;4(4):301.
Overview






Angiogenesis and Metastasis
Growth Factors, pro-angiogenesis
pathways
Metronomic Model
Supplements in Angiogenesis
Primary and Secondary Prevention
Controversies re: “concurrent use”
(during chemo- or radio-therapy)
Angiogenesis
The regulated formation of new
blood vessels from existing ones
Critical for tumor growth and
metastasis
Control angiogenesis – limit cancer
spread, morbidity, and mortality
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
Angiogenesis
(see diagram)




1. Endothelial cells (form the inside lining of
blood vessels) “ECs”
2. ECs stimulated by angiokinins, matrix
metalloproteinase (MMP), heparinases, VEFG
(vascular endothelial growth factor)
3. Extracellular Matrix (ECM) – framework
outside cells – dissolves
4. Tight junctions (between ECs) disrupted
Angiogenesis
(see diagram)



5. Opening occurs between ECs in the
wall of blood vessel
6. Growth Factors stimulate ECs to
multiply and move into space left over
by dissolution of ECM
7. New ECs develop tubular organization
form new blood vessel sprout
Metastasis



1. Transformation of normal cells into
tumor cells
2. Local growth of tumor (diffusion of
nutrients)
3. Angiogenesis (necessary for tumor to
grow over 1 mm) – recruit nearby blood
vessels
Metastasis




4. Local Invasion (through thin walls of
small arterioles/lymphatics)
5. Detachment and embolization (stuck
in capillary beds)
6. Invasion of new host organ
7. Proliferation
Angiogenesis
Necessary
for
Metastasis
Two Major Factors
Promoting Cancer

Absence of normal inhibitors of angiogenesis


INF-B (interferon-B) blocks IL-8, basic fibroblast
growth factor (bFGF) and collegenase type V
Overexpression of VEGF



Vascular Endothelial Growth Factor
Stimulate proliferation and migration of
endothelial cells (angiogenesis)
Increases tumor growth and metastasis
VEGF



Production of VEGF considered
essential to angiogenesis and metastasis
High levels ~ worse outcome
Increased by



Oncogenes H-ras, K-ras, src, p53, C-jun
Growth Factors (EGF/HER1, TGF-a, insulin-like
growth factor-1, platelet-derived growth factor
NFkB
Metronomic Dosing

Chronic use of low doses of
chemotherapy


Intent of inhibiting angiogenesis and
minimizing toxicity
Potential role in increasing survival and
quality of life (not necessarily diseasefree)
Metronomic Dosing

“When designing cytokine-targeted antiangiogenic growth
factors, one must also take into account the tumor
microenvironment.” (includes extracellular matrix, tissue, and
specific intrinsic factors in those cells)
“The more specific the intervention is to one domain of the
angiogenic pathway, the less likely there will be a beneficial
reduction in tumor growth, since alternative pathways can
compensate.”
Yance, Sagar. Integative Cancer Therapies. Vol 5 (1). 2006. p 12.
curcmin, artemsia,
mistletoe, ginger
scutellaria,
resveratrol,
grapeseed extract,
green tea, gingko, ginger
squalamine, Vit D
artemsia
silymarin, glycine, mistletoe
curcumin
scutellaria
VEGFR
curcmin,
scutellaria,
cartilege,
silymarin,
green tea
EGCG, silymarin,
quercetin,
resveratrol, soy
isoflavones,
curcumin, EPA
Multifocal
Angiostatic
Therapy
Cu antagonists
bFGFR and TNF-1:
Growth
Factors
NFkB
COX-2
Cu antagonists
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
Silymarin,
Glycine, Ginger
Anti-GFs:
green tea
quercetin
magnolia
resveratrol,
soy, curcumin
holy basil
rosemary
ganoderma
licorice Vit E
Anti-COX-2: quercetin,
scutellaria, EPA/DHA, licorice,
ginger, resveratrol, grapeseed
extract, curcumin, salicylates,
garlic, green tea, panax ginseng,
silymarin, bilberry, antioxidants,
boswellia, aloe
Anti- NFkB: poria,
coriolus, ginger,
resveratrol, green tea,
artemsia, quercetin,
carnosol, panax ginseng,
silymarin, salicylates,
curcumin, picentannol,
basil, Cu antagonists
rosemary
Pathway Players

NF-kB




Nuclear transcription factor
Stimulated by IL-1
Increased in tissue inflammation and cancer
Causes overactivation of COX-2 pathway


Increased angiogenesis
Inhibited by

Resveratrol, piceatannol, curcumin, green tea, ginger, holy
basil, panax ginseng, carnosol (rosemary)
Pathway Players

COX-2



Enzyme converts arachidonic acid to inflammatory
prostaglandins (PGE2 family)
Increases angiogenesis
Blocked by


