phytopharmaceuticals

8/8/2019 Phytopharmaceuticals

1/263

Phytopharmaceuticals:Your Key to Surviving Cancer!

Romulo S. de Villa, MD, PhD, Cert. Biochem.

Molecular & Nutritional Oncologist

Professor of Biochemistry & NutritionMolecular Biology & Biotechnology Consultant

www.drdevilla.com

This material may not be reproduced in any form without express written permission of Dr. de Villa.

www.drdevilla.com
http://www.drdevilla.com/http://www.drdevilla.com/


2/263

Cancer Development Steps

INITIATION Damage to genes

genetic and epigenetic

Phase I Enzymes convert procarcinogens to carcinogens that produce

defective genes Phase II Enzymes

eliminate carcinogens and other toxins by making themwater soluble

PROMOTION

Promoters stimulate proliferation or multiplication of cells withdefective genes making defective genes become permanentbecause there will be more cells containing the defectivegenes

PROGRESSION number of defective genes increase/multiply

DR. DE VILLA www.drdevilla.comEND


3/263

Carcinogenesis

INITIATION Oxidative Damage

producing defective genes






4/263

How CANCER and otherdiseases develop

TOXINS attack the cells,

cause cell damage and

transformation into CANCER.

damage

www.drdevilla.comENDPREVENTION


5/263

Carcinogenesis:

INITIATION Damage to genes

genetic and epigenetic




PROMOTION

Promoters stimulate proliferation or multiplication of cells withdefective genes making defective genes become permanentbecause there will be more cells containing the defectivegenes

PROGRESSION number of defective genes increase/multiply



6/263

Oncogenesis

Multi-step process consisting of randomdamaging events (years of trial and error eventsuntil success is achieved)

Stages Tumorigenesis (early battle) Consist of initiating and promoting events

Successive mutations of growth controlling genes

Transitional Event is Defective Repair

Tumor Progression (late battle)

Consist of initiating and promoting events

Mutation of repair genes leading to genomic instability

Multiplying defective genes



7/263

Oncogenesis

Multi-step process consisting of randomdamaging events (years of trial and error eventsuntil success is achieved)










8/263


9/263www.drdevilla.comEND

Normal Cells



2

Initiator(dna damaging)



2 2

Promoter(stimulate proliferation)



2 22

2



2 22

2

22

2 2



22

2

22

2 2

23



23



23 23



23 232323



23 232323

23

23

23

23

Homogenous

(monoclonal)


20/263

Oncogenesis

Multi-step process consisting of randommutational events (years of trial and error eventsuntil success is achieved)










21/263


22/263

www.drdevilla.comEND

23 232323

23

23

23

23

Homogenous

(monoclonal)


23/263

www.drdevilla.comEND

23 232323

23

23

23

234


24/263

www.drdevilla.com

23 232323

23

23

23

234

232323

23

23

2323

234


25/263

www.drdevilla.com

23 232323

23

23

23

234

232323

23

2323

234

238


26/263

www.drdevilla.com

23 232323

23

23

23

234

232323

23

2323

234

238238

234

234

23

2323

23

2323 23 23

23

23

2323

23


27/263

www.drdevilla.com

23 232323

23

23

23

234

232323

23

2323

234

238238

234

234

23

2323

23

2323 23 23

23

23

2323

236


28/263
http://www.drdevilla.com/


29/263


30/263


31/263


32/263


33/263


34/263


35/263


36/263


37/263


38/263


39/263


40/263


41/263


42/263


43/263

Up to 85%of cancers

can be prevented!MD Anderson Cancer Center

University of Texas, Houston

www.drdevilla.com www.drdevilla.comEND


44/263

Eat at least5-9 servings of

a variety offresh rawfruits & vegetables daily.

EAT 5 TO STAY ALIVE



45/263

Eating 5 Servings of Raw Fruits & Vegetables Daily

Reduces Cancer Risk

% Risk Reduction

33-50%

33-50%

66-75%

33-66%10-20%

10-20%

Type of Cancer

Lung Cancer

Breast Cancer

Colon/Rectal Cancer

Liver Cancer

Prostate Cancer

Cervical Cancer

andYou Stay Alive

Source: World Cancer Research Fund & American Institute for Cancer Research



46/263

Fruit and Vegetable Combinations

Fruits Only:

Apple, Orange, Melon, Watermelon Apple, Orange, Kiwi, Pineapple

Apple, Banana, Guava, Pineapple, Mango

Banana, Melon, Mango, Watermelon

Banana, Melon, Mango, Pineapple

Banana, Melon, Strawberry, Watermelon Pineapple, Orange

Fruits and Vegetables: Apple, Banana, Carrot, Mango

Apple, Banana, Carrot, Papaya

Apple, Carrot, Celery, Kiwi, Orange Apple, Carrot, Cucumber, Orange, Pineapple, Watermelon

Apple, Carrot, Strawberry, Watermelon

Vegetables Only: Carrot, Celery, Cucumber

END www.drdevilla.com


47/263

Phytochemicals and Bad Fats

Balance Each Other

The more fresh plant-based foods in the

diet, the less appetite for greasy bad fat-

laden foods

The more bad fats (pork, fried foods &

trans-fats) are in the diet, the greater the

likelihood that the person is eating less

fresh (raw) fruits and fresh (raw)

vegetables


48/263

PhytoPharmaceuticals

Even though a number of natural products may lessen

and/or ameliorate some cancers without causing any

significant adverse effects, more often than not these are

ignored, or at least not understood, by practicing

physicians. This is unfortunate because a significant

amount of research on phytopharmaceuticals has

validated their efficacy and usefulness in the prevention,

as well as treatment, of cancer. As a result, many patients

are deprived of these life improving, if not life saving,compounds.

Debasis Bagchi and Harry G. Preuss

Editors of Phytopharmaceuticals in Cancer Chemoprevention


49/263

PHYTOPHARMACEUTICALS

IN CANCER

CHEMOPREVENTION

Ph t t i t i F it


50/263

Phytonutrients in Fruits,

Vegetables & other Plant Foods

Red Grapes Resveratrol

Tomatoes Lycopene

Broccoli & Cauliflower SulforaneOther Plant Foods:

Green Tea Polyphenols

Garlic Allyl Sulfides Soy Bean Isoflavones

Flax Omega-3 Fatty Acids


H Ph t t i t i


51/263

How Phytonutrients in

Plant Foods May Prevent Cancer

Prevention of Initiation

Polyphenols & Lycopene (antioxidants)

Allylsulfides (reduce convertion of pro-cancer to cancercausing agents)

Sulforane (increase removal of cancer causing agentsfrom the body)



52/263

d-Glucarate

How Glucarate protects cellsfrom damage

GLUCURONIDIZED TOXINS

are kicked out of the body and thrown

into the urine. www.drdevilla.comENDTLN


53/263

d-Glucarate





l ll


54/263


d-Glucarate




Gl ll


55/263

d-Glucarate





H Gl ll


56/263

d-Glucarate






57/263

d-Glucarate




H Gl t t t ll


58/263

d-Glucarate






59/263

.

Thus, D-GLUCARATECLEANS THE BODY

by removing theTOXINS.

