Cancer, Supplements, and Cancer, Supplements, and FoodFood

When and What is OK?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 aWhat is a Cancer Guide? Cancer Guide?

If each day fallsIf each day fallsinside each night,inside each night,there exists a well there exists a well where clarity is imprisoned.where clarity is imprisoned.We need to sit on the rimWe need to sit on the rimof the well of darknessof the well of darknessand fish for fallen light.and fish for fallen light.

- Pablo - Pablo NerudaNeruda

Information SourcesInformation Sources

CancerGuides – Center for Mind-Body CancerGuides – Center for Mind-Body Medicine, National Cancer Inst, NIHMedicine, National Cancer Inst, NIH

Food as Medicine (same institutions)Food as Medicine (same institutions) Journal: Journal: Integrative Cancer TherapiesIntegrative Cancer Therapies Society for Integrative OncologySociety for Integrative Oncology John Boik: John Boik: Natural Compounds in Cancer Natural Compounds in Cancer

TherapyTherapy

Information SourcesInformation Sources

Yance and Sagar. Targeting Angiogenesis with Integrative Yance and Sagar. Targeting Angiogenesis with Integrative Cancer Therapies. Integrative Canc Ther. 2006;5(1):9.Cancer Therapies. Integrative Canc Ther. 2006;5(1):9.

Moss. Should Patients Undergoing Chemotherapy and Moss. Should Patients Undergoing Chemotherapy and Radiotherapy Be Prescribed Antioxidants? Integr Canc Ther. Radiotherapy Be Prescribed Antioxidants? Integr Canc Ther. 2006;5(1):63.2006;5(1):63.

Lamson and Brignall. Antioxidants and Cancer Therapy: Lamson and Brignall. Antioxidants and Cancer Therapy: Their Actions and Interactions with Oncologic Therapies. Their Actions and Interactions with Oncologic Therapies. Altern Med Rev. 1999;4(5):304.Altern Med Rev. 1999;4(5):304.

McCarty and Block. Multifocal Angiostatic Therapy: An McCarty and Block. Multifocal Angiostatic Therapy: An Update. Integr Canc Ther. 2005;4(4):301.Update. Integr Canc Ther. 2005;4(4):301.

OverviewOverview

Angiogenesis and MetastasisAngiogenesis and Metastasis Growth Factors, pro-angiogenesis Growth Factors, pro-angiogenesis

pathwayspathways Metronomic ModelMetronomic Model Supplements in Angiogenesis Supplements in Angiogenesis Primary and Secondary PreventionPrimary and Secondary Prevention Controversies re: “concurrent use” Controversies re: “concurrent use”

(during chemo- or radio-therapy)(during chemo- or radio-therapy)

AngiogenesisAngiogenesis

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

AngiogenesisAngiogenesis(see diagram)(see diagram)

1. Endothelial cells (form the inside lining 1. Endothelial cells (form the inside lining of blood vessels) “ECs”of blood vessels) “ECs”

2. ECs stimulated by angiokinins, matrix 2. ECs stimulated by angiokinins, matrix metalloproteinase (MMP), heparinases, metalloproteinase (MMP), heparinases, VEFG (vascular endothelial growth factor)VEFG (vascular endothelial growth factor)

3. Extracellular Matrix (ECM) – framework 3. Extracellular Matrix (ECM) – framework outside cells – dissolves outside cells – dissolves

4. Tight junctions (between ECs) disrupted4. Tight junctions (between ECs) disrupted

AngiogenesisAngiogenesis(see diagram)(see diagram)

5. Opening occurs between ECs in the 5. Opening occurs between ECs in the wall of blood vesselwall of blood vessel

6. Growth Factors stimulate ECs to 6. Growth Factors stimulate ECs to multiply and move into space left over multiply and move into space left over by dissolution of ECMby dissolution of ECM

7. New ECs develop tubular 7. New ECs develop tubular organization form new blood vessel organization form new blood vessel sproutsprout

MetastasisMetastasis

1. Transformation of normal cells into 1. Transformation of normal cells into tumor cellstumor cells

2. Local growth of tumor (diffusion of 2. Local growth of tumor (diffusion of nutrients)nutrients)

3. Angiogenesis (necessary for tumor 3. Angiogenesis (necessary for tumor to grow over 1 mm) – recruit nearby to grow over 1 mm) – recruit nearby blood vesselsblood vessels