EPA/DHA, licorice, ginger, aloe, green tea, resveratrol,
garlic, scutellaria, bilberry, grapeseed extract, panax
ginseng, silymarin, green-lipped mussel, boswellia,
bromelain, curcumin, quercetin
Antioxidants: Vit A, C, E, selenium, zinc, carotenoids,
flavonoids, CoQ10, N-acetyl cysteine, alpha lipoic acid
Pathway Players

Protein Kinases




Control progression of cell’s cycle of proliferation
Mutations common in breast and bladder CA and
CML
Ex: Abl, Src, cyclin-depedent kinases, PKC
Inhibited by

Holy basil, rosemary, genistein, daidzein, curcumin, Vit E,
green tea, resveratrol, ganoderma, licorice
Pathway Players

VEGF





Vascular Endothelial Growth Factor
by oncogenes, growth factors, NFkB, HER-2/neu, COX-2
Stimulate proliferation and migration of endothelial cells
(angiogenesis)
Increases tumor growth and metastasis, poor prognosis
bFGF (FGF2)



Basic Fibroblast Growth Factor
Mitogen – makes fibroblasts proliferate – creates structure
on which blood vessels can form
Increases Bcl-2 protein levels
Pathway Players

Bcl-2 Protein



Anti-apoptoic factor
Apoptosis – programmed cell death without
inflammation
Controls release of mitochondrial
cytochrome C


CytC triggers apoptosis
bFGF
Bcl-2
apoptosis
tumor growth & immortality
Pathway Players


Bcl-2 and oncogene p53 regulate VEGFmediated apoptosis
Inhibitors of Bcl-2

Green tea, scutellaria, baicalensis, hibiscus,
EPA, misteltoe, ginger, grapeseed extract,
ginseng, parthenolide (sesquiterpene from
feverfew), lapachone (from bark of lapacho
tree)
Pathway Players

EGFR (HER-1)




Epidermal growth factor receptor
Overexpressed in many cancers
More aggressive disease
Blocked by

Soy isoflavones, curcumin, resveratrol,
quercetin
Pathway Players

HER-2/neu



Gene amplified in >30% breast, ovarian,
prostate, stomach CA and NSCC of Lung
Highly aggressive tumors, poorer prognosis,
increased angiogensis ( VEGF and NFkB)
Inhibited by


Drug herceptin
Emodin (anthraquinone from polygonum
multiflorum – chinese knotweed root), aloe, oleic
acid (olive oil, grapeseed oil)
Foods & Supplements
Pharmaceuticals
vs. angiogenesis


Heparin – anticoagulation activity – possible
role
Bevacizumab (Avastin)




Monoclonal antibody
VEGF receptor blocker
survival a few months – metastatic colon cancer
Side effects

WBC, diarrhea, BP, blood clots, stroke, heart attack,
GI bleeding, intestinal perforation, hemoptysis
Screening Herbs for
Angiogenesis Influence




Recent science since 1990
Assays for each step vs. whole cascade
Some herbs impede AG at low doses and
others work at nearly toxic doses
Criteria for usefulness




Differential cytotoxcity
Alteration of EC function
Critical mechanistic effect
In vivo angiogenesis inhibition
Screening Herbs for
Angiogenesis Influence

In vitro endothelial cells

Immortilized 

Human umbilical vein ECs (HUVEC)



Loss of normal function and loss of molecular
markers
Practical (easily available)
Limited by differences between large and small
vessel endothelial cell phenotypes
Organ tissue (brain, adrenal, skin, adipose)

Not practical on large scale (availability)
Screening Herbs for
Angiogenesis Influence

In vivo

Chick Embryo Chorioallantoic Membrane



Blood vessel density around implanted tumor
tissue
72-96 hours (quick assessment)
Mouse/rat xenograft



Blood vessel density
Tumor size
Lifespan
Note re: Applying Info



Most (but not all) of what follows is from
animal studies and from human tumor tissue
studies on botanicals and other supplements.
The number of botanicals far outweighs the
number of clinical studies of them.
That doesn’t mean that physiological
information should be ignored, but it doesn’t
always turn into clinical improvement when
clinical studies are performed.
Artemisia




Chinese Wormwood
Antimalarial
Induces apoptosis and is antiangiogenic
In vivo mouse



tumor growth, angiogenesis
VEGF expression, No toxicity
Artesunate (ART) is semisynthetic analog



Dose-dependent antiangiogeneic effect in HUVEC
Inhibits activation of NFkB
Greater cytotoxic effect on CA & fibroblasts than normal
ECs
Mistletoe




Viscum Album
Iscador (common extract in homeopathic and
anthroposophical med)
In vitro VEGF and apoptosis
In vivo mouse