D-Glucarate

www.drdevilla.comENDTLN



60/263


Plant Foods May Prevent Cancer

Prevention of Initiation

Polyphenols & Lycopene (antioxidants)

Allylsulfides (reduce convertion of pro-cancer to cancercausing agents)

Sulforane (increase removal of cancer causing agentsfrom the body)


Prevention of Promotion

Omega-3 fatty acids (crowd out other fats, omega-6, that

promote cancer development) Isoflavones (reduce promotion of cancer)

Prevention of Progression

Resveratrol (suffocates cancer cells)

Ph t t i t P ti


61/263

Phytonutrient Prevention

of Cancer

Dietary Substances from Plant Foods withPotential Chemoprotective Properties

Polyphenols Lycopene

Allyl sulfides

Sulforaphane

Soy isoflavones Resveratrol



62/263

Nutrition Support for

Cancer Patients

www.drdevilla.com

LAYMAN DOCTORS:


N t iti l St t f


63/263

Nutritional Status of

Cancer Patients

Nutrition already impaired before start of therapy

Radio(Chemo) therapy may lead to furtherdeterioration of nutritional status

Enteral nutrition

preferred over parenteral nutrition for artificial long-term nutritional support in patients with advanced headand neck cancers

Feeding through PEG improves anthropometric, biochemicalparameters and quality of life

Fietkau R. Strahlenther Onkol. 1998 Nov;174 Suppl 3:47-51.

not indicated during radio(chemo) therapy of upper GImalignancies

www.drdevilla.com www.drdevilla.comENDTLN

N t iti l M t f


64/263

Nutritional Management of

Head and Neck Cancers

Before, During and After Surgery-Radio(Chemo)therapy

Prevents undernutrition

Improves quality of life Reduces adverse of effect of treatment

Prevents treatment delays

Good clinical practice in nutritional management of headand neck cancer patients. Meuric et. al., Bull Cancer. 1999Oct;86(10):843-54.



65/263

continuation

Before treatmentassess weight (10% weight lossin 6 months prior to treatment requires urgentnutritional intervention

Nutritional support started 7-10 days before surgerydecreases postoperative complications byapproximately 10% in malnourished patients withweight loss of 10% or more (Bertrand et. al., Curr OpinClin Nutr Metab Care. 2002 Jul;5(4):435-40)

Surgery During surgery enteral feeding must be stopped,

Post-operatively progressively introduce NGT feedingstarting day 1 post-op



66/263

continuation

During radiotherapy

adapt feeding to

swallowing mechanism,

side effects of treatment, and

age

early and constant enteral nutrition by PEG placed beforestart of radiotherapy can stabilize the nutritional state and thequality of life of patients during radiotherapy of head andneck tumors (Senft et. al., Support Care Cancer. 1993

Sep;1(5):272-5.) During chemotherapy

check and assess nutritional status at each cycle


M t b li St t f


67/263

Metabolic Status of

Cancer Patients Losing Weight Pancreatic Patients Losing Weight Compared to

Weight Stable Controls

Higher resting energy expenditure

Greater lean body mass Higher fat oxidation in the fasting state

Response to feeding Glucose intolerance

Lower percentage change in area under the curve of energy

expenditure

Metabolic response to feeding in weight-losing pancreaticcancer patients and its modulation by a fish-oil-enrichednutritional supplement. Barber et. al., Clinical Science(2000) 98, (389-399)


N t iti d C


68/263

Nutrition and Cancer

(feeding and starving cancer cells)

Feeds Cancer Cells

1. Excessive Free Radicalsor Oxidative Stress from

chemicals & toxins.

2. Excessive Glucose

.

.

3. Excessive Omega-6

.

.

.

.

Starves Cancer Cells

1. Antioxidant

Vitamins, Minerals, Trace

Elements, Phytonutrients

2. Reduce Available Glucose

High Fiber Diet

High Vitamin C

3. Balance excessive Omega-

6 with

Omega-3 (EPA & DHA)


E i f di l id ti


69/263

Excessive free radicals or oxidative

stress feeds cancer cells?

1. Free Radicals

Cause oxidative damage to genes

Firstnormal cells are converted to tumor cells

Thentumor cells become cancer cells that are

different (Increase heterogeneity) from each other

Increase chance of cancer cells surviving (biologic

principle of diversity increases chance of survival)



70/263

Reactive Oxygen Species

Role in Various Cellular Processes

Migration

Adhesion

Differentiation

Cell Growth


71/263


72/263

R f I i M t lit f


73/263

Reason for Increasing Mortality from

Non-communicable Disease

Agricultural Revolution

Pollution of air, land and water

Increased Corn and Soya Productivity Production of feeds using corn and soya meal for fattening

pork, cattle, poultry, and even fish Production of milk formula using corn oil and other vegetable

oil

Industrial Revolution

Pollution of air, land and water Production of margarine and butter compound that

contains trans fat produced from hydrogenation ofunsaturated fats

Refinement of Rice, Wheat and Sugar.

This material may not be reproduced in any form without express written permission of Dr. de Villa.

I d t i


74/263

Pro-Carcinogen CarcinogenDetoxified

Carcinogen

Diet

Industries

Phase II EnzymesPhase I Enzymes

Normal Cell Cancer Cell

Proto-OncogenesTumor Suppressor Genes

Anti-Mutator Genes

Xenobiotic Metab GenesOncogenesTumor Inducer Genes

Mutator Genes

Xenobiotic Anti-Metab Genes

- initiation- promotion



75/263

Pollution Accumulates in

Certain Foods

Bioaccumulation of

Herbicides and Pesticides

Industrial Chemicals

Mine Tailings

Biological Mechanisms of Accumulation

Food Chain

Water Cycle


76/263

PhotoChemical Smog


77/263

Air Pollution in the Philippines


78/263

Land Pollution

Guess Whats Coming


79/263

Guess What s Comingto Dinner


Toxic Chemicals that Damage


80/263


Genes are Found in Food Traces of man-made chemicals are found in food

Chemicals used to remove fibers and whiten the foodduring refinement




81/263




Pesticides, herbicides and manufactured feeds used byfarmers to increase productivity



82/263

3 Strikes on Pork

Strike 1

High levels of fat soluble chemicals (xenobiotics) thatgeneral free radicals

Strike 2 Rich in Omega-6 fatty acids that promote moreinflammation a factor in oncogenesis, atherogenesis &arthritis

Strike 3

Rich in long chain saturated fatty acids that promoteatherogenesis & diabetes

Pork and Pork Products ARE OUT




83/263





Chemical pollutants introduced into the environmentand accumulating in sea foods (shrimps, crabs, shells)that grow in the bottom of the sea


A new Swedish study by Professor Lennart


84/263

A new Swedish study by Professor LennartHardell indicates the carcinogenic effectsof the toxin PCB can manifest themselves

30 years later.

Norwegian men may now be developing

testicle cancer due their mothers eatingcontaminated seafood during pregnancy.

PCBs (Polychlorinated Biphenyls) are

common industrial chemicals and one ofthe world's most widespread and toxicpollutants.


3 Strikes on


85/263

3 Strikes on

Bottom Dwelling Animals Strike 1

Concentration of chemical (xenobiotic) pollutantsthrough the water cycle

Strike 2

Accumulation of pollutants within themselves throughthe food chain

Strike 3

Produces nerve poisons to defend themselves frombeing eaten

Shrimps, Crabs, Shells, Oyster, Squids, LobstersARE OUT




86/263





Chemical pollutants introduced into the environmentand accumulating in sea foods (shrimps, crabs, shells)that grow in the bottom of the sea

Cooking Produces powerful toxic mutagens (heterocyclic amines) on

the surface of meats

Heating oils produces Lipid Hydro Peroxides which damagecolon cells [Food Chem Toxicol. 2003 Nov;41(11):1481-9]


Processing Produces


87/263

g

Toxic Substances

Exposure to high heat of cooking above 100oCconverts unsaturated fatty acids to lipidperoxides

High temperature cooking (baking & frying) of

starch based foods produces acrylamide E.g. potato chips, french fries, cakes, cookies

Broiling meat in charcoal producescarcinogenic substances such as benzopyreneand methylcholanthrene