MetastasisMetastasis

4. Local Invasion (through thin walls 4. Local Invasion (through thin walls of small arterioles/lymphatics)of small arterioles/lymphatics)

5. Detachment and embolization 5. Detachment and embolization (stuck in capillary beds)(stuck in capillary beds)

6. Invasion of new host organ6. Invasion of new host organ 7. Proliferation 7. Proliferation

Angiogenesis

Necessary for

Metastasis

Two Major Factors Two Major Factors Promoting CancerPromoting Cancer

Absence of normal inhibitors of Absence of normal inhibitors of angiogenesisangiogenesis INF-B (interferon-B) blocks IL-8, basic fibroblast INF-B (interferon-B) blocks IL-8, basic fibroblast

growth factor (bFGF) and collegenase type Vgrowth factor (bFGF) and collegenase type V Overexpression of VEGFOverexpression of VEGF

Vascular Endothelial Growth FactorVascular Endothelial Growth Factor Stimulate proliferation and migration of Stimulate proliferation and migration of

endothelial cells (angiogenesis)endothelial cells (angiogenesis) Increases tumor growth and metastasisIncreases tumor growth and metastasis

VEGFVEGF

Production of VEGF considered essential Production of VEGF considered essential to angiogenesis and metastasisto angiogenesis and metastasis

High levels ~ worse outcomeHigh levels ~ worse outcome Increased byIncreased by

Oncogenes H-ras, K-ras, src, p53, C-junOncogenes H-ras, K-ras, src, p53, C-jun Growth Factors (EGF/HER1, TGF-a, insulin-like Growth Factors (EGF/HER1, TGF-a, insulin-like

growth factor-1, platelet-derived growth factorgrowth factor-1, platelet-derived growth factor NFkBNFkB

Metronomic DosingMetronomic Dosing

Chronic use of low doses of Chronic use of low doses of chemotherapy chemotherapy Intent of inhibiting angiogenesis and Intent of inhibiting angiogenesis and

minimizing toxicityminimizing toxicity Potential role in increasing survival Potential role in increasing survival

and quality of life (not necessarily and quality of life (not necessarily disease-free)disease-free)

Metronomic DosingMetronomic Dosing

““When designing cytokine-targeted antiangiogenic growth When designing cytokine-targeted antiangiogenic growth factors, one must also take into account the tumor factors, one must also take into account the tumor microenvironment.” (includes extracellular matrix, tissue, microenvironment.” (includes extracellular matrix, tissue, and specific intrinsic factors in those cells)and specific intrinsic factors in those cells)

“ “The more specific the intervention is to one domain of the The more specific the intervention is to one domain of the angiogenic pathway, the less likely there will be a beneficial angiogenic pathway, the less likely there will be a beneficial reduction in tumor growth, since alternative pathways can reduction in tumor growth, since alternative pathways can compensate.” compensate.”

Yance, Sagar. Integative Cancer Therapies. Vol 5 (1). 2006. p Yance, Sagar. Integative Cancer Therapies. Vol 5 (1). 2006. p 12.12.

Silymarin, Glycine, Ginger

VEGFR

EGCG, silymarin, quercetin, resveratrol, soy isoflavones, curcumin, EPA

Cu antagonists

VEGF, AKs, bFGF, IL8, MMPs,

TNF-1, heparinases, collagenases

curcmin, artemsia, mistletoe, ginger scutellaria, resveratrol, grapeseed extract, green tea, gingko, squalamine, Vit D silymarin, glycine,

ginger artemsia mistletoe curcumin scutellaria

curcmin, scutellaria, cartilege, silymarin, green tea

bFGFR and TNF-1:

Cu antagonists

Multifocal Angiostatic

Therapy

Growth FactorsNFkBCOX-2

Anti-GFs: green tea quercetin magnolia resveratrol, soy, curcumin holy basil rosemary ganoderma licorice Vit E

Anti- NFkB: poria, coriolus, ginger, resveratrol, green tea, artemsia, quercetin, carnosol, panax ginseng, silymarin, salicylates, curcumin, picentannol, basil, Cu antagonists rosemary

Anti-COX-2: quercetin, scutellaria, EPA/DHA, licorice, ginger, resveratrol, grapeseed extract, curcumin, salicylates, garlic, green tea, panax ginseng, silymarin, bilberry, antioxidants, boswellia, aloe