Lung metastases
Survival
In vivo human

Studies suggest survival variety of cancer but
poorly controlled.
Curcmin (tumeric)

Enhances efficacy of cytotoxic chemotherapy
and radiation in most studies (18 citations)







1 study suggested efficacy of chemotherapy
1 study suggested no difference
Downregulates MMPs, tumor invasiveness
TIMP-1 (tissue inhibition of MMPs)
Nitric oxide in ECs (NO ~ tumor growth)
gene transcription of VEGF, bFGF, MMP9
Blocks receptors for VEGF and EGF (HER1)
Curcumin (tumeric)

Inhibits growth factor Tyrosine Kinase




Signaling system that promotes
angiogenesis by levels of COX-2, VEGF,
IL8 and MMPs
Tumeric COX-2, VEGF, IL8, MMPs
No toxicity up to 800mg/day
Peaks at 1-2 hrs, lasts 12 hrs
Scutellaria




Chinese skullcap
Baicalin, Daicalein main derivatives
VEGF, bFGF, MMP, 12-lipooxygenase
One herb in a chinese forumla found to
be effective vs. advanced androgenindependent prostate CA
Resveratrol




Grapes, wine
Inhibit HUVEC division
VEGF activity by disrupting kinase
growth factor activity
growth of rat gliomas by angiogenesis
Proanthocyanidins




Grapeseed extract, many berries
Inhibits TNF-a-induced VEGF gene
expression
VEGF secretion in mice with xenograft
One study showed GSExt VEGF in
normal tissue as part of healing wounds

Different behavior in normal vs. tumor
tissue
Magnolia officinalis







Chinese magnolia tree bark
Honokiol is active constituent
platelet-derived ECGF
TGF-B gene expression
NO synthesis
TNF-a expression
Animal studies

proliferation of endothelium of blood vessels
greater than on endothelium of other tissue
Green Tea







Camilla Sinensis
Epigallocatechin-3 gallate (EGCG)
Inhibits breast CA cell proliferation
Inhibits HUVEC proliferation
breast CA xenograft growth & blood
vessel density
VEGF at gene transcription level
protein kinase C (another way to VEGF)
Green Tea




Dose 4oz three times per day or more
4oz ~ 1.0 g/m2
Extrapolated from antiangiogenic activity in
rodents and from human phase 1 trials
Typical presciption



2-4 grams/day 95% polyphenols 60% catechins
1 gram = 400-500mg EGCG
Dose-limiting effects


GI and Neuro from caffeine
Caffeine may potentiate the antiangiogenic effects
of EGCG
Ginkgo Biloba leaf



Downregulates VEGF - antiangiogenic
Gene-regulatory
Mice studies –





invasiveness of ER- breast, brain, colon, prostate
Human studies in gastric, pancreatic,
colorectal cancers pending
Level A evidence in claudication, dementia.
Level B cerebral insufficiency.
No significant adverse effects
80-240mg/day in 2-4 doses.
Quercetin





Flavone from apples, onions,
raspberries, red grapes, citrus fruits,
cherries, broccoli, leafy greens
COX-2, LOX-5, blocks EGFR(HER1)
Blocks HER-2 intracellular signaling path
NFkB
Prostate CA

Enhances cytotoxic effect of tomoxifen via
antiangiogenesis
Ginger



VEGF, bFGF activity
Induces cell-cycle arrest
Blocks capillary tube formation by ECs
in response to VEGF
Diindoylmethane
(DIM)



Broccoli and other cruciferous veggies
HUVEC proliferation (mechanism
unclear)
xenograft tumor growth
Glycine


Amino Acid
ECs have glycine-gated chloride
channels



Glycine opens channels – hyperpolarizes
plasma membrane
Inhibits NADPH oxidase
Upregulates tyrosine phosphatases which
oppose activity of VEGF and bFGF
Silymarin





Milk Thistle
Xenografts of Prostate CA and NSCCL
NFkB by IkB kinase-a activity
VEGF breast, prostate, colon CA lines
VEGFR-1 (Flt-1)


Acts as decoy receptor for VEGF
Therefore function of VEGF
Panax Ginseng



Induce tumor apoptosis
Antiangiogenic
Prospective cohort study

4,364 persons older than 40 years, the risk
of cancer was shown to be lower in those
who used ginseng (relative risk: 0.40).
Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective
study in Korea. Int J Epidemiol 1998;27:359-64
Copper Antagonists

Copper essential for function of


bFGF, VEGF, TNF-a, IL-1
Tetrathiomolybdate (TM)



Copper chelator
Shows promising effects vs cancer in small
studies
Inhibits NFkB (controls transcription of
many cytokines and angiogenic factors)
Shark/Bovine Cartilage