Heating food in plastic containers releaseschemicals in the plastic to the food

F i


88/263

Frying

Heated vegetable oils contain acrolein Heat treated foods produces acrylamides

Lipid Peroxidesfrom Thermally Oxidized Corn OilAccumulates in the Liver & Kidneys

Fried meat contains mutagens Oxidation of dietary oils produces genotoxic dicarbonyls

Oxidation of vegetable oil during frying

Frying alters oil levels

Heterocyclic amines from high temperature cooking ofmeat

Heterocyclic amines in well cooked pork beef chicken

Catechins inhibit lipid peroxidation

Toxicity of oxidized fats II: tissue levels of lipid peroxides
http://heatedvegetableoilscontainacrolein.htm/http://heattreatedfoodsproduceacrylamides.htm/http://friedmeatcontainmutagens.htm/http://oxidationofdietaryoilsproducesgenotoxicdicarbonyls.htm/http://ironincreasesoxidationofvegetableoilduringfrying.htm/http://fryingalteroillevel.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://catechinsinhibitlipidperoxidation.htm/http://catechinsinhibitlipidperoxidation.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://fryingalteroillevel.htm/http://ironincreasesoxidationofvegetableoilduringfrying.htm/http://oxidationofdietaryoilsproducesgenotoxicdicarbonyls.htm/http://friedmeatcontainmutagens.htm/http://heattreatedfoodsproduceacrylamides.htm/http://heatedvegetableoilscontainacrolein.htm/


89/263

in rats fed a thermally oxidized corn oil diet.Nwanguma BC, AchebeAC, Ezeanyika LU, Eze LC. (Food Chem Toxicol. 1999 Apr;37(4):413-6.) Department of Biochemistry,

Univ. of Nigeria, Nsukka, Enugu State.

Methodology:

Male Wistar albino rats were fed for 21 days on a diet in which fat(12%) was included either as fresh corn oil, malonaldehyde content= 0.11+/-0.05 micro microg/g (control) or thermally oxidized cornoil, malonaldehyde content = 0.20+/-0.03 microg/g (experimental)

and the tissue levels of lipid peroxides in six organs-namely, liver,kidney, brain, heart, lungs and testes-were determined.

Results:Of the organs studied, significantly (P < 0.1) higher concentrationsof lipid peroxides were observed only in the liver and kidney of the

experimental rats. In the course of the feeding, the experimentalrats showed significantly (P < 0.1) lower gains in body weights aswell as higher relative liver weights than the control rats.


90/263

Baking

Heat treated foods produces acrylamides

Acrylamide in ginger bread

Acrylamide in wheat bread

Heterocyclic amines from high temperaturecooking of meat

Heterocyclic amines in well cooked pork

beef chicken
http://heattreatedfoodsproduceacrylamides.htm/http://acrylamideingingerbread.htm/http://acrylamideinwheatbread.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://acrylamideinwheatbread.htm/http://acrylamideingingerbread.htm/http://heattreatedfoodsproduceacrylamides.htm/


91/263

Broiling / Grilling

Grilled fish contain heterocyclic aminemutagens


Heterocyclic amines from high temperaturecooking of meat

Heterocyclic amines in well cooked pork

beef chicken
http://grilledfishcontainheterocyclicaminemutagens.htm/http://grilledfishcontainheterocyclicaminemutagens.htm/http://heattreatedfoodsproduceacrylamides.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesinwellcookedporkbeefchicken.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heterocyclicaminesfromhightemperaturecookingofmeat.htm/http://heattreatedfoodsproduceacrylamides.htm/http://grilledfishcontainheterocyclicaminemutagens.htm/http://grilledfishcontainheterocyclicaminemutagens.htm/


92/263

Microwaving


Heating plastics releases trapped chemicals

into the food

ili
http://heattreatedfoodsproduceacrylamides.htm/http://heattreatedfoodsproduceacrylamides.htm/


93/263

Boiling

Acrylamide not found in boiled vegetables

Chemicals
http://acrylamidenotfoundinboiledvegetables.htm/http://acrylamidenotfoundinboiledvegetables.htm/


94/263

Chemicals

Weaken the Immune System

Triphenyltin pesticide

Reduce natural killer cell activity by 50-60%

Bisphenol A


A i id ll ?


95/263

Antioxidants starve cancer cells?

1. Antioxidant

Vitamins,

Minerals,

Trace Elements,

Phytonutrients

Carotenoids

Carotenes, lycopene, lutein, zeaxanthine

Polyphenols

Catechins, isoflavones Lipoic acid

Quercetin


Response to Oxidative Damage by


96/263

Response to Oxidative Damage by

Toxic Chemicals:

Anti-oxidant Supplementation of the

Chemically Polluted Diet


Carotenoids


97/263

Carotenoids

Predict Antioxidant Status

Recent paper published in the Journal of Nutrition,2004:

Carotenoids interact with the antioxidant network

Carotenoids (blood) are indicator of total antioxidant status

Vitamin E (blood) is not a good indicator of antioxidantstatus



98/263

Th Si l T t


99/263

The Simple Test

BIOPHOTONIC SCANNER

Have you been eating right?Do your supplements work?

The ability to

MEASURE is thebasis ofSCIENCE


Carotenoid Correlation Study


100/263

Journal of the American College of Nutrition, Vol.23, p.468, Oct 2004

Skin vs. Serum Carotenoids (n = 372)

r = 0.84

0

10000

20000

30000

40000

50000

60000

0 0.5 1 1.5 2 2.5 3 3.5 4

Total Serum Carotenoids (mcg/ml)

R

amanIntensity,C

ounts

.


Scanner Readings Correlate with Smoking


101/263

g g

19890

13030

17600 17591

1305611593

0

5000

10000

15000

20000

25000

30000

Non-

Smokers

Smokers

(all)

Past

Smokers

< 1/day 1-5/day > 5/day

n = 1047

n = 58

p < 0.01

n = 39 n = 10

n = 16

n = 32

ENDTLN

Scanner Readings Correlate with

B d M I d


102/263

Body Mass Index

29,236

25,612

20,835

16,603

10,000

15,000

20,000

25,000

30,000

35,000

< 25 25-29 30-39 > 40

Body Mass Index (BMI, kg/m2)

RamanIntes

ity,

Counts

.

n = 11,588 n = 8,475 n = 422

p < 0.01 p < 0.01 p < 0.01

n = 4,550

2004 Data of 25,035 Subjects Overweight people need extra

antioxidant protection through

diet and supplementation.

ENDTLN

Scanner Readings Correlate with

Fruits & Vegetable Intake


103/263

Fruits & Vegetable Intake

10,000

15,000

20,000

25,000

30,000

35,000

Reported Daily Fruit & Vegetable Servings

RamanInten

sity,

Counts

.

21,981

1 or Less

n = 9,336

24,773

2 to 3

n = 13,600

28,560

4 to 5

n = 6,916

p < 0.01 p < 0.01 p < 0.01

2004 Data of 32,648 Non-Supplement Users

6 or More

n = 2,796

31,100

ENDTLN

Effectiveness of Antioxidant*


104/263

32175

25991

28924

18828

10000

15000

20000

25000

30000

35000

40000

0 4 8 12

Time (Weeks)

RamanIntensity

,Counts

.

p < 0.001

p < 0.01

p = 0.23

Supplementation

* LifePak ENDTLN

E i l f d ll


105/263

Excessive glucose feeds cancer cells

2. Excessive Glucose Cancer cells utilize glucose anaerobically

producing lactic acid and obtaining less energy

(ATP) per glucose molecule Cancer cells are highly sensitive to insulin and

have more numerous glucose transporters on their

membranes

research shows insulin resistance of non-cancercells and hyperinsulinemia may be linked to

several kinds of cancer (breast & colon)


Refined Foods and Low Fiber


106/263

Diet

Processing2DR. DE VILLA


107/263

g

Removes Dietary Fiber Polished Rice, Refined Flour, and Refined Sugar

White Rice 0.4g/100g : Brown Rice 1.8g/100g

White Bread 2.3g/100g : Whole Wheat 6.9g/100g

White Sugar

Meat (beef, pork, poultry, fish) and Milk

do not have dietary fiber

Amount of fiber required in the diet

20-30 grams/day Ask audience to estimate the amount of fiber in

their last meal.