Pathway PlayersPathway Players

NF-kBNF-kB Nuclear transcription factorNuclear transcription factor Stimulated by IL-1Stimulated by IL-1 Increased in tissue inflammation and cancerIncreased in tissue inflammation and cancer Causes overactivation of COX-2 pathwayCauses overactivation of COX-2 pathway

Increased angiogenesisIncreased angiogenesis Inhibited byInhibited by

Resveratrol, piceatannol, curcumin, green tea, Resveratrol, piceatannol, curcumin, green tea, ginger, holy basil, panax ginseng, carnosol ginger, holy basil, panax ginseng, carnosol (rosemary)(rosemary)

Pathway PlayersPathway Players

COX-2COX-2 Enzyme converts arachidonic acid to Enzyme converts arachidonic acid to

inflammatory prostaglandins (PGE2 family)inflammatory prostaglandins (PGE2 family) Increases angiogenesisIncreases angiogenesis Blocked byBlocked by

EPA/DHA, licorice, ginger, aloe, green tea, EPA/DHA, licorice, ginger, aloe, green tea, resveratrol, garlic, scutellaria, bilberry, grapeseed resveratrol, garlic, scutellaria, bilberry, grapeseed extract, panax ginseng, silymarin, green-lipped extract, panax ginseng, silymarin, green-lipped mussel, boswellia, bromelain, curcumin, quercetinmussel, boswellia, bromelain, curcumin, quercetin

Antioxidants: Vit A, C, E, selenium, zinc, carotenoids, Antioxidants: Vit A, C, E, selenium, zinc, carotenoids, flavonoids, CoQ10, N-acetyl cysteine, alpha lipoic flavonoids, CoQ10, N-acetyl cysteine, alpha lipoic acidacid

Pathway PlayersPathway Players

Protein KinasesProtein Kinases Control progression of cell’s cycle of Control progression of cell’s cycle of

proliferationproliferation Mutations common in breast and bladder CA Mutations common in breast and bladder CA

and CMLand CML Ex: Abl, Src, cyclin-depedent kinases, PKCEx: Abl, Src, cyclin-depedent kinases, PKC Inhibited byInhibited by

Holy basil, rosemary, genistein, daidzein, curcumin, Holy basil, rosemary, genistein, daidzein, curcumin, Vit E, green tea, resveratrol, ganoderma, licoriceVit E, green tea, resveratrol, ganoderma, licorice

Pathway PlayersPathway Players

VEGFVEGF Vascular Endothelial Growth FactorVascular Endothelial Growth Factor by oncogenes, growth factors, NFkB, HER-2/neu, COX-2by oncogenes, growth factors, NFkB, HER-2/neu, COX-2 Stimulate proliferation and migration of endothelial cells Stimulate proliferation and migration of endothelial cells

(angiogenesis)(angiogenesis) Increases tumor growth and metastasis, poor prognosisIncreases tumor growth and metastasis, poor prognosis

bFGF (FGF2)bFGF (FGF2) Basic Fibroblast Growth FactorBasic Fibroblast Growth Factor Mitogen – makes fibroblasts proliferate – creates Mitogen – makes fibroblasts proliferate – creates

structure on which blood vessels can formstructure on which blood vessels can form Increases Bcl-2 protein levelsIncreases Bcl-2 protein levels

Pathway PlayersPathway Players

Bcl-2 ProteinBcl-2 Protein Anti-apoptoic factorAnti-apoptoic factor Apoptosis – programmed cell death Apoptosis – programmed cell death

without inflammationwithout inflammation Controls release of mitochondrial Controls release of mitochondrial

cytochrome Ccytochrome C CytC triggers apoptosisCytC triggers apoptosis

bFGF Bcl-2 apoptosis bFGF Bcl-2 apoptosis tumor growth & immortalitytumor growth & immortality

Pathway PlayersPathway Players

Bcl-2 and oncogene p53 regulate Bcl-2 and oncogene p53 regulate VEGF-mediated apoptosisVEGF-mediated apoptosis

