Aaron E. Katz, MD of Science-Based Nutraceuticals

Guiding Patients on the Safe & Effective Use
of Science-Based Nutraceuticals
Aaron E. Katz, MD
Associate Professor of Clinical Urology
Director, Center of Holistic Urology
Columbia University Medical Center
Center for Holistic Urology
Columbia University
ƒ Established 1998
ƒ Perform basic science investigations
ƒ Develop translational human clinical trials
ƒ Single Center
ƒ Multi-Center
ƒ Placebo controlled Phase 3
ƒ Educate patients and physicians
ƒ Generate manuscripts in peer-reviewed journals
ƒ www.holisticurology.columbia.edu
Center for Holistic Urology
Columbia University
ƒ Practitioners
Aaron E. Katz, MD (Urologist)
Debra Bemis, Ph.D (Scientist)
Jillian Capodice, LaC (Acupuncturist)
Geovanni Espinosa, ND (Naturopathic Physician)
Jun Yan, PhD (scientist)
ƒ
Current Clinical Trials
9
9
9
9
9
9
Prostate Cancer Prevention:
Prostate Cancer Treatment:
Prostate Cancer Recurrence:
Bladder cancer prevention:
Hot Flashes:
Pelvic pain
2
1
1
1
1
1
Why Investigate CAM?
ƒ Patient driven
ƒ Not all conventional therapies 100% effective
ƒ Supposedly non-toxic
ƒ Many tumors are not organ-confined:
Holistic Approach
What to Look for in Natural Therapies
• A known mechanism of action
• Evidence that it relieves symptoms
• Demonstrated safety
• Quality of Product
• Low cost
• No interaction with other meds
Plant-Derived Anticancer Drugs
1881
1958
1959
1960
Podophyllum
Catharanthus roseus
Ochrosia elliptica
Podophyllotoxin
Vincristine & Vinblastine
Ellipticine
1997
Taxus brevifolia
Paclitaxel
Anticancer
Drugs
1966
Raphanus sativus Olomucine
Roscovitine (synthetic)
Camptotheca acuminata
Camptothecin
1980
1989
Amoora rohituka
Flavopiridol (semi-synthetic)
1972
Cephalotaxus harringtonia
Combretum caffrum
Combretastatin A4
Homoharringtonine
Holistic Urology
Roles for Supplements
•
•
•
•
•
•
•
Urinary Tract Infections
BPH and Voiding Disturbances
PSA elevations
Pre-cancerous conditions (PIN)
Prostate Cancer
Bladder Cancer
Sexual Dysfunction
2009 Estimated US Cancer Cases*
Men
745,180
Women
692,000
Prostate
25%
26%
Breast
Lung & bronchus
15%
14%
Lung & bronchus
Colon & rectum
10%
10%
Colon & rectum
Urinary bladder
7%
6%
Uterine corpus
Non-Hodgkin
lymphoma
5%
4%
Non-Hodgkin
lymphoma
Melanoma of skin
5%
4%
Thyroid
Kidney & renal pelvis
4%
4%
Melanoma of skin
Oral cavity
3%
3%
Ovary
Leukemia
3%
3%
Kidney & renal pelvis
Pancreas
All Other Sites
3%
3%
20%
23%
Leukemia
All Other Sites
*Exclude s ba sal and squamous cell skin cancers and in situ carcinoma s except urinary bladder.
Source: American Cancer Society, 2008.
Target Populations for Prevention
in Your Practice
• Primary Prevention:
• African Americans
• Family History
• High Grade PIN
• Secondary Prevention:
• Elevated PSA, Negative biopsy
• Post-RRP/Radiation with Rising PSA
All Men Over 40 are at Risk!!