In vivo and in vitro studies suggest
antiangiogenic compounds


2005 Phase 3 RCT inadequate bioavailability
Neovastat (AE-941) bioactive extract




Metalloproteinase inhibitor
VEGFR binding
VEGF-dependent increase in vascular permeability
MD Anderson currently recruiting for NSCCLung
study
Squalamine

Squalamine




Steroid from liver of dogfish shark
Blocks VEGF-induced activation of MAP kinase
Antiangiogenic for ovarian ca xenografts
Advanced SCCLung Phase 2 study




300mg/m2 IV drip x 5 days
Paclitaxel & carboplatin Day 1
Positive survival and safety
Enhances cytotoxic effect of cisplatin

Independent of HER-2 status
Mushrooms


Coriolus versicolor (turkey tail)
Large body of Japanese literature of RDBPCTs






survival in NSCCLung
5-yr survival in Stomach CA 73% chemo plus coriolus vs
60% chemo alone
survival when combo w/ chemo in Breast and Colon CA
Hepatoprotective
TGF-B (transforming GF) and therefore NFkB
Immune support


B- and T-lymphocytes, NK cells, WBC & platelet counts
Stronger effect in myelodepressed vs normal patients
American Botanical Council Monograph
Mushrooms

Lentinula edodes - Shiitake

Study - Hepatogastroenterolgy 1999,
gastric cancer


1-year survival by 49% compared with 0% in
control
Pancreatic CA study

5-year survival 43% vs 29% in controls
Mushrooms

Grifola frondosa – Maitake



IL-12
NK cells
TNF-a and IFN-g ( angiogenesis)
Small Case Series




β-glucans lead to cancer regression or a
significant improvement of symptoms
58% of liver cancer patients
69% of breast cancer patients
62% of lung cancer patients
Mushrooms

Poria cocos



platelet aggregation
NFkB
Ganoderma lucidum – Reishi


Immunostimulant, platelet aggregation
Lung CA survival in mice
Essiac Tea





Burdock root, sheep sorrel, slippery elm bark and
either Turkey or Indian rhubarb root
Rene Caisse
Rare side effects: GI, tumor size increase
No published studies – lots of anecdotal reports
John Boik


Anthraquinones rhein and emodin greatest anticancer
potential
High molecular polysaccharides contained in the formula
could also have a stimulating effect on the immune system
but dose too low to likely be helpful
Hoxey Formula







Tonic taken by mouth or placed on the skin
Ingredients individualized according to cancer type
and medical history.
Potassium iodide is common ingredient
May include licorice, red clover, burdock, stillingia
root, berberis root, pokeroot, cascara, Aromatic USP
14, prickly ash bark, and buckthorn bark.
Red paste tends to be caustic (irritating), and
contains antimony trisulfide, zinc chloride, and
bloodroot.
Topical yellow powder contains arsenic sulfide, talc,
sulfur, and a "yellow precipitate."
Clear solution contains trichloroacetic acid.
Hoxey Formula




Anecdotal reports
Extended history of use
No published studies of safety or
efficacy
Colored history of political suppression
by AMA
curcmin, artemsia,
mistletoe, ginger
scutellaria,
resveratrol,
grapeseed extract,
green tea, gingko, ginger
squalamine, Vit D
artemsia
silymarin, glycine, mistletoe
curcumin
scutellaria
VEGFR
curcmin,
scutellaria,
cartilege,
silymarin,
green tea
EGCG, silymarin,
quercetin,
resveratrol, soy
isoflavones,
curcumin, EPA
Multifocal
Angiostatic
Therapy
Cu antagonists
bFGFR and TNF-1:
Growth
Factors
NFkB
COX-2
Cu antagonists
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
Silymarin,
Glycine, Ginger
Anti GFs:
green tea
quercetin
magnolia
resveratrol,
soy, curcumin
holy basil
rosemary
ganoderma
licorice Vit E
Anti-COX-2: quercetin,
scutellaria, EPA/DHA, licorice,
ginger, resveratrol, grapeseed
extract, curcumin, salicylates,
garlic, green tea, panax ginseng,
silymarin, bilberry, antioxidants,
boswellia, aloe
Anti- NFkB: poria,
coriolus, ginger,
resveratrol, green tea,
artemsia, quercetin,
carnosol, panax ginseng,
silymarin, salicylates,
curcumin, picentannol,
basil, Cu antagonists
rosemary
Complications
of Supplements







Overall risk is fairly low but real
Liver inflammation
Blood clotting
GI side effects
Delay of access to standard therapies
Quality control issues
Potential to interfere with Chemo/Rad
We’ve all been
waiting, wondering,
Will we ever know
the truth?
What it’s like
washing windows
When you know
that there are
pigeons on the roof?