Dietary fiber starves cancer cells


108/263

Dietary fiber starves cancer cells

2. Reduce Available Glucose

High Fiber Diet

High Vitamin C


High Fiber Diet


109/263

High Fiber Diet

Numerous Benefits from


110/263

Fiber in the Diet

Blood Cholesterol Control

Blood Sugar Control

Blood Pressure Control

GI Muscle Exercise

Maintain Normal GI Flora

Stimulate the Immune System

Satiety Control Toxin Control

Prevent Colon Cancer


High Fiber Diet


111/263

g

Prevents Colon Cancer

Reduces risk of colon cancer by half European Prospective Investigation on Cancer. Lancet.

May 3, 2003.

May prevent bile induced hyperproliferation

Dig Dis Sci. 2003 Jun;48(6):1094-101.

Adsorbs toxins that cause cancer

Promotes growth of beneficial bacteria

generating products that

enhance the immune system

Dietary Fiber Content: 35 grams / day


Clinical Benefits of


112/263

High Dose Vitamin C

4.2 times longer survival (Cameron, 1976)

1,000 terminally ill caner patients

10 g / day

Greater response to radiotherapy (Cheraskin,1968)

27 patients on each arm

750 mg / day

Amount of Vitamin C intake is inversely correlatedto cancer incidence

(Chope & Breslow, 1948)


High Dose Vitamin C


113/263

High Dose Vitamin C

Starves the cancer. Ascorbates neutralize free radicals and become

converted to dehydro-ascorbate

Cancer cells take in dehydro-ascorbates that looklike glucose

blocking energy supply from the metabolism of glucose

act as oxidants inside the cancer cells

Walls off the cancer cells by surrounding them with strong collagen fibers


Effects of High Dose Vitamin C


114/263

Effects of High Dose Vitamin C

High dose ascorbate cytotoxicity to cancer cellsenhanced by lipoic acid from spinach

Kidney stones occur among RARE patients whoconvert ascorbate to oxalate

Stone formation is associated with alkaline and acidicurine

Sodium ascorbateno effect on urine pH

Ascorbic acidacidic urine (promote urate stone formation)

Loose bowel movement Utilized for individualizing dose


Excess omega 6 feeds cancer cells
http://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htm


115/263

Excess omega-6 feeds cancer cells

3. Omega-3 to Omega-6 Imbalance

Healthy balance is 1:1 up to 1:4

(omega-3:omega-6)

Zusman et al, Anticancer Res 17(1A)349, 1997


Unsaturated Fatty Acids


116/263

and Cancer

Omega-6 fatty acids

linoleic

promote development of mammary tumors in

chemically induced rats

Oleic and Palmitoleic acid are protective Zusman et al, Anticancer Res 17(1A)349, 1997

Land Meat Eaters1 Omega-3 : 40 Omega-6


LAYMAN DOCTORS:

TLN

Cancer and Weight LossCancer and Weight LossCancer and Weight Loss


117/263

E0201257A 4

-80%

-60%

-40%

-20%

0%

5-10% >10%Weight loss in previous 6 months

Colon

Lungsmallcell

Lungnon-small

cell PancreasMeasurable

gastric

14%

14%

20%

14%

21%

15%

28%

26%

29%

38%

DeWys et al. 1980. Am J Med. 69:491

%Pa

tientswithWeig

htLoss

Cancer and Weight LossCancer and Weight LossCa ce a d e g t oss

www.drdevilla.com

Causes of Weight Loss inCauses of Weight Loss inCancer PatientsCancer Patients


118/263

E0201257A 5

Cancer PatientsCancer Patients

Mechanical obstruction of ingestionMechanical obstruction of ingestion

TreatmentTreatment--induced side effectsinduced side effects

Psychological issuesPsychological issues

TumorTumor--induced effectsinduced effects

Rivadeneira et al. 1998. CA Cancer J Clin. 48:69

www.drdevilla.com

Characteristics of TumorCharacteristics of TumorInduced Weight LossInduced Weight Loss


119/263

E0201257A 7

Induced Weight LossInduced Weight Loss

Anorexia and early satietyAnorexia and early satiety

Accelerated loss of protein and fatAccelerated loss of protein and fat

Altered energy metabolismAltered energy metabolism

Increased resting energy expenditureIncreased resting energy expenditure

Rivadeneira et al. 1998. CA Cancer J Clin. 48:69

www.drdevilla.com

Mechanism of ActionMechanism of Action


120/263

Weight Loss

Malignant Tumor Cells

Cytokine ProductionIL-1, IL-6 TNF-

Proteolysis-Inducing

Factor

Acute PhaseProtein ResponseInitiated ( CRP)

DepressedAppetite

Metabolism ofMacronutrients

Affected

Loss of LeanBody MassREEFood Intake

www.drdevilla.com



121/263

Weight Loss




Factor

Acute PhaseResponse

Initiated ( CRP)Depressed

Appetite


Affected

Loss of Lean

Body Mass

REEFood Intake

www.drdevilla.com



122/263

Weight Loss




Factor

Acute PhaseResponse


Appetite


Affected

Loss of Lean

Body Mass

REEFood Intake

www.drdevilla.com



123/263

Weight Loss




Factor

Acute PhaseResponse


Appetite


Affected

Loss of Lean

Body Mass

REEFood Intake

www.drdevilla.com


124/263

CANCER INDUCED

WEIGHT LOSS


Natural Progression of


125/263

Cancer Induced Weight Loss Normal

Initiating tumor factors

Metabolic changes

Mild weight loss / anorexia

Below ideal body weight

Moderate weight loss / reduced activity

Obvious muscle wasting

Severe weight loss / cachectic state Death


Comparison of Nutritional Alterations


126/263

Comparison of Nutritional Alterations

CANCER CACHEXIA STARVATION

Body weight Normal / decreased Decreased

Body cell mass Decreased Decreased

Body fat Decreased Decreased

Energy intake Decreased DecreasedTotal energy expenditure Decreased Decreased

Resting energy expenditure Increased Decreased

Protein synthesis Increased / decreased Decreased

Protein degradation Increased Decreased

Serum insulin Increased Decreased

Serum cortisol Increased Decreased

Adapted from Kotler, 2000


What is Cancer Cachexia?


127/263

What is Cancer Cachexia?