Inhibitors of Bcl-2Inhibitors of Bcl-2 Green tea, scutellaria, baicalensis, Green tea, scutellaria, baicalensis,

hibiscus, EPA, misteltoe, ginger, hibiscus, EPA, misteltoe, ginger, grapeseed extract, ginseng, parthenolide grapeseed extract, ginseng, parthenolide (sesquiterpene from feverfew), (sesquiterpene from feverfew), lapachone (from bark of lapacho tree)lapachone (from bark of lapacho tree)

Pathway PlayersPathway Players

EGFR (HER-1)EGFR (HER-1) Epidermal growth factor receptorEpidermal growth factor receptor Overexpressed in many cancersOverexpressed in many cancers More aggressive diseaseMore aggressive disease Blocked by Blocked by

Soy isoflavones, curcumin, resveratrol, Soy isoflavones, curcumin, resveratrol, quercetinquercetin

Pathway PlayersPathway Players

HER-2/neuHER-2/neu Gene amplified in >30% breast, ovarian, Gene amplified in >30% breast, ovarian,

prostate, stomach CA and NSCC of Lungprostate, stomach CA and NSCC of Lung Highly aggressive tumors, poorer Highly aggressive tumors, poorer

prognosis, increased angiogensis prognosis, increased angiogensis ( VEGF and NFkB)( VEGF and NFkB)

Inhibited by Inhibited by Drug herceptinDrug herceptin Emodin (anthraquinone from polygonum Emodin (anthraquinone from polygonum

multiflorum – chinese knotweed root), aloe, multiflorum – chinese knotweed root), aloe, oleic acid (olive oil, grapeseed oil)oleic acid (olive oil, grapeseed oil)

Foods & SupplementsFoods & Supplements

PharmaceuticalsPharmaceuticalsvs. angiogenesisvs. angiogenesis

Heparin – anticoagulation activity – Heparin – anticoagulation activity – possible rolepossible role

Bevacizumab (Avastin)Bevacizumab (Avastin) Monoclonal antibodyMonoclonal antibody VEGF receptor blockerVEGF receptor blocker survival a few months – metastatic colon survival a few months – metastatic colon

cancercancer Side effectsSide effects

WBC, diarrhea, BP, blood clots, stroke, heart WBC, diarrhea, BP, blood clots, stroke, heart attack, GI bleeding, intestinal perforation, hemoptysisattack, GI bleeding, intestinal perforation, hemoptysis

Screening Herbs forScreening Herbs for Angiogenesis Influence Angiogenesis Influence

Recent science since 1990Recent science since 1990 Assays for each step vs. whole cascadeAssays for each step vs. whole cascade Some herbs impede AG at low doses Some herbs impede AG at low doses

and others work at nearly toxic dosesand others work at nearly toxic doses Criteria for usefulnessCriteria for usefulness

Differential cytotoxcityDifferential cytotoxcity Alteration of EC functionAlteration of EC function Critical mechanistic effectCritical mechanistic effect In vivo angiogenesis inhibitionIn vivo angiogenesis inhibition

Screening Herbs forScreening Herbs for Angiogenesis Influence Angiogenesis Influence

In vitro endothelial cellsIn vitro endothelial cells Immortilized - Immortilized -

Loss of normal function and loss of Loss of normal function and loss of molecular markersmolecular markers

Human umbilical vein ECs (HUVEC)Human umbilical vein ECs (HUVEC) Practical (easily available)Practical (easily available) Limited by differences between large and Limited by differences between large and

small vessel endothelial cell phenotypessmall vessel endothelial cell phenotypes Organ tissue (brain, adrenal, skin, Organ tissue (brain, adrenal, skin,

adipose)adipose) Not practical on large scale (availability)Not practical on large scale (availability)

Screening Herbs forScreening Herbs for Angiogenesis Influence Angiogenesis Influence

In vivoIn vivo Chick Embryo Chorioallantoic MembraneChick Embryo Chorioallantoic Membrane

Blood vessel density around implanted Blood vessel density around implanted tumor tissuetumor tissue

72-96 hours (quick assessment) 72-96 hours (quick assessment) Mouse/rat xenograftMouse/rat xenograft

Blood vessel densityBlood vessel density Tumor sizeTumor size LifespanLifespan

Note re: Applying Note re: Applying InfoInfo

Most (but not all) of what follows is from Most (but not all) of what follows is from animal studies and from human tumor tissue animal studies and from human tumor tissue studies on botanicals and other studies on botanicals and other supplements.supplements.