Prostate Cancer Development
• Linked to Inflammation
• Many men have prostatitis on biopsy
• Cancers linked to Inflammation:
•
•
•
•
Colon
Breast
Bladder
Thyroid
Pathway for Human
Prostate Cancer Progression
NORMAL
EPITHELIUM
PROSTATIC
INTRAEPITHELIAL
NEOPLASIA (PIN)
INVASIVE
CARCINOMA
METASTASIS
ANDROGEN
INDEPENDENCE
Pre-Cancerous Condition
ImmunoKinoko AHCC
12
AHCC Production Facility
(Sapporo, Japan)
13
Annual Research Symposium
14
AHCC
(Active Hexose Correlated Compound)
1. Very low-molecular-weight (5,000Da), highly absorbable alphaglucan-rich compound
2. Produced from enzymatically fermented mycelium of Japanese medicinal mushrooms
3. Clinical shown to have strong immunomodulating properties
• Increase NK cell activity
• Increase number and activity of DC cells
• Increase cytokine response
4. Research
• 24 Pubmed-listed studies published in peer-reviewed journals
• Numerous other studies published in Japanese journals
5. Clinical Use: in over 1,000 clinics and hospitals, primarily in Asia
1. Primary Care Clinics (immune support and prevention)
2. Cancer Clinics (immunotherapy reduction of chemo side-effects)
3. Hospitals (reduction of hospital borne-infections)
4. Hepatology Clinics (reduce viral loads in Hep-C patients)
AHCC and NK Cells
• Significantly increases NK cell activity in immune
compromised patients
• Stimulates T-cells, macrophages and increases cytokines
• Increases activity and number of DC cells
• Appears to be able to stimulate and modulate because it
works on both the macrophages and the cytokines:
valuable links and network messengers
• Built in dampening system; can be taken continuously and
does not need to be stopped like other immune-enhancing
supplements
AHCC Research: Select Published Animal Studies
▪ Infections: influenza20, west nile virus15, bird flu11, MRSA19
▪ Tumor necrosis, improved survival of tumor-bearing mice
▪ Reduced side-effects of chemo8 & non-interaction with chemo3
▪ Anti-inflammatory properties (colitis26; diabetes13)
▪ Auto-immunity (Amyotrophic Lateral Sclerosis (ALS)12)
▪ Protective effect on bone marrow9 , thymus gland7, liver22, spleen8)
▪ Enhanced activity of NK cells, T-cells, macrophages, cytokines
AHCC: Select Published Clinical Studies
▪
269 liver cancer patient prospective cohort study (1992-2001) showed longer “no
recurrence” period and increased survival rate (Journal of Hepatology)33
▪
132 stomach cancer patients showed enhanced 5-yr survival rate34
▪
44 liver cancer patient placebo-controlled study showed prolonged survival and
improved Quality of Life36
▪
30 healthy elderly patient study at Yale Medical School showed increased cytokine
production (TNF-γ and IFN-α) 4
▪
20 healthy patient DBPC study showing increased number and activity of dendritic
cells (Nutrition and Cancer)5
▪
Phase-I 26-subject safety study at Faulkner Hospital (9g/day)10
TIME Feb. 23, 2004
Role of NF-kB in Development of Cancer
Anti-apoptosis/survival
Immortality
e.g; bcl-xl, cIAP, survivin, cFLIP,
TRAF, SOD, γ-GCS
e.g; telomerase
Inflammation
Proliferation
NF-κB
TNF, IL-1,Che mokines
Angiogenesis
e.g; TNF, IL-1, IL-6
CyclinD1, cMyc
Tumor promotion
VEGF, TNF, IL-1, IL-8
e.g; COX2, iNOS, MMP-9, uPA
Metastasis
e.g; ICAM-1, VCAM-1, ELAM-1
Aggarwal BB, Cancer Cell, 2004
Zyflamend: Herbal Anti-Inflammatory
Turmeric
(14.1%)
Holy basil
(12.8%)
Curcumin
Ursolic acid
Ocimum sanctum
Curcuma longa
Rosemary (19.2%)
Rosmarinic acid,
Camphor, Borneol, Cineol
Ginger
(12.8%)
Gingerol
Rosmarinus officinalis
Zingiber officinalis
Green tea (12.8%)
Epigallocatechin gallate
Huzhang
(10.2%)
Resveratrol,
Thymol
Camellia sinensis
Polygonum cuspidatum
Chinese goldthread (5.1%)
Berberine
Barberry
(5.1%)
Berberine
Berberis vulgaris
Coptis Chinensis
Baikal skullcap (2.5%)
Baicalin, Baicalein,
Wogonin
Scutellaria baicalensis
Oregano
(5.1%)
Thymol
Origanum vulgare
Clinical Trial Administering Zyflamend™ for
Prostatic Intraepithelial Neoplasia (PIN)