Severe weight loss

Characterized by Anorexia

Early satiety

Muscle wasting

Weakness

Anemia

Due to systemic tumor effects


Systemic Tumor Effects


128/263

Systemic Tumor Effects

Inadequate energy intake

Metabolic abnormalities Increased cori cycle activity

Dimished lipogenesis

Lypolysis

Protein catbolism

Decreaed muscle protein synthesis

Increased acute phase protein response

Increased pro-inflammatory cytokines

Increased energy expenditure

LAYMAN DOCTORS:


Pathways of Cancer Cachexia


129/263

Pathways of Cancer Cachexia

Increased proteolytic inducing factor

Altered protein metabolism

Decreased lean body mass

Weight loss

Altered carbohydrate metabolism

Increased resting energy expenditure

Weight loss

Cytokine production


Cytokine production


130/263

Cytokine production

Decreased appetite

Anorexia Weight loss

Initiate acute phase protein response Decreased lean body mass

Increased resting energy expenditure

Weight loss

Systemic effects Altered protein metabolism

Decrease lean body mass

Weight loss

Altered carbohydrate metabolism

Increase resting energy expenditure

Weight loss

Altered fat metabolism


Cytokine-associated Metabolic Alterations


131/263

y

METABOLIC ALTERATION CYTOKINES

Protein Metabolism TNF-alpha, IL-1, LIF, IL-6

Carbohydrate Metabolism IL-6, TNF-alpha

Fat Metabolism TNF-alpha, IL-1, LIF, IFN-

gamma

Hormonal Changes TNF-alpha, IL-1




132/263

y


Protein Metabolism

increased whole body protein turnover

increased hepatic protein synthesis

changes in circulating amino acid pattern

increased muscle protein degradation

decreased muscle amino acid uptake

increased branch chain amino acid turnover

TNF-alpha

TNF-alpha, IL-1, LIF, IL-6

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha, IL-1

Carbohydrate Metabolism

increased hepatic gluconeogenesis

increased cori cycle activity

increased glucose turnover

decreased muscle insulin-estim glucose uptake

IL-6

TNF-alpha

TNF-alpha

TNF-alpha




133/263

y


Fat Metabolism

hyperlipidemia

decreased white adipose tissue LPL activity

increased white adipose tissue lipolysisincreased brown adipose thermogenesis



TNF-alpha, IL-1, LIF, IL-6TNF-alpha

Hormonal Changes

insulin resistance

increased counter-regulatory hormones

TNF-alpha

TNF-alpha, IL-1


Omega-3 starves cancer cells


134/263

Omega 3 starves cancer cells

3. Balance excessive Omega-6 with

Omega-3 (EPA & DHA)


Health Benefits from Fish


135/263

Health Benefits from Fish

Source of omega-3 fatty acids and balance

the omega-6 fatty acids

Healthy balance is 1:4 (omega-3:omega-6)

Land meat eaters (1:40)

Pork is rich in omega-6

converted to inflammatory prostaglandins & leukotrienes

activate promotion step of cancer development

www.drdevilla.com

LAYMAN DOCTORS:



136/263

EPAEPA

www.drdevilla.com



137/263

Attenuation of Weight LossAttenuation of Weight Loss

Malignant Tumor CellsMalignant Tumor Cells

Cytokine ProductionCytokine ProductionILIL--1, IL1, IL--6 TNF6 TNF--

ProteolysisProteolysis--InducingInducing

FactorFactor

Acute PhaseAcute PhaseResponseResponse

AppetiteAppetite

Metabolism ofMetabolism ofMacronutrientsMacronutrients

NormalizedNormalized

LeanLean

Body MassBody Mass

REEREEFood IntakeFood Intake

EPAEPA

www.drdevilla.com

EPA and Tumor InducedEPA and Tumor InducedWeight LossWeight Loss


138/263

Wigmore. 1996. Nutrition. 12:27s

Weight change before and after a median of 3 months supplementationwith fish oil in patients with unresectable pancreatic cancer (n=18)

E0201257A 29

Wigmore. 1996. Nutrition. 12:27s

Weight LossWeight Loss

Weight change before and after a median of 3 months supplementationwith fish oil in patients with unresectable pancreatic cancer (n=18)

ChangeinWeigh

tkg/month

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

1 2 3 4 5 6 7 8 9 10 1 1 12 13 1 4 15 16 1 7 18

Before EPA

EPA

www.drdevilla.com



139/263

E0201257A 30

Wigmore. 2000. Nutrition and Cancer. 36:177


25

20

15

10

5

0

-5

-10

-15

-20

WeightChange(kg)

-10 -8 -6 -4 -2 0

EPA

Started

Time (months)

www.drdevilla.com



140/263


Time (months)

E0201257A 31



Time (months)

25

20

15

10

5

0

-5

-10

-15

-20

WeightChange(kg)

-10 -8 -6 -4 -2 0 108642 12 14 16 18

EPA

Started

www.drdevilla.com

LAYMAN DOCTORS:

Roles of EPARoles of EPA


141/263

E0201257A 32

Roles of EPARoles of EPA

Inflammatory responseInflammatory response ProPro--inflammatory cytokine productioninflammatory cytokine production Attenuates APPRAttenuates APPR

LLevel/activity of proteolysisevel/activity of proteolysis--inducinginducingfactor (PIF)factor (PIF)

AttenuatesAttenuates tumortumor--induced weight lossinduced weight loss

Increases survivalIncreases survival

www.drdevilla.com

HypothesisHypothesis


142/263

E0201257A 33

HypothesisHypothesis

If fish oil (EPA) stabilizes weight bysuppressing metabolic changes incancer, EPA in combination with

calories and protein will result in weightgain.

www.drdevilla.com


143/263

Clinical TrialsClinical Trials

www.drdevilla.com


144/263


145/263


146/263

Fearon KCH. 2001; Eur J Cancer37:27SFearon KCH. 2001; Eur J Cancer37:27S

Randomized Clinical TrialRandomized Clinical Trial

www.drdevilla.com

Study DesignStudy Design


147/263

Fearon KCH. 2001; Eur J Cancer37:27S

E0201257A 38

y gy g

Prospective, doubleProspective, double--blind, randomized,blind, randomized,

multimulti--center trialcenter trial

Unresectable pancreatic cancer (n=200)Unresectable pancreatic cancer (n=200)

High protein, energy dense oral supplement with orHigh protein, energy dense oral supplement with orwithout EPA.without EPA.


www.drdevilla.com

Study Supplement ComparisonStudy Supplement Comparison


148/263

E0201257A 39

y pp py pp p

Control/ExperimentalControl/Experimental

300 kcal per serving300 kcal per serving

ProteinProtein 16 g16 g

CarbohydrateCarbohydrate

50 g50 g

FiberFiber 5 g (2.6 g FOS)5 g (2.6 g FOS)

FatFat 6 g6 g

Complete range of vitamins andComplete range of vitamins andmineralsminerals

Experimental ProductExperimental Product

EPAEPA 1.09 g1.09 g

www.drdevilla.com

Recommended IntakeRecommended Intake (1.5(1.5--2.0 cans/day)2.0 cans/day)Change in Wt and LBM at 8 WeeksChange in Wt and LBM at 8 Weeks


149/263

n=30 n=28n=26 n=22

E0201257A 40

Change in Wt and LBM at 8 WeeksC a ge t a d at 8 ee s

0.46

0.09

1.21

1.46

0.00.2

0.4

0.6

0.81.0

1.2

1.4

1.6

Wt LBM

Control

ExperimentalProduct

p=NS

Kilograms

n=30 n=28n=26 n=22

www.drdevilla.com

ProSure Consumption vs. LeanProduct Consumption vs. LeanBody MassBody Mass


150/263

E0201257A 41

Body MassBody Mass

-10

-8

-6

-4

-2

02

4

6

8

10

0 0.5 1 1.5 2


Unit Intake (cans)

LeanBodyM

ass(kg)

P=0.036 r=0.332

www.drdevilla.com

Weight change vs. EQ5DWeight change vs. EQ5Dindexindex(Subjects on the Product)(Subjects on the Product)


151/263

E0201257A 42

( bj )( j )

-1

0

1

-10 -5 0 5 10

Weight Change (kg)

EQ5Dind

ex

n=49, r=0.46, p=0.001

www.drdevilla.com

Physical Activity Level As anPhysical Activity Level As anObjective Measure of Quality of LifeObjective Measure of Quality of Life