The number of botanicals far outweighs the The number of botanicals far outweighs the number of clinical studies of them. number of clinical studies of them.

That doesn’t mean that physiological That doesn’t mean that physiological information should be ignored, but it doesn’t information should be ignored, but it doesn’t always turn into clinical improvement when always turn into clinical improvement when clinical studies are performed.clinical studies are performed.

ArtemisiaArtemisia

Chinese WormwoodChinese Wormwood AntimalarialAntimalarial Induces apoptosis and is antiangiogenicInduces apoptosis and is antiangiogenic In vivo mouseIn vivo mouse

tumor growth, angiogenesistumor growth, angiogenesis VEGF expression, No toxicityVEGF expression, No toxicity

Artesunate (ART) is semisynthetic analogArtesunate (ART) is semisynthetic analog Dose-dependent antiangiogeneic effect in HUVECDose-dependent antiangiogeneic effect in HUVEC Inhibits activation of NFkBInhibits activation of NFkB Greater cytotoxic effect on CA & fibroblasts than normal Greater cytotoxic effect on CA & fibroblasts than normal

ECs ECs

MistletoeMistletoe

Viscum Album Viscum Album Iscador (common extract in homeopathic Iscador (common extract in homeopathic

and anthroposophical med)and anthroposophical med) In vitro VEGF and apoptosisIn vitro VEGF and apoptosis In vivo mouseIn vivo mouse

Lung metastasesLung metastases SurvivalSurvival

In vivo humanIn vivo human Studies suggest survival variety of cancer but Studies suggest survival variety of cancer but

poorly controlled.poorly controlled.

Curcmin (tumeric)Curcmin (tumeric)

Enhances efficacy of cytotoxic chemotherapy Enhances efficacy of cytotoxic chemotherapy and radiation in most studies and radiation in most studies (18 citations)(18 citations)

1 study suggested efficacy of chemotherapy1 study suggested efficacy of chemotherapy 1 study suggested no difference1 study suggested no difference

Downregulates MMPs, tumor invasivenessDownregulates MMPs, tumor invasiveness TIMP-1 (tissue inhibition of MMPs)TIMP-1 (tissue inhibition of MMPs) Nitric oxide in ECs (NO ~ tumor growth)Nitric oxide in ECs (NO ~ tumor growth) gene transcription of VEGF, bFGF, MMP9gene transcription of VEGF, bFGF, MMP9 Blocks receptors for VEGF and EGF (HER1)Blocks receptors for VEGF and EGF (HER1)

Curcumin (tumeric)Curcumin (tumeric)

Inhibits growth factor Tyrosine Inhibits growth factor Tyrosine KinaseKinase Signaling system that promotes Signaling system that promotes

angiogenesis by levels of COX-2, VEGF, angiogenesis by levels of COX-2, VEGF, IL8 and MMPsIL8 and MMPs

Tumeric COX-2, VEGF, IL8, MMPsTumeric COX-2, VEGF, IL8, MMPs No toxicity up to 800mg/dayNo toxicity up to 800mg/day Peaks at 1-2 hrs, lasts 12 hrsPeaks at 1-2 hrs, lasts 12 hrs

ScutellariaScutellaria

Chinese skullcapChinese skullcap Baicalin, Daicalein main derivativesBaicalin, Daicalein main derivatives VEGF, bFGF, MMP, 12-VEGF, bFGF, MMP, 12-

lipooxygenaselipooxygenase One herb in a chinese forumla found One herb in a chinese forumla found

to be effective vs. advanced to be effective vs. advanced androgen-independent prostate CAandrogen-independent prostate CA

ResveratrolResveratrol

Grapes, wineGrapes, wine Inhibit HUVEC divisionInhibit HUVEC division VEGF activity by disrupting kinase VEGF activity by disrupting kinase

growth factor activitygrowth factor activity growth of rat gliomas by growth of rat gliomas by

angiogenesisangiogenesis

ProanthocyanidinsProanthocyanidins

Grapeseed extract, many berriesGrapeseed extract, many berries Inhibits TNF-a-induced VEGF gene Inhibits TNF-a-induced VEGF gene

expressionexpression VEGF secretion in mice with xenograftVEGF secretion in mice with xenograft One study showed GSExt VEGF in One study showed GSExt VEGF in

normal tissue as part of healing woundsnormal tissue as part of healing wounds Different behavior in normal vs. tumor tissueDifferent behavior in normal vs. tumor tissue