HGPIN (+): Positive NF-kB
HGPIN (-): Negative NF-kB
Lycopene
ƒ Found in tomatoes, watermelon, guava and
even pink grapefruit
ƒ ProstaCell contains this antioxidant with
highest capacity for scavenging free radicals1
1 Gester.
J. Amer. Coll. Nutr. 16: 109-126, 1997
Lycopene: Epidemiological Data
ƒ Dietary consumption of lycopene associated with a
decreased cancer risk 1
ƒ 35/ 72 studies demonstrated a significant decrease in
risk1
ƒ The largest study found that 2-4 servings of tomato
sauce per week was associated with a reduction of
35% in the risk for CaP2
1
2
Giovannucci. J. Natl. Cancer Inst. 91:317, 1999
Barber. Prostate Cancer Pros. Dis. 5:6, 2002
Lycopene
ƒ Supplementation before radical prostatectomy,
20012
- Phase II randomized clinical trial
- ↓ involvement of surgical margins, ↓ extent
of HGPIN as well as ↓ in tumor size
2Kucuk
et al. Can. Epid. Bio. Pre. 8:861, 2001.
Soy Isoflavones
ƒ Properties
ƒ Active metabolites: genistein and daidzein
ƒ Adventist Health Study, 1998
↓ CaP risk1
- consumption of soy milk
ƒ Genistein has been shown to:
- Reduce DNA synthesis in LNCaP cells
- Inhibit the effect of testosterone in development of
CaP in rats2
1
2
Jacobsen et al. Cancer Causes Control, 9:553, 1998.
Geller et al. Prostate, 34:75, 1998.
Four Important Dietary Isoflavones
O
H0
Formononetin
O
H O
0 CH 3
O
Daidzein
O
H0
OH
O
Biochanin
OH
Genistein
H O
O
0 CH 3
O
OH
O
H
O
Dietary Sources of Isoflavones
• Legumes – plants with high protein levels
• Chick peas, lentils, soy, navy beans etc
• 20-50 mg per day intake in Asian, Mediterranean,
African diets
• 1-3 mg per day intake in Western diets
GeniKinoko GCP
31
A Concentrated Aglycone Isoflavone Preparation
(GCP)
Demonstrates Potent Anti-Prostate Cancer Activity
in vitro and in vivo
Debra L. Bemis, Jillian L. Capodice,
Manisha Desai, Ralph Buttyan, and
Aaron E. Katz
Department of Urology, College of Physicians and Surgeons and
ColumbiaUniversity Medical Center, New York, New York
Clinical Cancer Research, 2004
Effect of GCP on Growth of LNCaP Tumors
Mouse Tumor Volumes
Median Volume
250
200
150
Control
Treatment
100
Prevention
50
0
0
1
2
Week
3
4
Immunohistochemical Detection of
Apoptosis-TUNEL
100
*
*
Number of TUNEL-positive nuclei
90
LNCaP-untreated
80
70
60
50
40
30
20
10
0
*Error bars are ± SEM; p<0.001 compared to control
LNCaP+ 2% GCP diet
GCP + Radiation Reduces Clonogenic
Survival Better than Genistein
Survival, % of Control
100
80
60
40
20
0
Control
2 Gy
Genistein
Radiation Alone
GCP
Alone
Gen+2Gy GCP+2 Gy
Treatment of CWR22R cells
“Effects of a Genistein-Rich Extract GCP
on the Treatment of Prostate Cancer”
Urology 63:259-63, 2004
Ralph W. deVere White
Robert M. Hackman
Stephanie E. Soares
Laurel A. Beckett
Yueju Li
Buxiang Sun
Individual Changes in PSA Among Men
on Active Surveillance
10
8
PSA
(ng/ml)
6
Baseline
4
6 months
2
0
1
2 3 4 5 6 7 8
Subject number
Superficial Bladder Cancer
Evaluation
• Cystoscopy
– Sensitivity 70%
– Gold Standard For Detection
– Invasive
• Cytology
– Sensitivity 40% and Specificity 90%
– Less Sensitive for Low Grade Tumors
– False (+): Inflammation, Urothelial Atypia,
Radiation / Chemotherapy, Instrumentation