152/263

E0201257A 43

j yj y

Total energy expenditure/Resting energyTotal energy expenditure/Resting energy

expenditure Physical activity levelexpenditure Physical activity level

TEETEE measured using doubly labelled watermeasured using doubly labelled water

REEREE

measured by indirect calorimetrymeasured by indirect calorimetry

Physical activity levelPhysical activity level

~1.1 Morbid~1.1 Morbid

~1.5 Normal~1.5 Normal

~1.8 Active~1.8 Active

www.drdevilla.com

Effect on Physical Activity LevelEffect on Physical Activity Level


153/263

Moses et al. 2001 Clin Nutr20:21

E0201257A 44

y yy y

TEE/REE

PhysicalActivityLevel

Control Group (n=12) Experimental Group (n=7)

1.23

1.32

1.29

1.48

1.0

1.1

1.2

1.3

1.4

1.5

1.6

Baseline 8 W eeks Baseline 8 W eeks

NormalSedentary

Level

Confinedto Bed

p=NS p=0.005

Moses et al. 2001 Clin Nutr20:21

www.drdevilla.com

Total Energy and Protein IntakeTotal Energy and Protein Intake(Experimental group)(Experimental group)


154/263

E0201257A 45

( p g p)( p g p)

0

500

1000

1500

2000

Baseline 8 Weeks

p=0.001

Bauer et al. Nutrition Week. 2002

p=0.001

Calories(kc

al)

0

20

40

60

80

Baseline 8 Weeks

Protein(g

)

78

63

1800

1465

www.drdevilla.com


155/263

improvement of lean tissue mass, physical functionimprovement of lean tissue mass, physical function

E0201257A 47

Weight loss in cancer is driven by a varietyWeight loss in cancer is driven by a varietyof metabolic alterationsof metabolic alterations

These prevent the effective use of additional caloriesThese prevent the effective use of additional calories

EPA normalize some of these metabolic changesEPA normalize some of these metabolic changes

The combination of EPA with additionalThe combination of EPA with additionalcalories and protein allows for a gain in weight andcalories and protein allows for a gain in weight and

and quality of lifeand quality of life

www.drdevilla.com

What Starves the Cancer Cells?


156/263

1. AntioxidantVitamins, Minerals, Trace Elements,

Phytonutrients

2. Reduce Available GlucoseHigh Fiber Diet

High Vitamin C

3. Balance excessive Omega-6 with

Omega-3 (EPA & DHA)


Nutrition Therapy for

Cancer Patients


157/263

Cancer Patients

Malnutrition kills more than 40% of cancerpatients

Nutrition protects patient against toxic effects ofchemo & radiation without reducing

effectiveness

Nutrients support the immune system in killingcancer cells

Excessive Sugar feeds cancer cells

Nutrients can become biological responsemodifiers in changing the way the body worksto re-regulate cancer cells


Phyto-Pharmaceuticals


158/263

y

Definition: HERBAL MEDICINES (HM)

Are finished, labeled medicinal products

that contain as active ingredients aerial orunderground parts of plants or other plantmaterials, or combinations thereof, whether incrude state or as plant preparations. Plant

material includes juices, gums, fatty oils,essential oils, & any other substance of thisnature. (BFAD)

www.drdevilla.comwww.drdevilla.com www.drdevilla.comENDTLN

Herbs in Cancer Care


159/263

Plants have catered to the medical needs

of human civilization since prehistoric

times, but it is only during the last 100

years that mankind has begun toscientifically characterize their active

principles and put them to use in modern

medicine.Gottumukkala V. Subbaraju and Golakoti Trimurtulu

http://www.drdevilla.com/http://www.drdevilla.com/http://www.drdevilla.com/http://www.drdevilla.com/


160/263

"Herbs are powerful, biologically active productsthat do have important biological effects. Those

effects can be useful at some times and harmful

under other circumstancesBarrie Cassileth, chief of integrative medicine at

Memorial Sloan-Kettering

Research is under way around the globe to

scientifically document the effects of hundreds of

herbs and other dietary supplements.Jennifer Thomas, Health Scout


Nine Steps from Bench to Clinic


161/263

Selection of plants

Evaluation of extracts

Selection of active

fractions Determination of

novel chemical

structures

Synthesis of active

chemopreventive

agents

Examination of novelchemopreventive

agent

Synthesis of analogs Determination of

mechanism of action

Development of new

agents for clinical

trials

Herb Derived

Anti-Cancer Drugs


162/263

Anti-Cancer Drugs

Taxol

From yew tree

Kinetically stabilizes microtubule dynamics,

preventing depolymerization of microtubulenetwork essential for cell replication

Treatment of breast and ovarian cancer


Herb Derived

Anti-Cancer Drugs


163/263

Anti Cancer Drugs

Vinblastin and Vincristine

From Vinca rosea (rosy periwinkle, a common

garden plant)

Binds to tubulin protein preventing the cellfrom undergoing necessary changes for cell

division

Treatment of Hodgkins disease andd

childhood leukemia


Herb Derived

Anti-Cancer Drugs


164/263

Anti Cancer Drugs

Etoposide

Analog of podophyllotoxin derived from

Mayapple, a plant native to Minnesota

Podophyllotoxin is used against warts and wasshown to have anti-cancer activity in human

studies

Treatment of non-Hodgkinss lymphomas,

leukemias, small cell lung cancer, testicular

cancer


Herb Derived

Anti-Cancer Drugs


165/263

Anti Cancer Drugs

CPT-11, Irinotecan and Topotecan

Analog of camptothecin derived from

Camptotheca acuminata native to southern

China and Tibet and popularly called happytree

Inhibits topoisomerase I which mediates

winding/unwinding action of DNA strands

during cell proliferation

Treatment of ovarian cancer and metastatic

colorectal cancers


FOOD = MEDICINE


166/263

Let your food be your medicine and

your medicine be your food.Hippocrates

If you choosehealth promoting & maintaining foodsyour food is medicine.


What Foods are

Medicines Against Cancer?


167/263

Medicines Against Cancer?

Plant Foods

Vegetables (e.g. brocolli)

Beans (e.g. soybean)

Food Herbs (e.g. garlic)

Tea (e.g. green tea)

Animal Foods

Full Cream Powdered Milk

Boiled Eggs

Fish (e.g. salmon)


LAYMAN DOCTORS:

Pharmacologic Nutritional

Support for Cancer Patients


168/263

Support for Cancer Patients

Arginine

Reduce growth of transplantable tumors

Reduce incidence of metastasis

Reduce tumor producing potential of carcinogens Effects of dietetic supplementation with L-arginine in

cancer patients. A review of the literature. Novaes &

Lima. Arch Latinoam Nutr. 1999 Dec;49(4):301-8.