Magnolia officinalisMagnolia officinalis

Chinese magnolia tree barkChinese magnolia tree bark Honokiol is active constituentHonokiol is active constituent platelet-derived ECGFplatelet-derived ECGF TGF-B gene expressionTGF-B gene expression NO synthesisNO synthesis TNF-a expressionTNF-a expression Animal studiesAnimal studies

proliferation of endothelium of blood vessels proliferation of endothelium of blood vessels greater than on endothelium of other tissuegreater than on endothelium of other tissue

Green TeaGreen Tea

Camilla SinensisCamilla Sinensis Epigallocatechin-3 gallate (EGCG)Epigallocatechin-3 gallate (EGCG) Inhibits breast CA cell proliferationInhibits breast CA cell proliferation Inhibits HUVEC proliferationInhibits HUVEC proliferation breast CA xenograft growth & blood breast CA xenograft growth & blood

vessel densityvessel density VEGF at gene transcription levelVEGF at gene transcription level protein kinase C protein kinase C (another way to VEGF)(another way to VEGF)

Green TeaGreen Tea

Dose 4oz three times per day or moreDose 4oz three times per day or more 4oz ~ 1.0 g/m4oz ~ 1.0 g/m22

Extrapolated from antiangiogenic activity Extrapolated from antiangiogenic activity in rodents and from human phase 1 trialsin rodents and from human phase 1 trials

Typical presciptionTypical presciption 2-4 grams/day 95% polyphenols 60% catechins2-4 grams/day 95% polyphenols 60% catechins 1 gram = 400-500mg EGCG1 gram = 400-500mg EGCG

Dose-limiting effectsDose-limiting effects GI and Neuro from caffeineGI and Neuro from caffeine Caffeine may potentiate the antiangiogenic Caffeine may potentiate the antiangiogenic

effects of EGCGeffects of EGCG

Ginkgo Biloba leafGinkgo Biloba leaf

Downregulates VEGF - antiangiogenicDownregulates VEGF - antiangiogenic Gene-regulatory Gene-regulatory Mice studies –Mice studies –

invasiveness of ER- breast, brain, colon, invasiveness of ER- breast, brain, colon, prostateprostate

Human studies in gastric, pancreatic, Human studies in gastric, pancreatic, colorectal cancers pendingcolorectal cancers pending

Level A evidence in claudication, dementia. Level A evidence in claudication, dementia. Level B cerebral insufficiency.Level B cerebral insufficiency.

No significant adverse effectsNo significant adverse effects 80-240mg/day in 2-4 doses.80-240mg/day in 2-4 doses.

QuercetinQuercetin

Flavone from apples, onions, Flavone from apples, onions, raspberries, red grapes, citrus fruits, raspberries, red grapes, citrus fruits, cherries, broccoli, leafy greenscherries, broccoli, leafy greens

COX-2, LOX-5, blocks EGFR(HER1)COX-2, LOX-5, blocks EGFR(HER1) Blocks HER-2 intracellular signaling Blocks HER-2 intracellular signaling

pathpath NFkBNFkB Prostate CAProstate CA

Enhances cytotoxic effect of tomoxifen via Enhances cytotoxic effect of tomoxifen via antiangiogenesisantiangiogenesis

GingerGinger

VEGF, bFGF activityVEGF, bFGF activity Induces cell-cycle arrestInduces cell-cycle arrest Blocks capillary tube formation by Blocks capillary tube formation by

ECs in response to VEGFECs in response to VEGF

Diindoylmethane Diindoylmethane (DIM)(DIM)

Broccoli and other cruciferous Broccoli and other cruciferous veggiesveggies

HUVEC proliferation (mechanism HUVEC proliferation (mechanism unclear)unclear)

xenograft tumor growthxenograft tumor growth

GlycineGlycine

Amino AcidAmino Acid ECs have glycine-gated chloride ECs have glycine-gated chloride

channelschannels Glycine opens channels – hyperpolarizes Glycine opens channels – hyperpolarizes

plasma membraneplasma membrane Inhibits NADPH oxidaseInhibits NADPH oxidase Upregulates tyrosine phosphatases Upregulates tyrosine phosphatases

which oppose activity of VEGF and bFGFwhich oppose activity of VEGF and bFGF

SilymarinSilymarin

Milk ThistleMilk Thistle Xenografts of Prostate CA and NSCCLXenografts of Prostate CA and NSCCL NFkB by IkB kinase-a activityNFkB by IkB kinase-a activity VEGF breast, prostate, colon CA linesVEGF breast, prostate, colon CA lines VEGFR-1 (Flt-1) VEGFR-1 (Flt-1)