GCP Induces Apoptosis in Bladder Cancer Cell Lines:
Caspase-3 Activity After 24 hrs Exposure to GCP
HT-1376 Cell Line
T24 Cell Line
6
35
30
Fold Increase
Over Control
4
3
2
1
25
20
15
10
5
)
m
l
m
l
nM
(1
0
TP
A
ug
/
ug
/
25
50
P
P
G
C
l
l
ug
/m
en
is
te
en
ist
e
in
in
25
50
ug
/m
(1
0
A
G
G
C
nM
)
l
ug
/m
ug
/m
25
P
0
TP
ug
/m
l
50
GC
25
ein
G
CP
ug
/m
l
50
in
te
ni
st
en
is
Ge
G
l
0
G
Fold Increase
Over Control
5
Role for GCP in Bladder Cancer
• Prevent recurrent TCC
• Delay progression of disease
• Use in combination with existing
intravesical agents
• Delay/prevent radical surgical removal
ProstaCell
(Quality of Life Labs)
GCP
Selenium
Vitamin E
Lycopene
Green Tea
www.q-o-l.com
Pomegranates and Prostate Cancer
Pomegranates and Prostate Cancer
Pre-Clinical Data Summary
In vitro studies show:
• 59-75% growth inhibition of PC3
• Delayed progression into S phase
• Low levels of apoptosis
In vivo studies in SCID mice show:
• 52% growth inhibition of LAPC-9 tumors
• 70% reduction in PSA
• Prolonged survival
Phase II Study for Men
with Rising PSA after RRP or XRT
• Men with Recurrent Prostate Cancer
• Rising PSA after RRP or XRT
• Low risk: PSA < 5, Gleason < 8
• No evidence of metastatic disease
• No previous hormone therapy
• Baseline PSA DT
Interim Results: PSA Doubling Time
(Year 1)
Mean ± SD
PSADT Before
Baseline
PSADT
After Baseline
Change
14.3 months
25 months
11 months
Signed Rank
Test
P=0.0481 *
Interim Results: PSA Doubling Time
(Year 2)
Mean ± SD
PSADT Before
Baseline
PSADT
After Baseline
Change
14.3 ± 10.8
37.5 ± 33.5
23.2 ± 29.8
Signed Rank
Test
P=0.0481 *
Pantuck et al
PCF, AUA, 2005
“Final” Results: PSA Doubling Time
(Year 3)
Mean ± SD
PSADT Before
Baseline
PSADT
After Baseline
Change
15.0 ± 11.1
54.0 ± 53
39.00 ± 45.6
Signed Rank
Test
Pantuck et al
Clinical Cancer Research, 2006
P=0.0001
Phase III Study
Confirmation in a Randomized Study
Multi-Center
Double Blind
Placebo Controlled
3:1 Treatment to Control
250 patients
Option to cross over to open label at progression
Centralized Randomization/Data Management/CRO
CAM for Prostate Cancer:
Active Holistic Surveillance
Low-risk prostate cancer patients
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ƒ
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Low fat diet, increase fresh vegetables
Vitamin E and selenium
Lycopene
Soy supplementation
Pomegranite juice per day
2-4 cups of green tea
Zyflamend 3 tabs per day
CAM and Prostate Cancer:
What are the roles?
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ƒ
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Improve the health of our patients
Develop prevention protocols
Consider as an alternative to Watch and Wait
Active Holistic Surveillance with delayed
intervention
ƒ Consider in prevention of High Risk Patients that
have been treated
ƒ Prolong PSADT in patients post therapy
Acknowledgements
Department of Urology,
Columbia University, NY, NY
Debra Bemis,Ph.D.
Ralph Buttyan, Ph.D.
Jillian Capodice, M.S., L.Ac.
Yi Chen Cao
Geovanni Espinosa, ND
The Center for Holistic Urology
Columbia-Presbyterian Medical Center
www.holisticurology.columbia.edu
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