Glutamine

Cysteine


Chemopreventive Agents


169/263

Mechanisms and Targets for Selected Dietary Chemopreventive Agents

Polyphenols Cytochrome P450 Inhibits activation of Carcinogen5a reductase enzyme Modulates hormone activityornithine decarboxylase Inhibits polyamine synthesisCaspase enzyme Induces apoptosis

Genistein Cytochrome P450 Inhibits activation of carcinogenestrogen receptor Modulates hormone activityIGF-I receptor Modulates growth-factor receptorsTGF-beta Induces terminal differentiation/apoptosis

FGF receptor Inhibits angiogenesis

Substance Molecular Target Mechanism of Action


Chemopreventive Agents


170/263

Mechanisms and Targets for Selected Dietary Chemopreventive Agents

Resveratrol Aromatase enzyme Modulates hormone activityLDL cholesterol AntioxidationCOX enzymes Anti-inflammatoryNF-kB and API Signal transduction

Lycopene Connexin 43 Enhances intercellular junctionsDNA, lipids AntioxidationGST, GSH Deactivation of carcinogen

Substance Molecular Target Mechanism of Action


Nutraceutical Therapy of Cancer

with Food Supplements


171/263

pp

Dietary Substances with PotentialChemoprotective Properties

Green tea polyphenols (catechins)

ResveratrolSoy isoflavones (Genistein)

Lipoic acid

CurcuminLycopene

Chlorophyllin

DR. DE VILLA www.drdevilla.comENDTLN

Phenolic PhytoPharmaceuticals

T C C ll


172/263

Targets Cancer Cells

Studies of the Anticarcinogenic Effect of Phenolic Compounds

Substance Target Effect

Tea PolyphenolsGreen Tea Lung tumor formation InhibitionEGCG Lung cancer cells Increased apoptosis,

growth inhibitionProstate cancer cell lines Apoptosis

Black Tea Lung tumor formation Inhibition



T t C C ll


173/263



PhenolsResveratrol Promyelocytic Leukemia Decreased Viability &DNA synthesisCaffeic acid COX-2/Prostaglandin synthesis SuppressionEllagic acid,tannic acid Skin tumors InhibitionCaffeic acid,ferrulicAcid

Apigenin,tangeretin Liver epithelial cells Antagonism to tumor-induced

Inhibition of intercellularCommunication




T t C C ll


174/263


FlavonoidsFlavopiridol Prostate carcinoma cells Antitumor activity in vivo and in vitroHesperidin Skin Inhibition of polycyclic aromatic

Hydrocarbon-induced tumorInitiation

Quercetin MCF-7 breast cancer cells Decrease in cell protein content;Inhibitionof protein DNA and

RNA SynthesisRutin Nuclear DNA Reduction of aflatoxin B1




POLYPHENOLS


175/263

Large group of plant substances

Catechins,

Flavonol,Isoflavones,

and more


Catechins


176/263

Found in green tea, grapes, apples, pears

Forms found in green tea epicatechin (EC)

epigallocatechin (EGC)

epicatechin gallate (ECG)

epigallocatechin gallate (EGCG) Actions

antioxidant activity

anticarcinogenic

anti-inflammatory

anti-atherogenic

thermogenic antimicrobial activities



177/263

Studies on EGCG


178/263

Catechin reverses Tamoxifen induced liver injury Protects cells from free radical damage (w/ Ames

test) 80x more than Vit C

10x more than Vit E

2x more than anti-ox in red wine Blocks phase I enzymes and prevents formation of

nitrosoamines

Increase Glutathione Peroxidase

Catalase

Inhibit spontaneous & photoenhanced lipidperoxidation


Biological Effects of

Epigallocatechin-3-Gallate
http://polyphenols/CATECHINS/Green%20Tea%20Extract%20Reverses%20Tamoxifen%20induced%20liver%20toxicity.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://polyphenols/CATECHINS/Green%20Tea%20Extract%20Reverses%20Tamoxifen%20induced%20liver%20toxicity.htm


179/263

Go/G1 phase arrest 1999 (AACR abstract # 3507)

induce expression of p21 & p27 (cdki)

Lin et al, 1999

induce apoptosis by down regulating ras-

p21 & enhance p53 expression in MCF7 Jin et al, 1999 (AACR abstract # 3506)

inhibit EGFR, MAPK activation, AKT

activation & p21 induction Chen, 1999 (AACR abstract # 3518)


Biological Effects of

Epigallocatechin-3-Gallate


180/263

Induce WAF1/p21 in LNCAP & DU145 Gupta, 1999 (AACR abstract # 3509)

macrophage activation in mice which istumoricidal Naraparaju, 1999(AACR abstract # 3515)

inhibit erb-B1 activation and impair AKT

(PI3 kinase) activation Bhatia, 1999 (AACR abstract # 3517)


Flavonoids


181/263

Antitumor

Antimetastatic

to melanoma

down regulate MMP from DU145 prostate cancer cells

Induce apoptosis human leukemia cells

Reverse Multidrug Resistance

Modulate Organic Anion Transporting Polypeptide OATP1B1

Reverse multidrug resistance

Suppress angiogenesis


Resveratrol
http://polyphenols/FLAVONOLS/Flavonoids%20are%20antitumor.htmhttp://polyphenols/FLAVONOLS/Flavonoid%20antimetastatic%20to%20melanoma.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20from%20blueberry%20down%20regulate%20MMP%20used%20by%20Ca%20cells%20in%20metastasis.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20inhibit%20proteasom%20and%20induce%20apoptosis%20in%20human%20leukemia%20cells.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20Modulate%20Organic%20Anion%20Transporter%20Peptide%20in%20the%20Liver.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20such%20as%20silymarin%20may%20reverse%20multidrug%20resistance.htmhttp://polyphenols/FLAVONOLS/Flavonol%20chemical%20structure%20critical%20in%20modulation%20of%20angiogenesis%20and%20immune-enodthelial%20cell%20adhesion.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://polyphenols/FLAVONOLS/Flavonol%20chemical%20structure%20critical%20in%20modulation%20of%20angiogenesis%20and%20immune-enodthelial%20cell%20adhesion.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20such%20as%20silymarin%20may%20reverse%20multidrug%20resistance.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20Modulate%20Organic%20Anion%20Transporter%20Peptide%20in%20the%20Liver.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20inhibit%20proteasom%20and%20induce%20apoptosis%20in%20human%20leukemia%20cells.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20from%20blueberry%20down%20regulate%20MMP%20used%20by%20Ca%20cells%20in%20metastasis.htmhttp://polyphenols/FLAVONOLS/Flavonoid%20antimetastatic%20to%20melanoma.htmhttp://polyphenols/FLAVONOLS/Flavonoids%20are%20antitumor.htm


182/263

Actions Improved

function of T, B lymphocytes

killing activity of NK cells

release of antibodies total complement activity in serum

increased IL-2

TGF-beta1

reduced IL-8

VEGF



183/263

Biological Effects of Genistein


184/263

Growth inhibition of Melanoma cells invivo & in-vitro Rocoral et al, Int J. Cancer 72(5)860,1997

Inhibits lung tumor nodule formation in rats

& increases life span Menon et al, Nutri Cancer 30(1)74, 1998

Cytotoxic to breast cancer cells

Uckun et al, Clin Cancer Res 4(4)901, 1998

Chemoprevention of NMU induced rat

mammary tumors Gotoh et al, Jpn J Cancer Res 9(2)137, 1998


Biological Effects of Genistein


185/263

Induce cell cycle arrest at S/G2-M andapoptosis in HN4

upregulates CDKI, p21waf-1

induces BAX accompanied apoptosis

Alhasan, 1999 (AACR abstract # 1710)



186/263

Lipoic Acid

Phytonutrient found in spinach


187/263

y p

Differential Effect

Transformed vs Non-transformed Reversible cell cycle arrest of non-transformed cells

Apoptosis of human tumor cell lines (FaDu, Jurkat)

Transformed cells (Ki-v-Ras-transformed Balb/c-3T3 murine mesenchymal cell line)

Leukemic vs Normal T Lymphocytes Toxic via apoptosis of Jurkat cells

Non-toxic to normal T Lymphocytes

Low dose vs High dose Low dose (1 umol/L) acts as growth factor High dose (100 umol/L) antiproliferative

Enhances high dose ascorbate cytotoxicity to cancer cells

Prolongs survival of leukemic mice when added to Doxorubicin therapy

Reduces ROS and raises GPx which correlates with good ECOG performance status

Increase glutathione synthesis

Neuroprotective

Restores mitochondrial function in old rats Restores T-cell function of cancer patients