Acts as decoy receptor for VEGFActs as decoy receptor for VEGF Therefore function of VEGFTherefore function of VEGF

Panax GinsengPanax Ginseng

Induce tumor apoptosisInduce tumor apoptosis AntiangiogenicAntiangiogenic Prospective cohort studyProspective cohort study

4,364 persons older than 40 years, the 4,364 persons older than 40 years, the risk of cancer was shown to be lower in risk of cancer was shown to be lower in those who used ginseng (relative risk: those who used ginseng (relative risk: 0.40). 0.40).

Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol 1998;27:359-64 prospective study in Korea. Int J Epidemiol 1998;27:359-64

Copper AntagonistsCopper Antagonists

Copper essential for function ofCopper essential for function of bFGF, VEGF, TNF-a, IL-1bFGF, VEGF, TNF-a, IL-1

Tetrathiomolybdate (TM) Tetrathiomolybdate (TM) Copper chelatorCopper chelator Shows promising effects vs cancer in Shows promising effects vs cancer in

small studiessmall studies Inhibits NFkB (controls transcription of Inhibits NFkB (controls transcription of

many cytokines and angiogenic factors)many cytokines and angiogenic factors)

Shark/Bovine CartilageShark/Bovine Cartilage

In vivo and in vitro studies suggest In vivo and in vitro studies suggest antiangiogenic compoundsantiangiogenic compounds

2005 Phase 3 RCT inadequate bioavailability2005 Phase 3 RCT inadequate bioavailability

Neovastat (AE-941) bioactive extractNeovastat (AE-941) bioactive extract Metalloproteinase inhibitorMetalloproteinase inhibitor VEGFR bindingVEGFR binding VEGF-dependent increase in vascular VEGF-dependent increase in vascular

permeabilitypermeability MD Anderson currently recruiting for NSCCLung MD Anderson currently recruiting for NSCCLung

studystudy

SqualamineSqualamine

SqualamineSqualamine Steroid from liver of dogfish sharkSteroid from liver of dogfish shark Blocks VEGF-induced activation of MAP kinaseBlocks VEGF-induced activation of MAP kinase Antiangiogenic for ovarian ca xenograftsAntiangiogenic for ovarian ca xenografts Advanced SCCLung Phase 2 studyAdvanced SCCLung Phase 2 study

300mg/m300mg/m22 IV drip x 5 days IV drip x 5 days Paclitaxel & carboplatin Day 1Paclitaxel & carboplatin Day 1 Positive survival and safety Positive survival and safety

Enhances cytotoxic effect of cisplatinEnhances cytotoxic effect of cisplatin Independent of HER-2 statusIndependent of HER-2 status

MushroomsMushrooms

Coriolus versicolor (turkey tail)Coriolus versicolor (turkey tail) Large body of Japanese literature of RDBPCTsLarge body of Japanese literature of RDBPCTs

survival in NSCCLung survival in NSCCLung

5-yr survival in Stomach CA 73% chemo plus coriolus 5-yr survival in Stomach CA 73% chemo plus coriolus vs 60% chemo alonevs 60% chemo alone

survival when combo w/ chemo in Breast and Colon CAsurvival when combo w/ chemo in Breast and Colon CA HepatoprotectiveHepatoprotective TGF-B (transforming GF) and therefore NFkBTGF-B (transforming GF) and therefore NFkB Immune support Immune support

B- and T-lymphocytes, NK cells, WBC & platelet countsB- and T-lymphocytes, NK cells, WBC & platelet counts Stronger effect in myelodepressed vs normal patientsStronger effect in myelodepressed vs normal patients

American American Botanical Council MonographBotanical Council Monograph

MushroomsMushrooms

Lentinula edodes - ShiitakeLentinula 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

MushroomsMushrooms

Grifola frondosa – MaitakeGrifola frondosa – Maitake IL-12 NK cells TNF-a and IFN-g ( angiogenesis) Small Case SeriesSmall 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

MushroomsMushrooms

Poria cocosPoria cocos platelet aggregationplatelet aggregation NFkBNFkB

Ganoderma lucidum – ReishiGanoderma lucidum – Reishi Immunostimulant, platelet aggregationImmunostimulant, platelet aggregation Lung CA survival in miceLung CA survival in mice

Essiac TeaEssiac Tea

Burdock root, sheep sorrel, slippery elm bark and Burdock root, sheep sorrel, slippery elm bark and either Turkey or Indian rhubarb root either Turkey or Indian rhubarb root

Rene Caisse Rene Caisse Rare side effects: GI, tumor size increaseRare side effects: GI, tumor size increase No published studies – lots of anecdotal reportsNo published studies – lots of anecdotal reports John Boik John Boik

Anthraquinones rhein and emodin greatest anticancer Anthraquinones rhein and emodin greatest anticancer potentialpotential

High molecular polysaccharides contained in the formula High molecular polysaccharides contained in the formula could also have a stimulating effect on the immune could also have a stimulating effect on the immune system but dose too low to likely be helpfulsystem but dose too low to likely be helpful

Hoxey FormulaHoxey Formula

Tonic taken by mouth or placed on the skinTonic taken by mouth or placed on the skin Ingredients individualized according to cancer Ingredients individualized according to cancer

type and medical history. type and medical history. Potassium iodide is common ingredientPotassium iodide is common ingredient May include licorice, red clover, burdock, stillingia May include licorice, red clover, burdock, stillingia

root, berberis root, pokeroot, cascara, Aromatic root, berberis root, pokeroot, cascara, Aromatic USP 14, prickly ash bark, and buckthorn bark. USP 14, prickly ash bark, and buckthorn bark.

Red paste tends to be caustic (irritating), and Red paste tends to be caustic (irritating), and contains antimony trisulfide, zinc chloride, and contains antimony trisulfide, zinc chloride, and bloodroot. bloodroot.

Topical yellow powder contains arsenic sulfide, Topical yellow powder contains arsenic sulfide, talc, sulfur, and a "yellow precipitate." talc, sulfur, and a "yellow precipitate."

Clear solution contains trichloroacetic acid. Clear solution contains trichloroacetic acid.

Hoxey FormulaHoxey Formula

Anecdotal reportsAnecdotal reports Extended history of use Extended history of use No published studies of safety or No published studies of safety or

efficacyefficacy Colored history of political Colored history of political

suppression by AMAsuppression by AMA

Silymarin, Glycine, Ginger

VEGFR

EGCG, silymarin, quercetin, resveratrol, soy isoflavones, curcumin, EPA

Cu antagonists

VEGF, AKs, bFGF, IL8, MMPs,

TNF-1, heparinases, collagenases

curcmin, artemsia, mistletoe, ginger scutellaria, resveratrol, grapeseed extract, green tea, gingko, squalamine, Vit D silymarin, glycine,

ginger artemsia mistletoe curcumin scutellaria

curcmin, scutellaria, cartilege, silymarin, green tea

bFGFR and TNF-1:

Cu antagonists

Multifocal Angiostatic

Therapy

Growth FactorsNFkBCOX-2

Anti GFs: green tea quercetin magnolia resveratrol, soy, curcumin holy basil rosemary ganoderma licorice Vit E

Anti- NFkB: poria, coriolus, ginger, resveratrol, green tea, artemsia, quercetin, carnosol, panax ginseng, silymarin, salicylates, curcumin, picentannol, basil, Cu antagonists rosemary

Anti-COX-2: quercetin, scutellaria, EPA/DHA, licorice, ginger, resveratrol, grapeseed extract, curcumin, salicylates, garlic, green tea, panax ginseng, silymarin, bilberry, antioxidants, boswellia, aloe

ComplicationsComplicationsof Supplementsof Supplements

Overall risk is fairly low but realOverall risk is fairly low but real Liver inflammationLiver inflammation Blood clottingBlood clotting GI side effectsGI side effects Delay of access to standard therapiesDelay of access to standard therapies Quality control issuesQuality control issues Potential to interfere with Chemo/RadPotential 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?