Improves clinical outcome of cancer patients

Treats oxaliplatin induces polyneuropathy

Enhance cytotoxicity of high dose ascorbate and doxorubicin


Characteristics of Curcumin
http://lipoic%20acid/Lipoic%20Acid%20a%20Cofactor%20of%20Multi%20enz%20complexes%20induc%20cell%20cycle%20arrest%20apoptosis.htmhttp://lipoic%20acid/Lipoic%20Acid%20cytotoxic%20to%20leukemic%20cell%20line%20and%20inhibit%20prolif%20of%20jurkat%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Doxorubicin%20Increases%20Survival%20of%20Leukemic%20Mice.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Doxorubicin%20Increases%20Survival%20of%20Leukemic%20Mice.htmhttp://lipoic%20acid/Lipoic%20Acid%20effect%20on%20ROS%20levels%20correlate%20with%20ECOG%20performance%20status.htmhttp://lipoic%20acid/Lipoic%20Acid%20increases%20glutathione%20synthesis.htmhttp://lipoic%20acid/Lipoic%20Acid%20induces%20detoxification%20enz%20in%20astroglial%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20mitochondrial%20function%20in%20old%20rat%20and%20lowers%20oxidant%20to%20level%20of%20young%20rat.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20T-cell%20functions.htmhttp://lipoic%20acid/Lipoic%20Acid%20together%20w%20other%20agent%20improves%20clinical%20outcome%20in%20cancer%20patients.htmhttp://lipoic%20acid/Lipoic%20Acid%20treats%20oxaliplatin%20induced%20polyneuropathy.htmhttp://lipoic%20acid/Vitamin%20C%20at%20high%20dose%20increase%20doxorubicin%20efficacy.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://lipoic%20acid/Vitamin%20C%20at%20high%20dose%20increase%20doxorubicin%20efficacy.htmhttp://lipoic%20acid/Lipoic%20Acid%20treats%20oxaliplatin%20induced%20polyneuropathy.htmhttp://lipoic%20acid/Lipoic%20Acid%20together%20w%20other%20agent%20improves%20clinical%20outcome%20in%20cancer%20patients.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20T-cell%20functions.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20T-cell%20functions.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20T-cell%20functions.htmhttp://lipoic%20acid/Lipoic%20Acid%20restores%20mitochondrial%20function%20in%20old%20rat%20and%20lowers%20oxidant%20to%20level%20of%20young%20rat.htmhttp://lipoic%20acid/Lipoic%20Acid%20induces%20detoxification%20enz%20in%20astroglial%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20increases%20glutathione%20synthesis.htmhttp://lipoic%20acid/Lipoic%20Acid%20effect%20on%20ROS%20levels%20correlate%20with%20ECOG%20performance%20status.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Doxorubicin%20Increases%20Survival%20of%20Leukemic%20Mice.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Ascorbate%20toxic%20to%20tumor%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20and%20Doxorubicin%20Increases%20Survival%20of%20Leukemic%20Mice.htmhttp://lipoic%20acid/Lipoic%20Acid%20cytotoxic%20to%20leukemic%20cell%20line%20and%20inhibit%20prolif%20of%20jurkat%20cells.htmhttp://lipoic%20acid/Lipoic%20Acid%20a%20Cofactor%20of%20Multi%20enz%20complexes%20induc%20cell%20cycle%20arrest%20apoptosis.htmhttp://lipoic%20acid/Lipoic%20Acid%20a%20Cofactor%20of%20Multi%20enz%20complexes%20induc%20cell%20cycle%20arrest%20apoptosis.htmhttp://lipoic%20acid/Lipoic%20Acid%20a%20Cofactor%20of%20Multi%20enz%20complexes%20induc%20cell%20cycle%20arrest%20apoptosis.htm


188/263

Derived from the plant Curcuma longa, Type of compound: polyphenol

Chemical name: Diferuloylmethane

Common name: turmeric.

Extensive research over the last 50 years has indicated

this polyphenol can both prevent and treat cancer

Pharmacologically, curcumin has been found to be safe.

Human clinical trials indicated no dose-limiting toxicity when

administered at doses up to 10 g/day

www drdevilla com www drdevilla comENDTLN

Cellular Actions of Curcumin


189/263

suppress proliferation of a wide variety of tumorcells,

down-regulate transcription factors NF-kappa B, AP-1and Egr-1;

down-regulate the expression of COX2, LOX, NOS,MMP-9, uPA, TNF, chemokines, cell surfaceadhesion molecules and cyclin D1;

www drdevilla com www drdevilla comENDTLN


190/263

Cellular Actions of Curcumin


191/263

suppress proliferation of a wide variety of tumorcells,

down-regulate transcription factors NF-kappa B, AP-1and Egr-1;

down-regulate the expression of COX2, LOX, NOS,MMP-9, uPA, TNF, chemokines, cell surfaceadhesion molecules and cyclin D1;

down-regulate growth factor receptors (such as EGFRand HER2 (caution: do not combine with Herceptin)

inhibit the activity of c-Jun N-terminal kinase, proteintyrosine kinases and protein serine/threonine kinases

Curcuminoids inhibit human multi-drug resistanceprotein


Carotene
http://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htmhttp://curcuminoids/Curcuminoids%20modulate%20human%20multidrug%20resis%20protein.htm


192/263

Associated with lower mortality from cancer Differential Effect:

Smokers vs Non-smokers

Directly associated with risk among smokers

Inversely associated with risk among non-smokers Low vs High Levels

Low levels associated with disease progression

Lycopene at high conc reduces LNCaP cancer cell survival

Plasma carotenoidsmarkers of fruits and vegetable

intake

CELLULAR CAROTENOID MEAUREMENT


Chlorophyllin
http://carotenoids/Carotene%20inversely%20associated%20with%20mortality%20from%20all%20causes%20and%20with%20cancer%20and%20with%20cardiovasc%20mortality.htmhttp://carotenoids/Carotene%20beta%20inverse%20assoc%20w%20risk%20of%20tobacco%20related%20Ca%20in%20nonsmokers%20but%20assoc%20wi%20risk%20in%20smokers.htmhttp://carotenoids/Carotenoid%20levels%20at%20low%20levels%20correlate%20with%20disease%20progression.htmhttp://carotenoids/Lycopene%20at%20high%20conc%20reduces%20LNCaP%20cancer%20cell%20survival%20due%20to%20DNA%20damage.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://www.drdevilla.com/http://www.drdevilla.com/http://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Plasma%20carotenoids%20as%20biomarkers%20of%20fruits%20and%20vegetable%20intake.htmhttp://carotenoids/Lycopene%20at%20high%20conc%20reduces%20LNCaP%20cancer%20cell%20survival%20due%20to%20DNA%20damage.htmhttp://carotenoids/Carotenoid%20levels%20at%20low%20levels%20correlate%20with%20disease%20progression.htmhttp://carotenoids/Carotene%20beta%20inverse%20assoc%20w%20risk%20of%20tobacco%20related%20Ca%20in%20nonsmokers%20but%20assoc%20wi%20risk%20in%20smokers.htmhttp://carotenoids/Carotene%20beta%20inverse%20assoc%20w%20risk%20of%20tobacco%20related%20Ca%20in%20nonsmokers%20but%20assoc%20wi%20risk%20in%20smokers.htmhttp://carotenoids/Carotene%20beta%20inverse%20assoc%20w%20risk%20of%20tobacco%20related%20Ca%20in%20nonsmokers%20but%20assoc%20wi%20risk%20in%20smokers.htmhttp://carotenoids/Carotene%20inversely%20associated%20with%20mortality%20from%20all%20causes%20and%20with%20cancer%20and%20with%20cardiovasc%20mortality.htm

8/8/2019 Phytopharmaceut

phytopharmaceuticals

Documents